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Chimpanzees in Biomedical and Behavioral Research:
Assessing the Necessity

Bruce M. Altevogt, Diana E. Pankevich, Marilee K. Shelton-Davenport, and
Jeffrey P. Kahn, Editors; Committee on the Use of Chimpanzees in
Biomedical and Behavioral Research; National Research Council

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Chimpanzees in Biomedical and Behavioral Research: Assessing the Necessity

CHIMPANZEES IN
BIOMEDICAL
AND BEHAVIORAL
RESEARCH
ASSESSING THE NECESSITY
Committee on the Use of Chimpanzees in Biomedical
and Behavioral Research
Board on Health Sciences Policy
Institute of Medicine
Board on Life Sciences
Division on Earth and Life Studies
Bruce M. Altevogt, Diana E. Pankevich,
Marilee K. Shelton-Davenport, and Jeffrey P. Kahn, Editors

Chimpanzees in Biomedical and Behavioral Research: Assessing the Necessity

THE NATIONAL ACADEMIES PRESS • 500 Fifth Street, N.W. • Washington, DC 20001

NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from
the councils of the National Academy of Sciences, the National Academy of
Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance.
This study was requested by Contract No. N01-OD-4-239 Task Order No. 248
between the National Academy of Sciences and the Department of Health and
Human Services, National Institutes of Health. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the organizations or agencies
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Suggested citation: IOM (Institute of Medicine). 2011. Chimpanzees in biomedical and behavioral research: Assessing the necessity. Washington, DC: The
National Academies Press.

Chimpanzees in Biomedical and Behavioral Research: Assessing the Necessity

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Chimpanzees in Biomedical and Behavioral Research: Assessing the Necessity

COMMITTEE ON THE USE OF CHIMPANZEES IN
BIOMEDICAL AND BEHAVIORAL RESEARCH
JEFFREY P. KAHN (Chair), Johns Hopkins University
JOHN G. BARTLETT, Johns Hopkins University School of Medicine
H. RUSSELL BERNARD, University of Florida
FLOYD E. BLOOM, The Scripps Research Institute
WARNER C. GREENE, University of California, San Francisco
DIANE E. GRIFFIN, Johns Hopkins Bloomberg School of Public
Health
EDWARD E. HARLOW, Harvard University School of Medicine
JAY R. KAPLAN, Wake Forest School of Medicine
MARGARET S. LANDI, GlaxoSmithKline
FREDERICK A. MURPHY, The University of Texas Medical Branch
at Galveston
ROBERT SAPOLSKY, Stanford University
SHARON TERRY, Genetic Alliance
Study Staff
BRUCE M. ALTEVOGT, Study Director
MARILEE K. SHELTON-DAVENPORT, Senior Program Officer
DIANA E. PANKEVICH, Associate Program Officer
LORA K. TAYLOR, Senior Project Assistant
ALEX R. REPACE, Senior Project Assistant
ANDREW M. POPE, Director, Board on Health Sciences Policy
FRANCES E. SHARPLES, Director, Board on Life Sciences

Chimpanzees in Biomedical and Behavioral Research: Assessing the Necessity

Reviewers

This report has been reviewed in draft form by individuals chosen for
their diverse perspectives and technical expertise, in accordance with
procedures approved by the National Research Council’s Report Review
Committee. The purpose of this independent review is to provide candid
and critical comments that will assist the institution in making its published report as sound as possible and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the
study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We wish to
thank the following individuals for their review of this report:
Stephen W. Barthold, University of California, Davis
Thomas M. Butler, Independent consultant
Alexander M. Capron, University of Southern California
Timothy Coetzee, National Multiple Sclerosis Society
Frans B. M. de Waal, Emory University
Jane Goodall, Jane Goodall Institute
Beatrice H. Hahn, University of Pennsylvania
Donald A. Henderson, Johns Hopkins University
William D. Hopkins, Agnes Scott College
Steven E. Hyman, Harvard University
Stanley M. Lemon, University of North Carolina at Chapel Hill
Alexander Ploss, The Rockefeller University
Arthur Weiss, University of California, San Francisco
Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the convii

Chimpanzees in Biomedical and Behavioral Research: Assessing the Necessity

viii

REVIEWERS

clusions or recommendations, nor did they see the final draft of the report before its release. The review of this report was overseen by
Eli Y. Adashi, Immediate Past Dean of Medicine & Biological Sciences,
Brown University, and Peter H. Raven, President Emeritus, Missouri
Botanical Garden. Appointed by the National Research Council and Institute of Medicine, they were responsible for making certain that an independent examination of this report was carried out in accordance with
institutional procedures and that all review comments were carefully
considered. Responsibility for the final content of this report rests entirely with the authoring committee and the institution.

Chimpanzees in Biomedical and Behavioral Research: Assessing the Necessity

Contents

SUMMARY

STUDY BACKGROUND AND CONTEXT
Origin of Study and Committee Statement of Task, 12
Ethical Considerations, 14

METHODS AND ORGANIZATION OF THE REPORT

INTERNATIONAL POLICIES GUIDING
CHIMPANZEE USE

SUMMARY OF CHIMPANZEE RESEARCH
Analysis of Federally Supported Research, 20
Analysis of Private-Sector Supported Research, 23
Criteria That Guide the Current Use of Chimpanzees, 25

PRINCIPLES GUIDING THE USE OF CHIMPANZEES IN
RESEARCH
26
Ethologically Appropriate Physical and Social Environments, 27
Criteria to Assess the Necessity of the Chimpanzee for Biomedical
Research, 28
Criteria for Use of the Chimpanzee in Comparative Genomics and
Behavioral Research, 33

Chimpanzees in Biomedical and Behavioral Research: Assessing the Necessity

CONTENTS

REVIEWING THE NECESSITY OF CURRENT CHIMPANZEE
RESEARCH
35
Monoclonal Antibodies, 36
Development of Chimpanzee Monoclonal Antibodies, 37
Safety Testing of Monoclonal Antibody Therapies, 38
Respiratory Syncytial Virus, 42
HCV Antiviral Drugs, 47
Therapeutic HCV Vaccine, 50
Prophylactic HCV Vaccine, 52
Comparative Genomics, 55
Altruism, 59
Cognition, 62
FUTURE USE OF CHIMPANZEES IN BIOMEDICAL AND
BEHAVIORAL RESEARCH

CONCLUSIONS AND RECOMMENDATIONS

APPENDIXES
A References
71
B Commissioned Paper: Comparison of Immunity to Pathogens in
Humans, Chimpanzees, and Macaques
91
C Information-Gathering Agendas
167
D Committee Biographies
181

Chimpanzees in Biomedical and Behavioral Research: Assessing the Necessity

Summary

At the request of National Institutes of Health (NIH), and in response
to congressional inquiry, the Institute of Medicine (IOM) in collaboration
with the National Research Council (NRC) convened an ad hoc committee to consider the necessity of the use of chimpanzees in NIH-funded
research in support of the advancement of the public’s health.
Specifically, the committee was asked to review the current use of
chimpanzees for biomedical and behavioral research and:
•

Explore contemporary and anticipated biomedical research questions to determine if chimpanzees are or will be necessary for research discoveries and to determine the safety and efficacy of
new prevention or treatment strategies. If biomedical research
questions are identified:
o
o

•

Describe the unique biological/immunological characteristics of the chimpanzee that make it the necessary animal
model for use in the types of research.
Provide recommendations for any new or revised scientific
parameters to guide how and when to use these animals for
research.

Explore contemporary and anticipated behavioral research questions to determine if chimpanzees are necessary for progress in
understanding social, neurological, and behavioral factors that
influence the development, prevention, or treatment of disease.

Chimpanzees in Biomedical and Behavioral Research: Assessing the Necessity

ASSESSING THE NECESSITY OF THE CHIMPANZEE

In addressing the task, the committee explored existing and anticipated alternatives to the use of chimpanzees in biomedical and behavioral research. The committee based its findings and recommendations on
available scientific evidence, published literature, public testimony, submitted materials by stakeholders, and a commissioned paper, as well as
its expert judgment.
To conduct this expert assessment and evaluate the necessity for
chimpanzees in research to advance the public’s health, the committee
deliberated from May 2011 through November 2011. During this period,
the committee held three 2-day meetings and several conference calls,
including two public information-gathering sessions on May 26, 2011,
and August 11-12, 2011. Each information-gathering session included
testimony from individuals and organizations that both supported and
opposed the continued use of chimpanzees. The committee also reviewed
a number of background documents provided by stakeholder organizations and commissioned a paper, “Comparison of Immunity to Pathogens
in Humans, Chimpanzees, and Macaques.”
The committee identified a set of core principles and criteria that
were used to assess the necessity of chimpanzees for research now or in
the future.
Ethical Considerations
Neither the cost of using chimpanzees in research nor the ethical implications of that use were specifically in the committee’s charge. Rather,
the committee was asked for its advice on the scientific necessity of the
chimpanzee model for biomedical and behavioral research. The committee agrees that cost should not be a consideration. However, the committee feels strongly that any assessment of the necessity for using
chimpanzees as an animal model in research raises ethical issues, and
any analysis of necessity must take these ethical issues into account. The
committee’s view is that the chimpanzee’s genetic proximity to humans
and the resulting biological and behavioral characteristics not only make
it a uniquely valuable species for certain types of research, but also demand a greater justification for conducting research using this animal
model.

Chimpanzees in Biomedical and Behavioral Research: Assessing the Necessity

SUMMARY

Summary of Chimpanzee Research
The committee was asked, as part of its task, to review the current
use of chimpanzees for biomedical and behavioral research. To assess
the use of the chimpanzee as an animal model, the committee explored
research supported by the NIH and other federally and privately funded
research over the past 10 years.
The largest percentage of federally funded chimpanzee research has
been supported by the NIH, with additional projects funded by other federal agencies, including the Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDC), and National Science
Foundation. Of the 110 identified projects sponsored by the NIH between 2001 and 2010, 44 were for research on hepatitis; comparative
genomics accounted for 13 projects; 11 projects were for neuroscience
research; 9 projects were for AIDS/HIV studies; and 7 projects were for
behavioral research. The remaining projects funded a limited number of
studies in areas such as malaria and respiratory syncytial virus and projects supporting chimpanzee colonies.
Committee analysis of the use of chimpanzees in the private sector
was hindered by the proprietary nature of the information. However,
based on limited publications and public non-proprietary information, it
is clear that the private sector is using the chimpanzee model, especially
in areas of drug safety, efficacy, and pharmacokinetics. Although its use
appears to be limited and decreasing over the 10 years examined by the
committee, the chimpanzee model is being employed by industry in the
development of antiviral drugs and vaccines for hepatitis B and C as well
as in the development of monoclonal antibody therapeutics.
Principles Guiding the Use of Chimpanzees in Research
The task given to the committee by the NIH asked two questions
about the need for chimpanzees in research: (1) Is biomedical research
with chimpanzees “necessary for research discoveries and to determine
the safety and efficacy of new prevention or treatment strategies?” and
(2) Is behavioral research using chimpanzees “necessary for progress in
understanding social, neurological, and behavioral factors that influence
the development, prevention, or treatment of disease?” In responding to
these questions, the committee concluded that the potential reasons for
undertaking biomedical and behavioral research as well as the protocols
used in each area are different enough to require different sets of criteria.

Chimpanzees in Biomedical and Behavioral Research: Assessing the Necessity

ASSESSING THE NECESSITY OF THE CHIMPANZEE

However, the committee developed both sets of criteria guided by the
following three principles:
1. The knowledge gained must be necessary to advance the public’s
health;
2. There must be no other research model by which the knowledge
could be obtained, and the research cannot be ethically performed on human subjects; and
3. The animals used in the proposed research must be maintained
either in ethologically appropriate physical and social environments or in natural habitats.
These principles are the basis for the specific criteria that the committee
established to assess current and future use of the chimpanzee in biomedical and behavioral research (see Recommendations 1 and 2).
Conclusions and Recommendations
The committee based the following conclusions and recommendations in large part on the advances that have been made by the scientific
community using alternative models to the chimpanzee, such as studies
using other non-human primates, genetically modified mice, in vitro systems, and in silico technologies as well as human clinical trials. Having
reviewed and analyzed contemporary and anticipated biomedical and
behavioral research, the committee concludes that:
•
•

No uniform set of criteria is currently used to assess the necessity of the chimpanzee in NIH-funded biomedical and behavioral
research.
While the chimpanzee has been a valuable animal model in past
research, most current use of chimpanzees for biomedical research is unnecessary, based on the criteria established by the
committee, except potentially for two current research uses:
o

Chimpanzees in Biomedical and Behavioral Research: Assessing the Necessity

SUMMARY

The committee was evenly split and unable to reach consensus on the necessity of the chimpanzee for the development
of a prophylactic hepatitis C virus (HCV) vaccine. Specifically, the committee could not reach agreement on whether a
preclinical challenge study using the chimpanzee model was
necessary and if or how much the chimpanzee model would accelerate or improve prophylactic HCV vaccine development.

•
•
•

•

The present trajectory indicates a decreasing scientific need for
chimpanzee studies due to the emergence of non-chimpanzee
models and technologies.
Development of non-chimpanzee models requires continued
support by the NIH.
A new, emerging, or reemerging disease or disorder may present
challenges to treatment, prevention, and/or control that defy nonchimpanzee models and available technologies and therefore
may require the future use of the chimpanzee.
Comparative genomics research may be necessary for understanding human development, disease mechanisms, and susceptibility because of the genetic proximity of the chimpanzee to
humans. It poses no risk to the chimpanzee when biological materials are derived from existing samples or minimal risk of pain
and distress in instances where samples are collected from living
animals.
Chimpanzees may be necessary for obtaining otherwise unattainable insights to support understanding of social and behavioral factors that include the development, prevention, or
treatment of disease.
Application of the committee’s criteria would provide a framework to assess scientific necessity to guide the future use of
chimpanzees in biomedical, comparative genomics, and behavioral research.

Chimpanzees in Biomedical and Behavioral Research: Assessing the Necessity

ASSESSING THE NECESSITY OF THE CHIMPANZEE

Recommendation 1: The National Institutes of Health should limit
the use of chimpanzees in biomedical research to those studies that
meet the following three criteria:
1. There is no other suitable model available, such as in vitro, nonhuman in vivo, or other models, for the research in question;
2. The research in question cannot be performed ethically on human subjects; and
3. Forgoing the use of chimpanzees for the research in question will
significantly slow or prevent important advancements to prevent,
control, and/or treat life-threatening or debilitating conditions.
Animals used in the proposed research must be maintained either in
ethologically appropriate physical and social environments or in natural habitats. Biomedical research using stored samples is exempt
from these criteria.
Recommendation 2: The National Institutes of Health should limit
the use of chimpanzees in comparative genomics and behavioral research to those studies that meet the following two criteria:
1. Studies provide otherwise unattainable insight into comparative
genomics, normal and abnormal behavior, mental health, emotion, or cognition; and
2. All experiments are performed on acquiescent animals, using
techniques that are minimally invasive, and in a manner that
minimizes pain and distress.
Animals used in the proposed research must be maintained either in
ethologically appropriate physical and social environments or in natural habitats. Comparative genomics and behavioral research using
stored samples are exempt from these criteria.
The criteria set forth in the report are intended to guide not only current research policy, but also decisions regarding potential use of the
chimpanzee model for future research. The committee acknowledges that
imposing an outright and immediate prohibition of funding could cause
unacceptable losses to research programs as well as have an impact on
the animals. Therefore, although the committee was not asked to consider how its recommended policies should be implemented, it believes that
the assessment of the necessity of the chimpanzee in all grant renewals

Chimpanzees in Biomedical and Behavioral Research: Assessing the Necessity

SUMMARY

and future research projects would be strengthened and the process made
more credible by establishing an independent oversight committee that
builds on the Interagency Animal Model Committee and uses the recommended criteria.

Chimpanzees in Biomedical and Behavioral Research: Assessing the Necessity

STUDY BACKGROUND
AND CONTEXT
The chimpanzee (Pan troglodytes) is a current animal model in biomedical and behavioral research supported by the U.S. government and
industry. In fiscal year 2011, of the more than 94,000 active projects
sponsored by the National Institutes of Health (NIH), only 53 used the
chimpanzee (0.056 percent). However, members of the public, Congress,
and some scientists question this use. They argue that research that has
relied on chimpanzees could be accomplished using other models, methods, or technologies (Bailey, 2010a, 2010b; Bettauer, 2011) or that
chimpanzees are not appropriate models for human disease research
(Bailey, 2008; Physicians Committee for Responsible Medicine, 2011).
Ongoing biomedical and behavioral research on chimpanzees is
largely conducted at four facilities: the Southwest National Primate
Research Center, the New Iberia Research Center at the University of
Louisiana-Lafayette, the Michale E. Keeling Center for Comparative
Medicine and Research of the University of Texas MD Anderson Cancer
Center, and the Yerkes National Primate Research Center at Emory University. Much of the research supported by the first three facilities is focused on proof-of-principle studies for hepatitis C vaccines and
therapies, with a lesser amount of research devoted to assessing safety
and efficacy of large molecules such as monoclonal antibodies (Watson,
2011). In addition, research supports studies on deriving chimpanzee cell
lines, antibodies and other biological materials, as well as comparative
genomics research. The Yerkes Center primarily sponsors studies
pertaining to developmental and cognitive neuroscience, as well as aging-related comparative neurobiology (Yerkes National Primate
Research Center, 2011). In addition to these four centers, the National
Center for Research Resources (NCRR) also supports the Alamogordo
Primate Facility (APF). Unlike the other facilities, Alamogordo is a research reserve facility that does not have an active chimpanzee research
program; no invasive research is conducted on these chimpanzees while
on the premises1 (NCRR, 2011a). However, the animals may be used for
cardiovascular disease and behavioral studies with data obtained during
their annual physicals (Watson, 2011). If these chimpanzees are needed
1

According to solicitation NHLBI-CSB-(RR)-SS-2011-264-KJM (HHS, 2011c), “the
current agreements between the National Institutes of Health (NIH) and the U.S. Air
Force (USAF) prescribe that no invasive research shall be conducted on chimpanzees
currently held at the APF.”

Chimpanzees in Biomedical and Behavioral Research: Assessing the Necessity

ASSESSING THE NECESSITY OF THE CHIMPANZEE

for other types of research, they are relocated to another facility and,
once removed, cannot return to Alamogordo Primate Facility (HHS,
2011d).
As of May 2011, 937 chimpanzees, ranging in age from less than 1
year old to greater than 41, were available for biomedical and behavioral
research (Tables 1 and 2). The U.S. government currently supports 436
of these animals at four NCRR-supported facilities; the remaining animals are privately owned and supported (HHS, 2011a). The NCRR at the
NIH provides programmatic oversight of these facilities and ensures they
comply with the Animal Welfare Act, and with policies concerning
laboratory animal care and use. Within the NCRR, the Division of Comparative Medicine oversees the NIH Chimpanzee Management Program
(ChiMP), which supports the long-term, cost-effective housing and
maintenance of chimpanzee facilities (NCRR, 2011a).
In 1995, the NIH instituted a moratorium on the breeding of chimpanzees that they owned or supported (NCRR, 2011b). Soon after, the
Chimpanzee Management Plan Working Group was created to periodically assess the need for chimpanzees in research and report its findings
to NCRR’s advisory body, the National Advisory Research Resources
Council. This Working Group of non-government scientists and nonscientists analyzes relevant issues and drafts proposed position papers. In
2007, this Working Group issued a report2 that “did not make a definitive
recommendation as to whether the chimpanzee breeding moratorium
should be continued,”3 but the NIH National Advisory Research Resources
Council extended the breeding moratorium indefinitely (Cohen, 2007b).
Given the life expectancy of chimpanzees in captivity, it is estimated that
by 2037 the federally funded chimpanzee research population will
“largely cease to exist” in the United States (Cohen, 2007a; NCRR,
2007).

2
Report of the Chimpanzee Management Plan Working Group—March 9, 2007
(NCRR, 2007).
3
The 1997 National Research Council report, Chimpanzees in Research: Strategies for
their Ethical Care, Management, and Use also recommended a 5-year breeding moratorium (NAS, 1997).

Chimpanzees in Biomedical and Behavioral Research: Assessing the Necessity

ASSESSING THE NECESSITY OF THE CHIMPANZEE

TABLE 1 Number of Chimpanzees Available in the United States for
Research

Alamogordo Primate
Facility
Michale E. Keeling
Center for Comparative
Medicine and Research
New Iberia Research
Center
Southwest National
Primate Research Center
Yerkes National Primate
Research Centerc

Total Number
of Chimpanzeesa
176

TOTAL

Number of Chimpanzees
Supported by the NCRR,
NIHb
176

176

159

347

124

153

937

612

Number of chimpanzees as of October 2011 (Abee, 2011c; Else, 2011; Lammey,
2011; Landry, 2011; Langford, 2011).
b
Number of NIH-supported chimpanzees current as of April 15, 2011 (HHS, 2011a).
c
The Yerkes National Primate Research Center does not use any core funds from the
NCRR to support the costs for maintaining humane care and welfare of chimpanzees.

TABLE 2 Ages of Chimpanzees Available in the United States for
Researcha,b
Alamogordo Primate Facility
Michale E. Keeling Center for
Comparative Medicine and
Research
New Iberia Research Center
Southwest National Primate
Research Center
Yerkes National Primate
Research Centerc
TOTAL

< 10
0
0

10 to 20
24
53

21 to 30
99
67

31 to 40 41+
40
13
27
29

100
4

134
61

84
69

6
13

23
5

105

301

349

Ages of chimpanzees as of October 2011 (Abee, 2011c; Else, 2011; Lammey, 2011;
Landry, 2011; Langford, 2011).
b
The committee was unable to match the age of each chimpanzee with the funding
source. Numbers represent a mix of federal and other sources of funding.
c
The Yerkes National Primate Research Center does not use any core funds from the
NCRR to support the costs for maintaining humane care and welfare of chimpanzees.

Chimpanzees in Biomedical and Behavioral Research: Assessing the Necessity

ASSESSING THE NECESSITY OF THE CHIMPANZEE

Origin of Study and Committee Statement of Task
The formation of the present committee activity and subsequent report was precipitated by events that took place in 2010, when the NIH
announced its decision to transfer the chimpanzees located at the Alamogordo Primate Facility to the Southwest National Primate Research
Center, where they would be consolidated with the chimpanzee colony
that was already maintained and available for research (HHS, 2011b,
2011d). As the NIH’s 10-year contract with Charles River Laboratories
to manage the Alamogordo Primate Facility neared its completion, the
NIH stated that consolidating the chimpanzees into a single colony at the
Southwest National Primate Research Center facility would save $2 million a year and make the animals available for future research (HHS,
2011a; Korte, 2010). This decision stirred controversy. Animal rights
activists and primate experts objected to returning the Alamogordo
chimpanzees to a location where research is allowed, advocating instead
for their permanent retirement (The Humane Society of the United
States, 2010). Then–New Mexico Governor Bill Richardson also objected to closing the facility, which employs about 35 people (Korte, 2010).
He asked the NIH to reverse its plans and requested that the U.S. Department of Agriculture (USDA) formally evaluate the way in which relocation plans were made. Governor Richardson requested that the
Alamogordo Primate Facility be converted to an official sanctuary4 or be
operated by local universities for non-invasive behavioral research
(Ledford, 2010).
In December 2010, amid increasing attention to the issue,5 U.S. Senators Jeff Bingaman (D-NM), Tom Harkin (D-IA), and Tom Udall (D-NM)
requested the National Academies conduct an in-depth analysis of the
current and future need for chimpanzee use in biomedical research, an
analysis they anticipated would consider the “great progress the science
4

The U.S. Chimpanzee Health Improvement, Maintenance, and Protection Act of 2000
(106th Cong., 2nd sess.) required sanctuaries to house chimpanzees no longer needed for
medical research.
5
While not directly related to this study, it is of historical interest that bills were introduced in the U.S. Congress in 2008, 2009, 2010, and 2011 to ban research using chimpanzees and other great apes. Legislation included the Great Ape Protection Act of 2008,
110th Cong., 2d sess.; Great Ape Protection Act of 2009, 111th Cong., 1st sess.; Great
Ape Protection Act of 2010, 111th Cong., 2d sess.; and Great Ape Protection and Cost
Savings Act of 2011, 112th Cong., 1st sess. To date, the bills have not been adopted into
law; however, activities related to the proposed legislation have also contributed to the
national discussion about the necessity of chimpanzees for research.

Chimpanzees in Biomedical and Behavioral Research: Assessing the Necessity

ASSESSING THE NECESSITY OF THE CHIMPANZEE

community has made in research techniques” and “allow our nation’s
research institutions to make long-range decisions about the merits of
continued invasive research using chimpanzees.” In January 2011, the
NIH announced it would suspend transfer of the Alamogordo colony and
that it had tasked the Institute of Medicine (IOM) to study this issue
(HHS, 2011b). Upon completion of this study, the NIH will revisit its
decision regarding the Alamogordo colony.
In response to the request from the NIH, the IOM, in collaboration
with the National Research Council, assembled the Committee on the
Use of Chimpanzees in Biomedical and Behavioral Research to conduct
a study and issue a report on the use of chimpanzees in NIH-funded research that is needed for the advancement of the public’s health. The
committee’s statement of task is in Box 1.

BOX 1
Statement of Task
In response to a request from the National Institutes of Health (NIH), the
Institute of Medicine, in collaboration with the National Research Council, will
assemble an ad hoc expert committee that will conduct a study and issue a
letter report on the use of chimpanzees in NIH-funded research that is needed
for the advancement of the public’s health. The primary focus will be animals
owned by the National Institutes of Health, but will also include consideration
of privately owned animals that are currently financially supported by the NIH.
Specifically, the committee will review the current use of chimpanzees for
biomedical and behavioral research and:
•

Explore contemporary and anticipated biomedical research questions to
determine if chimpanzees are or will be necessary for research discoveries and to determine the safety and efficacy of new prevention or
treatment strategies. If biomedical research questions are identified:
o
o

•

Describe the unique biological/immunological characteristics of the
chimpanzee that make it the necessary animal model for use in the
types of research.
Provide recommendations for any new or revised scientific parameters to guide how and when to use these animals for research.

Explore contemporary and anticipated behavioral research questions to
determine if chimpanzees are necessary for progress in understanding
social, neurological, and behavioral factors that influence the development, prevention, or treatment of disease.

In addressing the task, the committee will explore contemporary and anticipated future alternatives to the use of chimpanzees in biomedical and behav-

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ioral research that will be needed for the advancement of the public’s health.
The committee will base its findings and recommendations on currently available protocols, published literature, and scientific evidence, as well as its expert
judgment.

Ethical Considerations
This report is based on the committee’s evaluation of the ongoing
chimpanzee research and its expert judgment and assessment of the
needs for chimpanzee research. Neither the cost of using chimpanzees in
research nor the ethical implications of that use were specifically in the
committee’s charge. Rather, the committee was asked for its advice on
the scientific necessity of the chimpanzee as a human model for biomedical and behavioral research. The committee agrees that cost should not
be a consideration. However, it recognizes that any assessment of the
necessity for using chimpanzees as an animal model in research raises
ethical issues, and any analysis must take these ethical issues into account. The committee’s view is that the chimpanzee’s genetic proximity
to humans and the resulting biological and behavioral characteristics not
only make it a uniquely valuable species for certain types of research, but
also demand a greater justification for their use in research than is the
case with other animals. Reports over many decades have established the
principles and guidelines dictating that animal subjects must be used in
studies only where the risk to the health and welfare of humans is too
great (European Union, 2010; NAS, 2010; Parliament of the United
Kingdom, 1987). Chimpanzees share biological, physiological, behavioral, and social characteristics with humans, and these commonalities may
make chimpanzees a unique model for use in research. However, this
relatedness—the closeness of chimpanzees to humans biologically and
physiologically—is also the source of ethical concerns that are not as
prominent when considering the use of other species in research. This is
consistent with the 2010 European Union Directive, which notes that
ethical issues are raised by the genetic proximity to human beings
(European Union, 2010).
In simplest terms and following the committee’s focus on necessity,
the research use of animals that are so closely related to humans must
offer insights not possible when using other animal models. In addition,
the research must be of sufficient scientific or health value to offset these
moral costs. There are many ethical approaches to analyze and either

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justify or proscribe the use of animals in research, and the committee was
neither tasked nor appropriately composed to evaluate and reach consensus on a particular approach or to apply it to research on chimpanzees.
However, in animal research policy, utilitarian justifications form part of
the rationale for continued research in animals; that is, animals are subjected to risk for the benefit of humans, and justification relies on assessments that the benefits gained from research on animals are sufficient
to outweigh the harms caused in the process. Purely utilitarian justifications are tempered in animal research through policy requirements for
humane treatment and the use of appropriate species and minimal number of animals. Furthermore, imposing requirements for justifying the
use of higher species is an implicit recognition that the use of higher animals comes at higher moral costs. Thus, the use of chimpanzees should
face the most stringent requirements for justification, and constraints that
acknowledge the characteristics that make chimpanzees unique among
animal research subjects. For the committee, this ethical context is reflected in its assessment of when, if ever, the use of chimpanzees in biomedical research is necessary.
METHODS AND ORGANIZATION OF THE REPORT
To conduct this expert assessment and evaluate the need for chimpanzees in research to advance the public’s health, the committee deliberated from May through November 2011. During this time, the committee
held three 2-day meetings and several conference calls, including two public
information-gathering sessions on May 26, 2011, and August 11-12, 2011
(see Appendix C for meeting agendas). Each information-gathering
session included testimony from individuals and organizations that both
supported and opposed the continued use of chimpanzees. The objectives of
the information-gathering sessions were to:
•
•
•

Obtain background data on the current use of chimpanzees in biomedical and behavioral research;
Explore potential alternative models to chimpanzees; and
Seek public comment about the scientific need for chimpanzees
in biomedical and behavioral research.

In addition, during the course of the study the committee solicited and
received over 5,700 comments via the Internet.

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The committee examined the current availability of chimpanzees and
use of the chimpanzee as an animal model. The committee also reviewed
the use of chimpanzees in the peer-reviewed scientific literature, as described later in the section titled “Summary of Chimpanzee Research.” In
addition, it reviewed NIH projects that supported chimpanzee research
from 2001 to 2010. The committee reviewed a number of background
documents provided by stakeholder organizations. The committee also
commissioned a paper titled “Comparison of Immunity to Pathogens in
Humans, Chimpanzees, and Macaques” (see Appendix B).
The committee completed its task by identifying a set of core principles to guide current and future use of the chimpanzee, and based on these
principles derived a set of criteria used to assess whether chimpanzees
are necessary for research now or in the future.
INTERNATIONAL POLICIES GUIDING CHIMPANZEE USE
Many countries have legislation banning the use of great apes, and
therefore chimpanzees.6 Legal action may have been deemed unnecessary in countries where chimpanzee biomedical and behavioral research
no longer occurs. The most recent legislative action around great ape use
took place within the European Union (EU), with its 27 member states.
In November 2010, following an eight-year political process, the EU
adopted Directive 2010/63 outlining the protection of animals used for
research purposes (European Union, 2010). This directive bans the use of
great apes in research (Article 8), except for a specific safeguard clause
that is described below (Article 55). Limitation of the ban to great apes,
but not other non-human primates, and inclusion of the safeguard clause
were based on political compromise that occurred over several years.
Factors in the development of this compromise may have included
•
•

No research using chimpanzees has been conducted at an EU facility since 1999 (European Parliament, 2007; Vogel, 2001);
The last facility to house chimpanzees stopped all research in
2004 (BPRC, 2011);

6
As will be discussed later in the “Summary of Chimpanzee Research” section, the
committee did find that investigators from countries outside the United States have supported limited use of chimpanzees in the United States.

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•

Support by the European Commissions’ Scientific Committee on
Health and Environmental Risks (SCHER) for the continued use
of non-human primates (NHPs) (Bateson, 2011; SCHER, 2009);
and
Recognition of the claims by the research community that the direction of new research is by definition unpredictable, as are the
development of epidemics and emergence of new diseases.

The safeguard clause states that the use of great apes is permitted
only for the purposes of research aimed at the preservation of those species or where action in relation to a potentially life-threatening, debilitating condition endangering human beings is warranted, and no other
species or alternative method would suffice in order to achieve the aims
of the procedure. While this clause was already in place in the previous
version of the directive (European Communities and Office for Official
Publications, 1986; Hartung, 2010), further details in the new directive
(European Union, 2010) stipulate that in order for a member state to authorize a study involving great apes the member state must obtain approval from the European Commission in consultation with a relevant
Committee (European Communities and Office for Official Publications,
1986) and (European Union, 2010). At the time of this report, Directive
2010/63 is still to be implemented in all European Union member states.
A number of countries, including EU member states, have specific
laws or regulations involving the use of great apes and in some cases
other NHPs (Table 3). The committee was unable to find any official
policies guiding the use of chimpanzees in biomedical and behavioral
research in other countries with large research investments, such as China and India, or to determine whether these countries maintain research
populations of chimpanzees.

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TABLE 3 International Policies on the Use of Great Apes in Scientific
Research
Country or Entity (Year)

Policy or Statement

Australia (2003)

Restricts research and stipulates that
“great apes may only be used for scientific purposes if the following conditions are met: Resources, including
staff and house, are available to ensure
high standards of care for the animals;
the use would potentially benefit the
individual animal and the species to
which the animal belongs; the potential
benefits of the scientific knowledge
gained will outweigh harm to the animal” (Australian Government National
Health and Medical Research Council,
2003).
The principal law on animal experimentation was amended with the
insertion of a new Sec. 10e, which prohibits experimentation on chimpanzees,
bonobos, orangutans, and gorillas. An
exception was made in the case of experiments commenced before January 1,
2003, in which chimpanzees were used
with a view to developing a vaccine
against hepatitis C (WHO, 2003).
The Animal Welfare Act stipulates that
the Director-General must not give approval unless he or she is satisfied that
the use of the non-human hominid in that
research, testing, or teaching either (1) it
is in the best interests of the non-human
hominid; or (2) it is in the interests of the
species to which the non-human hominid
belongs and that the benefits to be derived from the use of the non-human
hominid in the research, testing, or teaching are not outweighed by the likely
harm to the non-human hominid (Animal
Welfare Act 1999 [New Zealand], 1999).

Netherlands (2003)

New Zealand (1999)

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Country or Entity (Year)

Policy or Statement

Spain (2008)

The Commission on Environment,
Agriculture and Fishing submitted a
proposal to the Spanish Parliament to
approve a resolution urging the country
to comply with the Great Apes Project,
founded in 1993, which argues that nonhuman great primates—chimpanzees,
gorillas, orangutans and bonobos, should
have the right to life, the protection of
individual liberty, and the prohibition of
torture (Congress of Spain, 2008).
In November 1997, the government
issued a supplementary note to its response to an interim report in which it
published a policy statement on the use
of animals in scientific procedures. It
promised: the use of great apes in scientific procedures would not be allowed. While such animals have never
been used under the 1986 Act, the
government decided that it would be
unethical to use such animals for research purposes due to their cognitive
and behavioral characteristics and qualities. In the Home Office “News Release” accompanying the publication of
the Interim Report, Lord Williams is
quoted as follows: “Although these
proposed bans cannot be statutory under current legislation, I do not foresee
any circumstances in which the Home
Office would issue licenses in such
cases” (Reynolds and CEECE, 2001;
Secretary of State for the Home
Department and Parliament of the
United Kingdom, 1998).

United Kingdom (1997)

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SUMMARY OF CHIMPANZEE RESEARCH
The committee was asked, as part of its task, to review the current
use of chimpanzees for biomedical and behavioral research. To assess
the use of the chimpanzee as an animal model, the committee explored
research supported by the NIH and other federally and privately funded
research over the past 5 years, and where possible, 10 years. A summary
of this analysis is presented in the following section.
Analysis of Federally Supported Research
The largest percentage of federally funded chimpanzee research over
the past 10 years has been supported by the NIH, with additional projects
funded by other federal agencies, including the Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDC), and
National Science Foundation (NSF).
NIH-Supported Research
To explore NIH-supported research, the committee used the Research Portfolio Reporting Tools Expenditures and Results (RePORTER)
system to search for projects that included the terms “chimpanzee(s)” or
“Pan troglodyte(s).” The search, conducted on July 6, 2011, was refined
to exclude projects that were found to not use chimpanzees. Finally, the
projects were categorized. From 2001 to 2010, the NIH funded 110 projects that used chimpanzees, chimpanzee genomic sequences, or other
chimpanzee-derived compounds (Table 4). Hepatitis research,7 the largest category with 44 projects, has included projects that range from molecular studies of the virus to immune responses in chimpanzees
chronically infected with hepatitis C. In addition, studies have examined
the pathogenesis of acute and chronic liver disease following infection.
Comparative genomics studies included analysis of human and chimpanzee polymorphism rates. Some of the 11 neuroscience research projects
focused on studies of neurodevelopment, while behavioral research studies examined task engagement and sociocommunicative development.8
7

The term “hepatitis” is inclusive of all types of hepatitis, including A, B, C, D, and E.
Behavioral research studies may also fall under additional categories, such as neuroscience.
8

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Additional research areas included acquired immune deficiency syndrome (AIDS)/human immunodeficiency virus (HIV), malaria, and immunology. Of the remaining 22 projects, a portion was for research on a
variety of topics, including studies of respiratory syncytial virus (RSV)
and vaccines against anthrax toxin, while the remaining group of projects
supported chimpanzee colonies, including the care and maintenance of
the animals. Because each project varied in the number of years of funding, a breakdown of the number of research projects ongoing in each
year in each disease category was performed (Figure 1). The number of
annually funded NIH projects varied from 38 projects in 2002 to 52 in
2007.
TABLE 4 Number of Projects and Types of Funding per Disease Area:
2001-2010
Types of Funding
Projects

Hepatitis

Comparative genomics

Neuroscience

AIDS/HIV

Behavioral

Malaria

Immunology

Other

Colony maintenance

110

TOTAL
1

Research project grants.
Program project/research center grants.
3
Research contracts.
4
Intramural grants.
5
Cooperative agreements.
2

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60

Number of Projects

Colony Maintenance
Other

Malaria
Immunology

Behavior
AIDS/HIV

Neuroscience
Comparative Genomics

Hepatitis
0
2001 2002 2003 2004 2005 2006 2007 2008 2009 2010

Year

FIGURE 1 Chimpanzee research supported by the NIH: 2001-2010.

Other Federally Supported Research
Over the past decade, the FDA has funded a number of studies using
chimpanzees, including the funding of the Laboratory of Hepatitis Research. The research supported by the FDA has focused on understanding the immunobiology and pathogenesis of hepatitis C virus and
studying the safety of vaccines under development.
Other government agencies, including the NSF and CDC, have also
funded chimpanzee research in the past 10 years, although to a significantly smaller degree than the NIH. During the past 3 years, the NSF has
funded nine such studies, ranging from wild female chimpanzee emigration patterns to morphometric analysis of specific neocortical brain regions (NSF, 2011). Overall, the NSF has funded studies that include the
use of both captive and wild chimpanzees, imaging data, and chimpanzee
genomic information. While the CDC no longer funds chimpanzee research, previous research has included hepatitis vaccine development.
Beyond these agencies, the committee did not find any evidence of current chimpanzee work funded by other federal agencies, including the
Department of Defense.

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Analysis of Private-Sector Supported Research
Animal models are used throughout discovery, development, preclinical testing, and production phases of new medicines and vaccines.
Pharmaceutical and biotechnology companies use animals in the research
and development of candidate compounds. In addition, regulatory agencies require that all new prescription drugs and biologics be subjected to
thorough efficacy and safety testing prior to licensing. These requirements are in place to not only prevent potentially dangerous products
from reaching human clinical trials and eventually the market, but also to
ensure that only effective medications reach patients. In this context,
many pharmaceutical companies state that NHPs are used when no other
acceptable alternative exists and that the usual goal of using NHPs is to
evaluate efficacy and safety as a final step prior to testing in humans.
Several pharmaceutical companies no longer use chimpanzees, including
GlaxoSmithKline, which has an official published policy indicating it has
voluntarily ended the use of great apes, including chimpanzees, in research and will no longer initiate or fund studies (GlaxoSmithKline,
2011).
Committee analysis of the use of chimpanzees in the private sector
was hindered by the proprietary nature of the information. However,
based on limited publications and public non-proprietary information, it
is clear that the private sector is accessing both the whole-animal model
as well as stored biological samples (Carroll et al., 2009; Olsen et al.,
2011). In addition, from data provided by the four NCRR-supported centers, the committee learned that from 2006 to 2010, 144 chimpanzees
were used for efficacy, safety, and pharmacokinetic (PK) studies, suggesting that chimpanzees have been a part of the process of drug and/or
vaccine development. These data do not make clear, however, which of
these studies were funded by private companies and which, if any, were
funded by the federal government. In addition, between 2005 and 2010,
more than 300 requests for biological samples have come from individuals or groups with private funding, but, again, it was not possible to determine what percentage was funded by industry (Abee, 2011b;
Langford, 2011; Rowell, 2011).
Use of chimpanzees in the United States is not limited to U.S.-based
investigators, agencies, or companies. Between 2005 and 2010, 27 studies were funded by either non-U.S.-based companies or non-U.S.-based
academic investigators (Watson, 2011). The majority of these studies
were for hepatitis C therapy or vaccine development, with a few addi-

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tional studies on monoclonal antibody efficacy and immunogenicity.
Eight studies were funded by companies/investigators from Italy, followed by Japan and Denmark (five studies each). In addition, companies
from Belgium, Spain, and France funded one study each. The committee
hypothesizes that, among other reasons, foreign companies are using
U.S. resources because of the EU ban on great ape research, the lack of
research facilities in their respective countries capable of supporting
chimpanzee research and, for industry, regulatory requirements both in
the United States and abroad (Box 2).
While the committee was able to determine that both U.S.- and nonU.S.-based companies conduct limited chimpanzee research in the United States, it was not able to determine if companies independently house
chimpanzees, how often the animals are used, and what compounds, if
any, currently on the market or in human clinical trials were tested using
this model.

BOX 2
Regulatory Requirements
Food and Drug Administration
The FDA regulatory policies regarding the approval of new drugs, vaccines,
and other biological products do not specifically refer to chimpanzees. The FDA
does provide guidance that safety and toxicology studies must be completed
using the most appropriate, or relevant, species prior to preclinical testing. The
FDA relies on the sponsor to select the species and demonstrate the usefulness
of the model while encouraging dialogue between sponsors and the agency
regarding the type of animal models considered for testing. While there are no
official policies about the content of these dialogues, the committee was able to
learn about internal, unwritten practices of different branches of the FDA. The
Center for Drug Evaluation and Research (CDER) does not ask for chimpanzee
data and specifically discourages the use of chimpanzees when approached by
sponsors. This decision is based on, in part, the availability of other methods for
developing the required data, including the use of transgenic and chimeric animals, surrogate antibodies, and the minimal anticipated biological effect level
approach. CDER, however, does not turn away applications that contain chimpanzee data, including seven applications in the past 5 years. Like CDER, the
Center for Biologics Evaluation and Research (CBER) does not have a specific
policy on the use of chimpanzees and does not require their use, if the sponsor
is able to demonstrate the relevance or appropriateness of a different animal
model. However, in contrast to CDER, CBER does not actively discourage the
use of chimpanzees, in particular for use in vaccine development to prove effectiveness or demonstrate safety.

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The Special Case of the FDA’s Animal Rule
In some selected circumstances, when it is not possible to conduct human
studies, the FDA can grant marketing approval based the Animal Rule (FDA,
2011a, 2011b). The Animal Rule states that approval would require adequate
and well-controlled animal studies whose results show that the drug or biologic
is reasonably likely to produce clinical benefit in humans (CDER and CBER,
2009).
European Medicines Agency
European Union (EU) regulatory requirements related to marketing authorization of medical products do not specifically refer to chimpanzees, although there
is some guidance on the use of the most sensitive and relevant species (EMEA,
2008; 2011a). Within the European Medicines Agency (EMEA), the Committee
for Medicinal Products for Human Use (CHMP) is responsible for determining
whether or not medicines meet quality, safety, and efficacy requirements
(CHMP, 2011). In preclinical safety evaluation guidance, the CHMP defines a
relevant species as “one in which the test material is pharmacologically active
due to the expression of the receptor or an epitope (in the case of monoclonal
antibodies)” (EMEA, 2011a). Additionally, the CHMP recommends that safety
evaluation programs should include the use of two relevant species, although
one species may be sufficient if justification is provided. The EMEA does not
require or recommend the use of chimpanzees for product approval. However,
should a marketing authorization application contain results from chimpanzee
studies, this does not disqualify the product or data. Between 2004 and 2010,
the EMEA has authorized nine products based, in part, on chimpanzee data
(European record assessment reports). No marketing ban on medicines or vaccines developed using chimpanzees was provided for in current legislation. Directive 2010/63, which makes the ban of great apes more explicit, does not
change anything in EMEA practice as there was no specific requirement for the
use of chimpanzees in place before the revision of the previous directive.

Criteria That Guide the Current Use of Chimpanzees
Each chimpanzee research center has individual, but similar, processes by which a researcher has resource requests evaluated (Abee et
al., 2011). At each center an ad hoc committee, composed of researchers,
veterinarians, behavioral biologists, and other experts, reviews each request using a unique set of questions. These questions are designed to
evaluate the study rationale, determine if the chimpanzee is needed, and
then assess how many animals are required. The dialogue continues until
either it is determined the chimpanzee is no longer required or every
member of the advisory committee is convinced that the study will be

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conducted appropriately and that all the preliminary studies have been
completed.
In addition to the review performed by the Chimpanzee Research
Centers, additional reviews occur prior to the start of any chimpanzee
study. For all projects, the investigator’s institutional animal care and use
committee must approve the study protocol. In addition, the NIH Interagency Animal Model Committee must determine that the chimpanzee is
the appropriate model for any project approved by a Chimpanzee Research Center that will use an NIH-owned chimpanzee (Bennett et al.,
1995; DHS, 2007). However, as is the case for the reviews performed by
the Chimpanzee Research Centers, the Interagency Animal Model
Committee does not evaluate protocols against a uniform set of criteria.
Finding
There are currently no uniform set of criteria used to assess the necessity of the chimpanzee in NIH-funded biomedical and behavioral research.
PRINCIPLES GUIDING THE USE OF CHIMPANZEES
IN RESEARCH
The task given to the committee by the NIH asked two questions
about the need for chimpanzees in research: (1) Is biomedical research
using chimpanzees “necessary for research discoveries and to determine
the safety and efficacy of new prevention or treatment strategies?” and
(2) Is behavioral research with chimpanzees “necessary for progress in
understanding social, neurological, and behavioral factors that influence
the development, prevention, or treatment of disease?” In responding to
these questions, the committee concluded that the potential reasons for
undertaking biomedical and behavioral research as well as the protocols
used in each area are different enough to require different sets of criteria.
However, the committee developed both sets of criteria guided by the
following three principles:
1. The knowledge gained must be necessary to advance the public’s
health;

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2. There must be no other research model by which the knowledge
could be obtained, and the research cannot be ethically performed on human subjects; and
3. The animals used in the proposed research must be maintained
either in ethologically appropriate physical and social environments or in natural habitats.
Ethologically Appropriate Physical and Social Environments
Chimpanzee research should be permitted only on animals maintained in an ethologically appropriate physical and social environment or
in natural habitats. Chimpanzees live in complex social groups characterized by considerable interindividual cooperation, altruism, deception, and
cultural transmission of learned behavior (including tool use). Furthermore, laboratory research has demonstrated that chimpanzees can master
the rudiments of symbolic language and numericity, that they have the
capacity for empathy and self-recognition, and that they have the humanlike ability to attribute mental states to themselves and others (known as
the “theory of mind”). Finally, in appropriate circumstances, chimpanzees display grief and signs of depression that are reminiscent of human
responses to similar situations. It is generally accepted that all species,
including our own, experience a chronic stress response (comprising behavioral as well as physiological signs) when deprived of usual habitats,
which for chimpanzees includes the presence of conspecifics and sufficient space and environmental complexity to exhibit species-typical
behavior. Therefore, to perform rigorous (replicable and reliable) biomedical and behavioral research, it is critical to minimize potential
sources of stress on the chimpanzee. This can be achieved primarily by
maintaining animals on protocols either in their natural habitats, or by
consistently maintaining with conspecifics in planned, ethologically appropriate physical and social environments in facilities accredited by the
Association for Assessment and Accreditation of Laboratory Animal
Care International (AZA Ape TAG, 2010; Council of Europe, 2006;
NRC, 1997, 2010). Examples of appropriate physical and social environments currently accredited by the Association for Assessment and
Accreditation of Laboratory Animal Care International include
primadomes or corrals with environmental enrichment, outdoor caging
with access to shelter, and indoor caging.

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The committee recognizes exceptions to this criterion may be warranted. For example, as a result of previously approved protocols, there
are currently a few long-term research projects in which the living conditions and the relationships with humans have been idiosyncratic and integral to the protocols (e.g., studies where a chimpanzee is being taught a
symbolic language and lives and/or intensely interacts with a small number of researchers). In addition, current health and prior infectious exposures might prevent social housing for particular animals in potential
experiments that may need to be performed in biosafety level (BSL) 3 or
4 facilities. Therefore, while the committee encourages that animals be
maintained in planned, ethologically appropriate physical and social settings or natural habitats, existing protocols should be judged on a caseby-case basis, and changes made should impose minimal physiological
and psychological harm to the animals and disruption to their existing
relationships with people. All future studies should conform to the need
for ethologically appropriate housing.
Criteria to Assess the Necessity of the Chimpanzee
for Biomedical Research
As previously discussed, the chimpanzee raises unique considerations due to the ethical issues that arise as a result of the chimpanzee’s
genetic proximity to human beings. Therefore, based on the principles
previously defined, the committee developed the following criteria to
guide its assessment of NIH-funded biomedical research using the chimpanzee:
1.
2.
3.

There is no other suitable model available, such as in vitro, nonhuman in vivo, or other models, for the research in question;
The research in question cannot be performed ethically on human subjects; and
Chimpanzees are necessary to accelerate prevention, control,
and/or treatment of potentially life-threatening or debilitating
conditions.

Specific and full scientific justification for use of the chimpanzee must
meet all three of the above criteria. Assessment of which uses meet these
criteria should be done prospectively on a study-by-study basis. It is

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important that justification is substantiated and provides adequate evidence; statements such as the following would not be acceptable to the
committee:
•
•

“The chimpanzee is immunologically, physiologically, anatomically, and/or metabolically similar to human beings.” This statement is too broad.
“Chimpanzees have previously been used in safety studies for
this class of drug.” This statement is not specific as to the science driving the decision.

It is important to note that the committee focused its task on the type of
research supported by the NIH. The committee acknowledges that biomedical research aimed at the preservation and welfare of the chimpanzee species may also necessitate use of the chimpanzee, but this research
is not be supported by the NIH unless it has direct application towards
advancing human health and so on its own is outside the committee’s
task.
Assessing Suitability of Available In Vitro or Non-Human In Vivo Models
Continued advances over the past decade in imaging, genetics, in
vitro, and in silico models, and sophisticated rodent disease models have
provided scientists with more tools that could be used in place of the
chimpanzee. Federal regulations require that animals selected for a protocol should be of an appropriate species and quality and that the minimum number required to obtain valid results should be used (U.S. Office
of Laboratory Animal Welfare, 2002). Methods such as mathematical
models, computer simulation, and in vitro biological systems should also
be considered before chimpanzees are considered for research.
When assessing the necessity of the chimpanzee as a model, a more
stringent process of eliminating (“deselecting”) models of species less
closely related to human beings should be required, similar to the process
adopted by many countries in Europe (European Union, 2010). For example, in the United Kingdom, Section 5 of the Animals Scientific Procedures Act states that the Secretary of State may not authorize any
procedures where an alternative exists (Parliament of the United
Kingdom, 1987). The rationale for selection of the chimpanzee as the
necessary model must be supported by facts and data (Box 3). The pro-

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cess must be rigorous and principles for deselection must be clearly defined and consistent across institutions.
BOX 3
Deselection Criteria
The following are specific examples of deselection criteria that the committee
used to assess the suitability of available in vitro or non-human in vivo models.
In Vitro Culture System
In vitro models must be deselected if specific data required can only be obtained through the use of in vivo models.
In Vivo Models
Other species—such as monkeys, dogs, mini-pigs, and rodents, including transgenic and chimeric animals modified to mimic specific disease attributes—must
be deselected prior to determining that data required from a specific experiment
can only be obtained through the use of a chimpanzee. Non-chimpanzee models in most cases sufficiently mimic the aspect of the disease (e.g., susceptibility, sustainability, progression) or disease pathways or targets, to the extent that
they will provide sufficient data for the question being asked. The model system
chosen does not need to replicate the complete pathophysiology of the disease/disorder being studied.
Species Differences in Absorption, Distribution, Metabolism, and Excretion
(ADME)
Other species—such as monkeys, dogs, mini-pigs, and rodents, including
transgenic and chimeric animals modified to mimic specific disease attributes—
must be deselected by determining that ADME profiles do not adequately match
the profile generated by humans.
Other species—such as monkeys, dogs, mini-pigs, and rodents, including
transgenic animals modified to mimic specific disease attributes—must be
deselected prior to determining that pharmacokinetic data (bioavailability, distribution, or metabolic data) obtainable from these species are significantly less
suitable than data that are expected to be obtained from chimpanzees. For
example, if a species fails to convert a pro-drug (inactive drug) to the active
moiety, that species would be unsuitable as a toxicology species.
The standard in vitro (e.g., microsomal) model must be deselected when metabolism and pharmacokinetic data must show qualitative or substantial quantitative differences, and incremental differences are not considered sufficient.
Species Differences in Vehicle Tolerability
Other species—such as monkeys, dogs, mini-pigs, and rodents, including transgenic and chimeric animals modified to mimic specific disease attributes—must be
deselected by determining that the test article is unable to be formulated in a
vehicle tolerated by these models. In these limited cases, the chimpanzee may
be justified if the formulation is tolerated in the chimpanzee and if testing in humans is not ethically possible (see below).

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Species Differences in Response to Test Article Tolerability
Deselecting other species—such as monkeys, dogs, mini-pigs, and rodents,
including transgenic and chimeric animals modified to mimic specific disease
attributes—must be data driven. These data can be derived from in vitro studies
(e.g., test articles demonstrated to be potent COX2 inhibitors or SSRIs are contraindicated in dogs, and some antimicrobials are contraindicated in rabbits and
guinea pigs) if there is strong historical evidence of compound class intolerability.
Poor tolerability is justification for not using other species only if it precludes
assessment of other relevant toxicities (e.g., if emesis precludes achieving adequate systemic exposure). If the basis for intolerability of a test article is clinically relevant, it may be a reason for selection rather than deselection of a nonrodent or non-human primate (NHP) species.
Pharmacology
The standard non-rodent and NHP species must be deselected if there is a
lack of pharmacologic response (demonstrated inactivity) in these animals. In
these cases, the chimpanzee may be justified if there is scientific evidence that
pharmacological activity will occur in chimpanzees and those specific safety
concerns of exaggerated pharmacology need to be characterized in animal toxicity studies. If other species—such as monkeys, dogs, mini-pigs, and rodents,
including transgenic animals modified to mimic specific disease attributes—have
pharmacological sensitivity that precludes testing at adequate multiples of clinical exposure, use of chimpanzees may be justified if toxicity studies in chimpanzees could achieve significantly greater exposure. However, if safety
concerns of exaggerated pharmacology can be adequately characterized in
other species—such as monkeys, dogs, mini-pigs, and rodents, including transgenic animals modified to mimic specific disease attributes—pharmacological
responsiveness of chimpanzees is not necessarily a factor in species selection.
Immunogenicity
Other species—such as monkeys, dogs, mini-pigs, and rodents, including
transgenic animals modified to mimic specific disease attributes—must be deselected if there is a scientifically based expectation for significant antigenicity for
test articles not intended to be immunogenic. Vaccine research and development requires an appropriate immunogenic response to the vaccine and/or to
an adjuvant, which in some cases may necessitate the use of chimpanzees, if
human experiments cannot be ethically performed (see below).
Availability of Test Article or Cost of Species
A limited supply of the most suitable experimental animal or individual cost of
the proposed species is not a justification for deselecting the standard nonrodent or NHP species.

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Assessing Whether the Research Can Be Performed on Human Subjects
As the criteria regarding necessity outline, chimpanzee research is
not necessary if it can be ethically performed on humans. Standard arguments about protection of human subjects require that there be an acceptable balance of the risks and potential benefits of proposed research,
that the distribution of the risks and benefits are equitable (higher risk
research can be justified when the potential therapeutic benefits accrue to
the subjects themselves), and that the subjects are voluntary and informed of potential liabilities during their decision making. Relevant examples of critical human health-related research that would not meet
human subjects’ protection standards include trials that intentionally expose subjects to untreatable infectious diseases and exposure trials to
hazardous substances that pose significant health risks without prospect
of benefit.
When research on humans is justified, federal policies on protection
of human subjects impose limits, including for research on subjects who
cannot consent for themselves. Subparts of the federal regulations concerning research on human subjects also impose clear limits on acceptable research on children and prisoners (HHS, 2005). These include
restrictions on research that poses greater than minimal risk to subjects;
such research cannot be approved unless it has the potential for offsetting
therapeutic benefit to the subjects themselves.
These standards and additional protective restrictions mean that more
research may take place using animal models than would otherwise be
the case if additional risks to human subjects were deemed acceptable.
Assessing Advancements to Treat Potentially Life-Threatening or Debilitating
Conditions
The standard non-rodent and NHP species may be deselected if it can
be demonstrated that forgoing the use of chimpanzees for the research in
question will significantly slow or prevent important advancements to
treat potentially life-threatening conditions in humans or debilitating
conditions that have a significant impact on a person’s health, and thus
slow or prevent important advancements for the public’s health. This
assessment is based on the potential impact on human health and potential to improve well-being, which can be partially assessed by the burden
of the disease or disorder. The committee notes that for emerging infec-

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tious diseases and biodefense-related threats, this information may not
exist for low-probability, high-consequence threats.
Criteria for Use of the Chimpanzee in Comparative Genomics
and Behavioral Research
As previously discussed, research using the chimpanzee raises
unique ethical issues because of its genetic proximity to human beings
and highly developed cognitive and social skills. Therefore, based on the
principles previously defined, the committee developed the following
criteria to guide its assessment of NIH-funded comparative genomics and
behavioral research using the chimpanzee:
1. Studies provide otherwise unattainable insight into comparative
genomics, normal and abnormal behavior, mental health, emotion,
or cognition; and
2. All experiments are performed on acquiescent animals, in a
manner that minimizes pain and distress, and is minimally invasive.
Specific and full scientific justification for the continued and future use
of the chimpanzee must meet the above criteria, as well as the housing/
maintenance requirements described earlier in the document. This
assessment should be applied prospectively on a study-by-study basis.
Assessing the Objectives of the Project
The review of research projects on a study-by-study basis must
demonstrate that the primary objective of the research is to provide otherwise unattainable, specific insight into human evolution, normal and
abnormal behavior, mental health, emotion, or cognition. Research may
be either basic or applied, but must be consistent with the mission of the
NIH “to seek fundamental knowledge about the nature and behavior of
living systems and the application of that knowledge to enhance health,
lengthen life, and reduce the burdens of illness and disability” (NIH,
2011).
The committee recognizes that most behavioral research differs fundamentally from biomedical research in the sense that mental or behavioral disorders (with few exceptions) cannot be modeled explicitly using

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chimpanzees. This is because the naturally occurring prevalence of such
disease is likely to be low if compared to what is observed in human
populations, thus precluding reasonably sized studies using chimpanzees.
Some conditions (e.g., depression or post-traumatic stress syndrome)
may be inducible in chimpanzees, but likely only using procedures that
would be judged unacceptably invasive. This is especially true inasmuch
as other animals, including other nonhuman primates, have been used to
model these disorders. It is for the forgoing reasons that the majority of
comparative genomics or behavioral studies using chimpanzees have
focused on continua of behavioral and developmental phenomena from
normal to abnormal, taking advantage of similarities in behavioral and
brain complexity that mark chimpanzees and humans apart from virtually
all other species.
Assessing Animal Acquiescence and Distress
Comparative genomics and behavioral research should only be performed on acquiescent animals and in a manner that minimizes distress
to the animal. Evidence of acquiescence includes situations in which animals do not refuse or resist research-related interventions and that do not
require physical or psychological threats for participation. In addition,
only minimally invasive protocols should be performed. Examples of
minimally invasive procedures include behavioral observation and the
introduction of novel objects to the living area. In performing some comparative genomics or behavioral research, it also may be necessary to
temporarily isolate an animal from its social group to perform behavioral
tasks or for anesthesia. It is anticipated that anesthesia may be necessary
for noninvasive imaging studies, the collection of biological samples (including blood, skin, adipose, or muscle) that do not involve surgical invasion of body cavities, the implantation of radio transmitters to measure
autonomic nervous system function or physical activity, and the use of
biosensors for recording central nervous system responses in freely moving animals. Whenever possible, anesthesia for comparative genomics or
behavioral purposes should coincide with scheduled veterinary examination. Research on elderly or infirm animals in particular should take full
advantage of anesthesia performed as part of routine veterinary care. It is
recognized, however, that some study protocols may require that animals
be anesthetized apart from veterinary examinations. The annual occurrence of such episodes of anesthesia should be minimized in number and
the length of time the animals are sedated, consistent with accepted vet-

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erinary practice, including post-procedure analgesia as required. In all
instances, anesthesia protocols should be designed to ensure that effects
on the central nervous system or other organs are transient, and anesthesia for research purposes only should be avoided when possible in elderly or infirm animals. When animal protocols for anesthesia are not
available, protocols used for human patients under similar circumstances
may guide the choice of procedures.
Finally, when temporary removal from the social group is required
for behavioral manipulation or anesthesia, animals must be handled in a
manner that minimizes stress. Successful strategies have included positive reinforcement training that allows animals to be called by name or
otherwise enticed to leave their habitual setting to engage in research
procedures.
REVIEWING THE NECESSITY OF CURRENT
CHIMPANZEE RESEARCH
The following case studies are meant to demonstrate how the committee envisions its criteria for the use of chimpanzees in research might
be employed. In each case, the committee reviews the current use of the
chimpanzee against the criteria and makes a determination of whether or
not the research should be continued or prohibited. It is important to note
that the committee is not reviewing any specific research grant, but rather
the larger body of research in each area. As reviewed previously in the
report, chimpanzees are used in multiple research areas (see Figure 1).
Based on the propensity of current research, the committee chose to assess the necessity of the chimpanzee in areas of research where there is
significant on-going research or a potential for significant research. The
committee assessed the following research areas: monoclonal antibodies,
RSV, hepatitis C virus (HCV) antiviral drug development, HCV vaccine
development, comparative genomics, cognition, and neurobehavioral
function. Other areas, for example, malaria research, have limited ongoing studies using the chimpanzee. From 2001-2010 there were only
two studies that were done in the field of malaria, both currently still
funded. For this reason, the committee chose not to use this and similar
areas for case studies. However, the use of the chimpanzee in this and
other research areas not reviewed by the committee can be assessed by
using the same criteria.

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Monoclonal Antibodies
Background
Currently, two separate uses of monoclonal antibodies rely on the
chimpanzee. These are the production of chimpanzee monoclonal antibodies and preclinical safety testing of monoclonal antibodies prior to
their introduction into humans. The development of monoclonal antibodies for use in any laboratory or clinical application follows the groundbreaking methods pioneered by Georges Köhler and César Milstein in
the mid-1970s (Köhler and Milstein, 1975). Köhler and Milstein developed robust cell culture methods to immortalize individual B cells and
thus create clonal cell lines that produce one type of antibody, hence the
term “monoclonal antibody.” The ability to produce essentially unlimited
supplies of a unique monoclonal antibody provides a powerful technological platform for the generation and use of a wide range of affinity
reagents in a myriad of applications.
In recent years the utility of having antibodies that bind to a single
site on a molecule of interest has been expanded by the ability to produce
affinity reagents using any of a series of in vitro molecular cloning methods (reviewed extensively over the years, but see de Marco, 2011;
Demarest and Glaser, 2008; and Kneteman and Mercer, 2005, for recent
comprehensive reviews). These approaches range from simple cloning of
cDNA copies of the antibody mRNAs from immortal B cells, which allows the production of the monoclonal antibody in other cells and in
vitro systems, to complete synthetic methods that identify individual
binding domains from pools of expression vectors. The sequences that
encode the binding domains can be expressed to produce a wide range of
affinity reagents. It is now common to place the antigen interaction domains in antibody sequences from any organism, including humans, or in
any antibody subtype, allowing the functional activities to be selected to
achieve the best results. The antigen binding sites can be fused to other
domains to make chimeric molecules that allow the production of reagents that bind to an antigen of choice and bring essentially any functional activity to the location of the antigen. These methods allow
researchers to tailor affinity reagents to fulfill a wide range of desired
activities. While monoclonal antibodies are still most commonly made
by immunization of animals and immortalization of their B cells, synthetic or semi-synthetic methods are gaining increasing application.

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Development of Chimpanzee Monoclonal Antibodies
For slightly over a decade researchers have been using the chimpanzee for the production of monoclonal antibodies (Altaweel et al., 2011;
Chen et al., 2006a, 2006b, 2007b, 2009; 2011b, 2011c; Goncalvez et al.,
2004a, 2004b, 2007, 2008; Men et al., 2004; Schofield et al., 2000, 2002,
2003). Typically these monoclonal antibodies are prepared by cloning
antibody-encoding cDNAs from immunized chimpanzees. In brief, one
or a small number of chimpanzees are injected with an immunogen of
interest. Immunogens that have been used for successful monoclonal antibody production have included such agents as inactivated human viruses or bacterial toxins. At a chosen interval after the final boost, a bone
marrow sample is collected from the chimpanzee. Lymphocytes are purified from the bone marrow samples, RNA is isolated, and cDNA is prepared for cloning in various expression vectors. Coding sequences that
express protein fragments can bind to the desired immunogen and are
then isolated. In most procedures the chimpanzee-coding region for antigen-binding domains are cloned as chimpanzee/human chimeric antibodies and used for subsequent experiments.
It has been suggested that this approach provides two potential advantages over monoclonal antibody production in other species. First,
because the antibody protein sequences between the chimpanzee and the
human are so similar (Ehrlich et al., 1990), further subcloning and humanization of the chimpanzee antibody sequences are not needed, and
the resulting antibodies can be used directly in humans without further
work. Second, because the immune responses of the chimpanzee and the
human are so similar, it is likely that chimpanzees would mount immune
responses that are similar to analogous immune challenges seen in humans. The chimpanzee/human chimeric monoclonal antibodies produced
in these manners have proven to be effective in both in vitro and in vivo
assays to neutralize infectious viruses or to block the action of bacterial
toxins.
Criteria 1: Alternative Models
It is possible to develop monoclonal antibodies with these types of
binding specificities in species other than chimpanzees. As is commonly
done, these binding domains can readily be converted into fully humanized antibodies (see Nelson et al., 2010, and the references within for a
review of this procedure and its common use in antibody therapeutics).

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Monoclonal antibodies prepared in other species with properties similar
to the chimpanzee antibodies are already described in the literature (reviewed by Marasco and Sui, 2007). Further, genetic humanization of the
immunoglobulin locus in mice allows for rapid and high throughput production of fully human antibodies. For example, Regeneron Pharmaceuticals has created the so-called VelocImmune mouse by directly
replacing mouse antibody gene segments with their human counterparts
at the same location (Valenzuela et al., 2003). Alternatively, human antibodies can be induced in human xenotransplantation models (Becker et
al., 2010). While the chimpanzee is clearly capable of making an effective humoral response to these immunogens, there seems to be no unique
properties to the resultant antibodies to suggest that the continued use of
the chimpanzee is required.
Finding
The committee finds that the continued use of chimpanzees for the
production of monoclonal antibodies does not meet the suggested criteria
for the use of the chimpanzee in biomedical research. Production of
monoclonal antibodies following immunization in other species or
through in vitro synthetic methods is equally powerful for the generation
of such reagents. There appear to be no obvious reasons to suggest that
the immunogenic regions of the antigens used for monoclonal antibody
production in the chimpanzee are unique to this species. Neutralizing
antibodies appear in other species in high frequency, and therefore it
seems likely that antigen-binding domains seen in species other than the
chimpanzee can be identified and used for the production of these reagents. The humanization of these antibodies should be similar in scope
and difficulty to the approaches used with the chimpanzee, and the resulting reagents should be equally useful in humans. No added time savings are inherent in approaches compared to work in other species.
Safety Testing of Monoclonal Antibody Therapies
Monoclonal antibodies used in treatment of human disease bind to a
carefully chosen antigen, often a protein, and through this interaction
interfere with a cellular process that underlies disease development.
Therapeutic monoclonal antibodies have become important front-line
treatments for a wide range of human diseases and clinical procedures,

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including inflammation, autoimmunity, cardiovascular disease, cancer,
macular degeneration, and transplantation. The first monoclonal antibodies approved for clinical use were introduced in the mid-1980s. The pace
of FDA approval of monoclonal antibody-based therapies continues to
increase—one treatment was approved in the 1980s (FDA, 1986), 7 in
the 1990s, and 18 in the 2000s (An, 2010; Beck et al., 2010; Nelson et
al., 2010; Reichert et al., 2005; Reynolds, 2011). Given the number of
current clinical trials that are exploring new uses of monoclonal antibodies, it is likely that the introduction of novel therapies that rely on monoclonal antibodies will continue at least at this level in the future, and it is
reasonable to speculate that the rate of FDA approval for new therapies
may increase significantly over time.
Criteria 1: Alternative Models
When developing monoclonal antibody therapies for human clinical
use, it is important to determine what, if any, unexpected effects these
treatments might provoke in humans (see ICH Harmonized Tripartite
Guideline, 2011, for regulatory practices and Chapman et al., 2009, and
Tabrizi et al., 2009, for discussions of the process and needs for preclinical safety testing). Good preclinical models should mimic the biological
effects of introducing the monoclonal antibody into humans and thus
would provide predictions of any unexpected effects in humans. Issues
that are important for the measurement of safety include the display of
target molecules with analogous binding sites for the monoclonal antibody therapeutics, immune responses that are as similar to the human as
possible, similar kinetics of monoclonal antibody presentation and clearance, and minimal immune response to the monoclonal antibody. The
chimpanzee provides this close relationship, and has often been used as a
model (Chapman et al., 2007).
Preclinical tests in the chimpanzee may lead to adverse events, and
these adverse events may arise from three sources. First, the antibody
could bind with the intended targeted protein, but the target may have
unknown roles in the body that are unrelated to its disease-causing effects, thus giving on-target toxicity. Second, the monoclonal antibody
may bind to proteins other than the intended target, and these interactions
could give rise to unwanted side effects, yielding off-target toxicity.
Third, analogous types of on- or off-target toxicities could arise from
functional domains on the monoclonal antibody other than the antigenbinding domain. Other models, such as other monkey species, have not

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proven to be as effective for detecting such toxicities, and over time it
has become common to test for such unwanted effects using appropriately monitored and carefully sized trials in the chimpanzee. Undesired results in chimpanzee safety tests have led to the termination of a number
of monoclonal antibody programs before they have advanced to clinical
tests in humans, presumably saving unwarranted human suffering in the
process (Abee, 2011a; Reynolds, 2011). In addition, there are also rare
examples of monoclonal antibodies that have been tested directly in humans without previous chimpanzee safety tests and that have caused severe and undesired responses in humans (see Eastwood et al., 2010, for a
potential biological explanation of one such undesired response). Therefore, the use of the chimpanzee for safety tests has proven to be valuable,
and such studies have been used to protect human health.
Although safety trials for monoclonal antibody therapies continue to
be performed in the chimpanzee, the committee also has noted that in
recent years there is a trend in many groups to avoid its use. This trend is
driven both by advances in monoclonal antibody technology and by
changes in how potential monoclonal antibody treatments are first introduced into humans.
There are currently four methods in use that lessen the need for safety tests in the chimpanzee: (1) genetic engineering of the target protein in
rodents; (2) selection of antibodies that recognize target epitopes shared
across species; (3) selection of multiple antibodies that can serve as surrogates for responses; and (4) microdosing in humans (Chapman et al.,
2007; Reynolds, 2011).
The first of these approaches relies on expressing the target protein
in a rodent, expressing the target epitope’s ortholog in the rodent, or developing mice with xenotransplanted human tissue. This is an approach
that offers some benefits, but there is considerable worry that the target
protein may not function identically in the rodent, and other functional
domains on the monoclonal antibody may not be recognized in an identical fashion in the rodent compared to the human. Since much of the potential response to monoclonal antibody treatment cannot be mimicked
by this method, it has a limited potential to change the necessity for
chimpanzee use. Nonetheless, this is a useful experimental approach and
can help guide researchers to potential problems. By itself, however, this
approach does not significantly change the need for chimpanzee research.
Two other approaches to lower the need for chimpanzees in safety
testing rely on changes in how monoclonal antibodies are chosen for potential clinical development. As mentioned above, the development of

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various recombinant antibody methodologies has dramatically expanded
the range of properties that can be selected or developed during antibody
creation. In one useful approach, researchers select monoclonal antibodies that bind to the target antigen at sites found both in the human and in
other species beyond the chimpanzee, often in another NHP (Reynolds,
2011). In these cases, the safety of interfering with the activity of a
disease-specific protein can be tested in species other than the chimpanzee. If this species has other features that mimic the human, confidence
in the safety profile of a preclinical candidate being considered for human studies is raised. There is still some considerable concern about how
well the preclinical model mimics the human, and it is commonly argued
that even good results in such tests cannot ensure how human tests will
proceed. Here, as in other cases, safety studies in more than one species
raise confidence about prediction of response in the human.
In a third approach, researchers choose two or more monoclonal antibodies that bind to the same target protein. These antibodies are frequently called surrogate antibodies. With two or more antibodies that
bind to the same target antigen, on-target effects can be established by
comparing the responses in dose-escalating safety studies. These studies
are performed in preclinical safety models. On-target effects can be identified as those that are common to all antibodies, while undesired effects
are specific to one of the agents. While surrogate antibodies may not
have all of the best properties of a true clinical development candidate,
studying the responses to multiple agents can increase the confidence of
the potential safety profiles of monoclonal antibodies prior to introduction into humans.
Criteria 2: Testing on Human Subjects
A fourth approach that may lower the dependence on safety testing
in the chimpanzee relies on microdosing in humans. Monoclonal antibody treatments, which have previously shown good Pharmacokinetics/Pharmacodynamies (PK/PD) and toxicology results in preclinical
studies in other models, can be tested for safety directly in humans using
microdosing schedules, such as using minimal anticipated biological effect level strategies (see Muller et al., 2009, for a careful review of the
use of microdosing strategies). Starting with very low doses enables clinical researchers to carefully monitor for any unexpected side effects in
settings where adverse events can be detected before serious harm is
done to the patient. These microdosing approaches can be teamed with

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the introduction of radiolabeled tracer preparations of the monoclonal
antibody to follow the in vivo localization of the antibodies and thus potentially link side effects to particular organ sites for further studies.
Finding
These approaches—use of genetically engineered rodents, directed
strategies to select monoclonal antibodies with broader binding specificities across species, use of surrogate antibodies, and different methods to
introduce antibodies into humans—combined with the recognition that
the FDA does not require safety testing of new monoclonal antibody
therapies in chimpanzees, promise to provide a series of methods that can
be used to protect human safety while avoiding use of the chimpanzee.9
Therefore, the committee finds that use of these methods, often in combination, can make the chimpanzee largely unnecessary in the development of future monoclonal antibodies therapies.
Not all companies and few academic laboratories have fully adopted
monoclonal antibody approaches, such as recombinant antibody production, that allow the selection of monoclonal antibody therapeutic agents
that meet these more defined criteria. Therefore, there may be a limited
number of monoclonal antibodies currently in the development pipeline
that may require the continued use of chimpanzees. For these specific
cases, the use of the chimpanzee should be assessed against the committee’s
criteria for biomedical research. In addition, the NIH should be expeditious in supporting the development of broadly accessible recombinant
technologies for development of novel therapeutic monoclonal antibodies.
Respiratory Syncytial Virus
Prevalence and Treatment Options
Respiratory syncytial virus is a pneumovirus initially described as
chimpanzee coryza agent in 1955 and renamed “respiratory syncytial
virus” in 1956 following virus isolation from infants with bronchiolitis
9

It is important to note that if data from safety testing in the chimpanzee are presented
as part of an investigational new drug application, the FDA requires that these studies
reach appropriately high standards to contribute to the prediction of eventual safety in
humans.

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and pneumonia (Blanco et al., 2010; Chin et al., 1969; Wright and
Piedimonte, 2011). Overall, RSV is the most common cause of acute
lower respiratory tract infections and bronchiolitis in children under the
age of 5 years (Krilov, 2011; Nair et al., 2011). Nearly all children have
been infected with RSV at least once by age 2, with a large percentage of
infants infected during their first RSV season (Fulginiti et al., 1969;
Weisman, 2009; Wright and Piedimonte, 2011). RSV is believed to account for 85 percent of bronchiolitis and 20 percent of pneumonia cases
globally, with 1 in 200 infants requiring hospitalization (Nair et al.,
2011). Today, RSV is the leading cause of hospitalizations in U.S. children less than 1 year old, with an estimated 100,000 to 126,000 infants
hospitalized each year due to bronchiolitis (Krilov, 2011; Wright and
Piedimonte, 2011). In addition to children, RSV is reported to have similar rates of hospitalization and mortality in the elderly (Shadman and
Wald, 2011). Another at-risk population includes patients who have undergone hematopoietic stem cell transplantation, with RSV affecting approximately 2-17 percent of these transplant recipients (Shah and
Chemaly, 2011).
Current treatment and prevention options for RSV are very limited.
Treatment for hospitalized infants and children primarily includes supportive care, but may also include administration of α-adrenergics or corticosteroids (Krilov, 2011). For severe RSV-induced lower respiratory
tract infections or where there is a high risk of mortality, Ribavirin is the
only licensed antiviral currently on the market. Its use is limited due to
factors such as minimal clinical benefits and high cost (Krilov, 2011;
Wright and Piedimonte, 2011). Palivizumab, the only approved prophylactic RSV drug, is a humanized monoclonal antibody that is administered intramuscularly every 30 days during RSV season. It is only used
to reduce severity and morbidity in high-risk populations, including
premature infants less than 35 weeks of gestation, infants with chronic
lung or congenital heart disease, or infants and children with lung abnormalities such as cystic fibrosis (Nair et al., 2011; Shadman and Wald,
2011). Palivizumab is not commonly used in low-risk populations due to
the high cost of treatments and limited evidence of clear benefit in these
populations (Krilov, 2011; Prescott et al., 2010; Shadman and Wald, 2011).
Criteria 1: Alternative Models
Multiple cell lines from human and animal sources are currently used
in preclinical research of RSV, including differentiated normal human

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bronchial epithelial (NHBE) cells (DeVincenzo et al., 2010; Tayyari et
al., 2011). Recently bronchial epithelial cells derived from human lung
adenocarcinoma were found to be susceptible to RSV infection and release infectious virus similar to NHBE cells, indicating a new cell line
for potential use (Harcourt et al., 2011). The use of cell culture has limitations, including the inability to replicate tissue organization and disease
manifestations, such as respiratory infection in the case of RSV. Therefore, animal models of human RSV (hRSV) provide an important link
between mechanistic cell culture research and human clinical trials.
No single animal model, including the chimpanzee, reproduces all
aspects of RSV infection. Chimpanzees are susceptible to infection with
hRSV with replication of the virus in high titers in the upper and lower
respiratory tracts (Murphy et al., 1992). The chimpanzee also has the
same body temperature as humans, unlike other animal models, which is
important when investigating the degree of attenuation of candidate
temperature-sensitive vaccine strains (Murphy et al., 1992). Seronegative
chimpanzees can serve as surrogates for seronegative infants, the target
population for vaccines. However, identification of animals that are
seronegative can be difficult since the infection commonly spreads between animal handlers and chimpanzees (Murphy et al., 1992). The inability of chimpanzees to develop lower respiratory diseases such as
bronchiolitis and pneumonia, the limited availability of specific reagents,
and large size are noted disadvantages of this model (Bem et al., 2011;
Graham, 2011). Alternative models for RSV research, including sheep,
cotton rats, and mice, have significantly reduced the use of chimpanzees
in RSV basic research; the last published research paper to use the chimpanzee appeared in 2000.
Sheep are susceptible to hRSV infection; neonatal lambs develop
upper respiratory tract disease, bronchiolitis, and mild pneumonia. In
addition to showing clinical signs of the disease, the respiratory tracts of
sheep share many structural and developmental features with humans,
unlike rodents (Bem et al., 2011). The limited availability of immunological reagents and other molecular tools, along with animal size, are two
disadvantages of this model. Cattle provide another useful model of RSV
infection because bovine RSV (bRSV) shares many common characteristics with hRSV, including respiratory tract infections, increased susceptibility of the young, and seasonal outbreaks (Byrd and Prince, 1997). Like
sheep, however, the limited availability of reagents and animal size are
disadvantages of this model. Currently the most commonly used animal
models for hRSV are mice and cotton rats. The cotton rat is a semi-

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permissive model of hRSV replication that develops mild to moderate
bronchiolitis or pneumonia following exposure. Studies have demonstrated
that this model can develop vaccine-enhanced disease at all ages and that
the disease is similar to that seen in humans (Mohapatra and Boyapalle,
2008). However, cotton rats do not show clinical signs of respiratory
tract disease (Bem et al., 2011; Graham, 2011). Mice, specifically the
BALB/c inbred strain, develop lower respiratory tract disease symptoms
following infection along with signs of illness such as weight loss (Bem
et al., 2011; Domachowske et al., 2004; Nair et al., 2011). In addition,
the immunohistopathology of RSV infection in mice resembles that of
human infection (Mohapatra and Boyapalle, 2008). The ability to develop transgenic mouse lines offers a distinct advantage to the mouse model
in comparison to other models. However, the difference in innate and
adaptive immune responses between mice and humans and the inability
for hRSV to robustly replicate in mouse lung tissue and spread between
the upper and lower airway are disadvantages of this model (Bem et al.,
2011; Mohapatra and Boyapalle, 2008).
Together these alternative models to the chimpanzee for RSV research demonstrate both susceptibility to the human form of the virus
and the ability to develop clinical signs of the virus, including bronchiolitis and pneumonia; therefore, they cannot be deselected from use. Their
availability and suitability, along with increasing number of cell culture
systems, indicates that the first criteria for the use of chimpanzees are not
met in the case of RSV research.
Criteria 2: Testing on Human Subjects
RSV antiviral drug and prophylactic vaccine clinical trials progress
from Phase I studies in adults to trials with seropositive children and then
seronegative infants (Nair et al., 2011). While time consuming, clinical
testing is possible on human subjects, but the development of novel vaccines may be limited by an inability to predict adverse reactions to vaccines, something that can be accomplished in chimpanzees. This obstacle
may be overcome with the recent development of a human experimental
infection model (DeVincenzo et al., 2010). Healthy adult volunteers were
infected with RSV, causing a self-limited upper respiratory illness. The
researchers then tested the safety and efficacy of a small interfering RNA
(siRNA) antiviral, ALN-RSV01. This proof-of-concept trial suggests a
mechanism for development of a challenge model for testing vaccines
against RSV in the future. While this human infection model is new and

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has only been examined in one study so far, it suggests future avenues
for immunogenicity, efficacy, and safety testing in human subjects. The
development of a human challenge model suggests that RSV research
can be performed ethically on human subjects; therefore, the use of
chimpanzees does not meet the second criteria for biomedical research.
Criteria 3: Impact of Forgoing Chimpanzee Use
Forgoing the use of the chimpanzee will not significantly slow or
prevent advancement of either therapeutic or prophylactic drugs for RSV
and therefore, chimpanzee use does not meet the third criteria. This finding is based, in part, on both the availability of multiple non-human animal models that recapitulate several aspects of RSV disease and the
ability to conduct proof-of-concept trials in a human model of infection.
Currently three vaccines and two antiviral compounds are in clinical trials. MicroDose Therapeutx is in a Phase I trial of MDT-637, an inhalable
small molecule antiviral (MicroDose Therapeutx, 2011). Alnylam is
conducting a Phase II efficacy and safety trial of the siRNA antiviral
ALN-RSV01 in RSV-infected lung transplant patients (Alnylam
Pharmaceuticals, 2011). Novavax and MedImmune are in Phase I and
I/IIa clinical trials of potential vaccines, respectively. Novavax is testing
four different recombinant RSV-F formulations of NVX 757 01 in
healthy adults (Novavax, 2011). MedImmune is testing two attenuated
intranasal vaccines (MEDI-534 and MEDI-559) in children and infants
(MedImmune LLC, 2011a, 2011b). In addition to these, at least seven
other pharmaceutical companies have preclinical RSV programs in development for either therapeutics or prophylactics, including a trivalent
anti-RSV-F nanobody (Nb ALX-0171) derived from immunized camels
(Pharmaceutical Business Review, 2011).
Finding
The committee finds that currently, chimpanzee use for RSV research is not necessary. This finding is based on the inability of the use
of the chimpanzee to meet the three criteria for biomedical research, the
current state of research, availability of alternative models, and the large
number of drug development efforts. However, the committee cannot
completely eliminate the potential for a future need of this animal model.
The development of a safe and effective vaccine would confer the greatest benefit on the most vulnerable of populations, infants under 6 months

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of age. The committee acknowledges that there are still barriers in the
development of a prophylactic vaccine for RSV, including the need to
immunize young infants who potentially may not respond to vaccines or
have adverse reactions, possible interactions with other pediatric vaccines, or enhanced reactivity (Blanco et al., 2010). The chimpanzee may
be required in the future for testing of novel vaccines because of the ability of the chimpanzee to serve as an early surrogate model for
seronegative infants (Mohapatra and Boyapalle, 2008; Pollack and
Groothuis, 2002; Weisman, 2009).
HCV Antiviral Drugs
Prevalence and Treatment Options
Hepatitis C virus currently infects 130-170 million people worldwide
(WHO, 2011). In the United States, 3.2 million people are chronically
infected with hepatitis C virus (Williams et al., 2011). More than
350,000 individuals die each year due to HCV-induced cirrhosis, endstage liver disease, or hepatocellular carcinoma (Klevens and Tohme,
2010). Current therapy for patients chronically infected with HCV includes pegylated interferon α and ribovarin plus the recent addition of an
HCV protease inhibitor, telaprivir (Incivek) or boceprivir (Victrelis).
This regimen leads to viral cures in a high percentage of HCV-infected
subjects, including those with more-difficult-to-treat genotype 1 infections common in the United States and Europe (Ilyas and Vierling,
2011). The two new NS3/NS4A protease inhibitors, telaprevir and
boceprevir, were approved by the FDA in 2011 based on their effectiveness in in vitro culture systems (Sheehy et al., 2007) and then in large
controlled clinical trials (Jacobson et al., 2011; Jensen, 2011; Kwo et al.,
2010). Additional inhibitors of HCV’s NS5A replication complex assembly factor and the NS5B RNA polymerase are currently in advanced
clinical development, offering future hope for a highly effective, completely oral, and interferon-free therapeutic regimen for patients chronically infected with HCV (Ilyas and Vierling, 2011). The current HCV
pipeline now includes four drugs in Phase III and 22 in Phase II of development.

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Criteria 1: Alternative Models
Because of their unique susceptibility to HCV infection and the initial lack of in vitro culture systems, chimpanzees were particularly valuable during the early phases of HCV research. For example, molecular
clones of HCV were first isolated from a cDNA expression library prepared with mRNA from a chimpanzee infected with non-A, non-B hepatitis virus (Choo et al., 1989). More recently, the use of chimpanzees has
declined as both HCV replicons (Lohmann et al., 1999) and fully infectious HCV molecular clones (Lindenbach et al., 2005; Wu et al., 2005;
Zhong et al., 2005) were identified, enabling the establishment of in vitro
culture systems. Various animal models (reviewed in Boonstra et al.,
2009) have also emerged, including immunotolerized rats containing
human hepatocytes (Wu et al., 2005); immunodeficient mice with heterotopic human liver grafts (Galun et al., 1995); SCID mice expressing the
urokinase plasminogen activator transgene that destroys the endogenous
mouse liver, permitting xenotransplantation of human hepatocytes
(Mercer et al., 2001; Meuleman et al., 2005); and genetically humanized,
immunocompetent mice containing human surface receptors required for
HCV entry (Dorner et al., 2011). While culture systems are not yet available for genotypes 3, 4 and 6, the replicon system could be used to screen
inhibitors against the protease and polymerase, but not NS5A. However,
it is very likely that infectious molecular clones will soon emerge for
these genotypes—a blueprint for their development now exists—and further alternative small animal models supporting the growth of these viruses will also likely progress rapidly.
The currently available experimental systems, coupled with the challenges inherent to chimpanzee experiments, including limited numbers of
animals and high costs, have resulted in a steady deemphasis of the
chimpanzee model in HCV antiviral drug design and development. For
example, both boceprevir and telaprevir were developed and approved
without the use of chimpanzees; instead, preclinical experiments were
conducted in mice, rats, rabbits, dogs, and cynomolgus monkeys
(EMEA, 2011b; Vertex Pharmaceuticals Incorporated, 2011). However,
a few companies continue to use previously HCV-infected chimpanzees
(Chen et al., 2007a; Olsen et al., 2011).

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Criteria 2: Testing on Human Subjects
Chimpanzees have been used to establish PK/PD relationships of
candidate drugs and to assess antiviral activity in vivo. An ethical alternative to performing PK studies in chimpanzees is now available. Specifically, Phase 0 studies can be performed in consenting humans involving
microdosing of a drug candidate (Ings, 2009). Such microdosing studies
involve the administration of the drug at very low, subtherapeutic
amounts that are unlikely to produce toxic side effects, followed by monitoring of drug distribution and clearance using highly sensitive
bioanalytical methods. Drugs with unacceptable pharmacokinetic profiles can be rapidly excluded from further development. For Phase I toxicity studies or more advanced efficacy studies, consenting individuals
chronically infected with HCV could be recruited. The use of humans for
evaluation of these HCV antivirals is further supported by the fact that
HCV infection in chimpanzees only partially recapitulates the clinical
and laboratory features of HCV infection in humans. Specifically, hepatic disease is milder in chimpanzees (Bukh et al., 2001) and a greater fraction of these animals spontaneously clear the virus (Bassett et al., 1998).
Chronic HCV infection in chimpanzees also does not generally result in
hepatic fibrosis or cirrhosis (Bukh et al., 2001), and chimpanzees, unlike
humans, fail to transmit HCV vertically from mother to infant (Zanetti et
al., 1995). Finally, chimpanzees mount weaker neutralizing antibody responses to HCV than humans (Su et al., 2002; Thimme et al., 2002). The
current pace of HCV drug development is testimony to the adequacy of
human subjects for most of this work.
Criteria 3: Impact of Forgoing Chimpanzee Use
Forgoing the use of chimpanzees will not significantly slow the development of new HCV antivirals. Many new classes of HCV antivirals
are already approved or in advanced clinical trials (Ilyas and Vierling,
2011). Progress in their development has been driven not by the availability of a chimpanzee model, but rather by the emergence of powerful in
vitro culture systems supporting production and spread of fully infectious
HCV virions and by the large number of HCV-infected patients who are
willing to participate in clinical trials. Additionally, new small animal
models are further reducing the need for chimpanzees in HCV antiviral
drug development (Dorner et al., 2011; Galun et al., 1995; Mercer et al.,
2001; Wu et al., 2005). As noted, the pharmaceutical industry is steadily

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moving away from the chimpanzee model for HCV drug discovery and
development.
Finding
The committee finds that chimpanzees are not necessary for HCV
antiviral drug discovery and development and does not foresee the future
necessity of the chimpanzee model in this area.
Therapeutic HCV Vaccine
Prevalence and Treatment Options
Approximately one out of every 30-50 persons in the world is chronically infected with HCV (WHO, 2011) but, encouragingly, 15-30 percent of humans acutely infected with HCV succeed in clearing the virus
(Wang et al., 2007). Many individuals exhibiting chronic HCV viremia
lack specific T cell responses to the virus, including production of interferon-γ (Cooper et al., 1999). This finding suggests it may be possible to
create a therapeutic HCV vaccine eliciting the type of missing immune
response required for a sustained viral response and viral clearance
(Houghton and Abrignani, 2005). A therapeutic vaccine would be given
to individuals already infected with HCV in contrast to a prophylactic or
preventive HCV vaccine that would be given to uninfected individuals
who are at risk for infection. By redirecting the immune response and
clearing the virus, a therapeutic vaccine could halt and potentially reverse progression of hepatic disease. A therapeutic vaccine also represents an attractive and cost-effective alternative to antiviral drugs in the
management of patients with chronic hepatitis C infection. It could be
particularly useful in patients who either are unable to tolerate interferonα or fail to respond to this cytokine. The intrinsic sequence variation of
HCV within each of its 6 recognized genotypes and more than 50 subtypes poses a major challenge to the successful development of a therapeutic HCV vaccine (Kurosaki et al., 1993).

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Criteria 1: Alternative Models
Because of its tropism and growth requirements, HCV infection in
vivo is limited to chimpanzees and humans. Small animal models involving implantation of human liver into immunodeficient mice (Galun et al.,
1995) or engineering wild-type mice to express HCV entry receptors on
hepatocytes (Dorner et al., 2011) have been developed. However, these
mouse models are currently not appropriate and will require additional
improvements for testing a therapeutic HCV vaccine where high-titer
HCV infection in an immunocompetent host is required. Currently,
chimpanzees and humans represent the only acceptable options for testing of an HCV therapeutic vaccine.
Criteria 2: Testing on Human Subjects
Subjects chronically infected with HCV are frequently used to test
therapeutic HCV vaccine candidates. Therapeutic vaccine candidates are
now being tested in humans without prior testing in the chimpanzee
model (Halliday et al., 2011). The fact that chimpanzees produce weaker
neutralizing antibody responses than humans (Thimme et al., 2002) and
fail to respond to interferon like many humans (Lanford et al., 2007) argues that humans might represent a better system for testing therapeutic
HCV vaccines.
Criteria 3: Impact of Forgoing Chimpanzee Use
The fact that therapeutic vaccine testing can be performed in consenting human subjects chronically infected with HCV without prior experimentation in chimpanzees indicates that forgoing the use of
chimpanzees would have little or no impact. It is possible that direct testing in humans might accelerate development of an efficacious therapeutic vaccine for HCV.
Finding
The committee finds that chimpanzees are not necessary for development and testing of a therapeutic HCV vaccine.

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Prophylactic HCV Vaccine
Prevalence and Treatment Options
HCV is an important cause of human disease—about 3.2 million
Americans are chronically infected with hepatitis C virus, mostly from
initial infections occurring years ago; however, there are about 17,000
new infections each year, according to the CDC (Williams et al., 2011).
The U.S. incidence has fallen dramatically over recent years, but the disease remains a major problem worldwide, with 130-170 million infected.
Persistent infection is common and can lead to liver fibrosis, cirrhosis,
and hepatocellular carcinoma; hepatitis C has become the most common
cause of liver failure and liver transplantation.
Rapid advances are being in made in the development of new therapeutics for subjects chronically infected with HCV, but an efficacious
prophylactic vaccine against this virus has not yet been produced. Creation of such a vaccine will be especially challenging because of the great
genetic and antigenic diversity manifested within HCV’s multiple genotypes, subtypes, and quasi-species (Halliday et al., 2011).
Chimpanzees are highly susceptible to experimental HCV infection—in
fact, the virus was initially identified by its transmission to chimpanzees,
followed by molecular methods to detect viral RNA in infected chimpanzee plasma. The unique tropism of HCV for chimpanzee and human
hepatocytes makes the chimpanzee model of experimental infection valuable for studies of pathogenesis, including mechanisms of persistence,
and for development and testing of prophylactic HCV vaccine candidates
by helping to identify those that are safe and efficacious.
The chimpanzee model could also provide important insights into the
correlates of immune protection (Strickland et al., 2008); however, research is proceeding on prophylactic HCV vaccine development in the
absence of testing in chimpanzees (Catanese et al., 2010; Garrone et al.,
2011). Although the determinants of protective immunity against persistent infection with multiple strains have not yet been defined, studies of
the outcome of vaccination and challenge of chimpanzees suggest that
immune responses to envelop glycoproteins are important for protection,
while responses to nonstructural proteins may be detrimental (Dahari et
al., 2010; Houghton, 2011). Both neutralizing antibodies and T cell responses are likely to be important (Choo et al., 1994; Folgori et al., 2006;
Meunier et al., 2011; Shoukry et al., 2003; Verstrepen et al., 2011). Of
note, interpretation of many of these studies is complicated by the use of

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small numbers of animals (Bettauer, 2010), coupled with the fact that
chimpanzees more effectively clear HCV infections than humans and are
less likely to develop hepatic fibrosis, cirrhosis, or hepatocellular carcinoma than humans (Bassett et al., 1998, 1999; Boonstra et al., 2009;
De Vos et al., 2002; Erickson et al., 2001; Thomson et al., 2003).
Criteria 1: Alternative Models
Chimpanzees and humans are the only two species that are susceptible to HCV infection. Currently, no other suitable animal models exist
for evaluation of a prophylactic HCV vaccine. Although progress is being made in the development of various mouse models that can be infected with HCV, these do not allow evaluation of the human protective
immune response against HCV. One model developed requires engraftment of human hepatocytes into the injured liver of an immunodeficient
mouse, so HCV infection can be established, but the mouse is not capable of an adaptive immune response (Bissig et al., 2010). A second model involves ectopic implantation of human liver tissue into an
immunocompetent mouse, so infection could theoretically occur, but any
immune response would be murine in origin (Chen et al., 2011a). In the
most recent model, transgenic mice have been engineered to express human HCV entry receptors, so infection can be established in an
immunocompetent mouse and immune-mediated protection evaluated,
but again, the immune response is murine (Dorner et al., 2011; Gewin,
2011). Likewise, no in vitro systems currently exist that display both
HCV infectivity and the capability of an effective anti-HCV adaptive
immune response. It is not known whether the recent identification of a
canine hepacivirus, which is closely related to HCV and causes respiratory disease (Kapoor et al., 2011), will provide an additional relevant animal model system for vaccine testing and development.
Criteria 2: Testing on Human Subjects
Studies in consenting humans at high risk for HCV infection can be
ethically performed to evaluate prophylactic HCV vaccine candidates,
provided these vaccines are first shown to be safe and immunogenic in
experimental animals such as mice and nonhuman primates. This type of
human study will ultimately be required for any prophylactic HCV vaccine to gain licensure for widespread use. These studies require large
numbers of subjects that are at increased risk of HCV infection. In de-

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veloped countries, most new infections occur in people who inject drugs,
a population that presents biological, methodological, and ethical challenges for vaccine trials (Maher et al., 2010).
One clear advantage offered by the chimpanzee model is the ability
to infect the animals at a precise time following administration of a vaccine candidate. This could facilitate identification of promising vaccines
and help define correlates of immunity and determine the durability of
protection. However, a truly efficacious HCV vaccine must provide
long-lasting protection within the human population, making such timing
less important.
Criteria 3: Impact of Forgoing Chimpanzee Use
While ethical prophylactic vaccine studies in high-risk human populations can and ultimately must be performed, such trials are likely to
prove challenging and time-consuming. Use of the chimpanzee HCV
model of experimental infection could potentially speed identification of
promising prophylactic HCV vaccine candidates for testing in humans,
though the FDA does not have policies requiring data from chimpanzees
for the development of any compound or vaccine (though will accept
such data if submitted). However, differences in the pathogenesis of
HCV infection in chimpanzees and humans with respect to immune responses, including weaker neutralizing antibody responses and higher
rates of spontaneous viral clearance in chimpanzees, must be considered
in judging the various vaccines. In addition, preclinical experiments using chimpanzees must be designed to include adequate numbers of animals for the generation of statistically meaningful results. Ongoing
research that is proceeding without using chimpanzees may avoid these
weaknesses, though such efforts are in their early stages.
Finding
The committee finds that while there are limitations to the current
chimpanzee preclinical model, it has provided valuable knowledge for
the development of prophylactic HCV vaccines. The committee is aware
of progress on non-chimpanzee models that can be infected with HCV.
Such models, if further improved, may reduce or obviate the need for the
continued use of the chimpanzee for prophylactic HCV vaccine research.
Moving directly to human trials in high-risk populations, without prior
testing in chimpanzees, can be ethically performed and could lead to the

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development of an HCV prophylactic vaccine. After consideration of all
of these facts, the committee was evenly split and unable to reach consensus on the necessity of the chimpanzee model, and on whether or how
much the chimpanzee model would accelerate or improve prophylactic
HCV vaccine development. Specifically, the committee could not reach
agreement on whether a preclinical challenge study using the chimpanzee model was necessary and if or how much the chimpanzee model
would accelerate or improve prophylactic HCV vaccine development.10
Comparative Genomics
Molecular genetics and comparative genomics hold enormous potential for developing biomedical therapies as well as for a more basic understanding of the origins of our own species. However, true genomic
advances require two components beyond genetic material: (1) phenotypes
10

As elaborated in the case study discussion, the committee could not agree on the necessity of the chimpanzee for research involving the development of a prophylactic HCV
vaccine. In summary, the disagreement centered on whether chimpanzee testing is a necessary step in the path to human trials of candidate vaccines.
Some members of the committee held the view that chimpanzees provide the only
available challenge model for testing a candidate vaccine and that without the use of
chimpanzees (1) important data regarding the immunogenicity, protective efficacy, and
safety of candidate vaccines would be foregone; (2) studies in populations of humans at
high risk of HCV infection are likely to be difficult based on population demographics
and currently available HCV treatment options; and (3) some candidate vaccines of limited promise might make their way into human trials, at the cost of additional time and
resources.
An equal number of committee members held the view that (1) rodent and other
rapidly-developing alternative models can provide sufficient immunogenicity and safety
data to proceed to human efficacy trials without the need for prior studies in chimpanzees, that chimpanzee data is not always predictive of vaccine toxicity or efficacy in humans, and that use of the chimpanzee model is frequently complicated by the lack of a
sufficient number of animals to generate statistically significant results; these committee
members felt that foregoing chimpanzee models may actually spur greater attention to
developing more tractable experimental alternatives; (2) studies in populations of humans
at high risk of HCV infection studies can be designed and carried out successfully; and
(3) the likelihood and length of any possible delay in vaccine development caused
by foregoing chimpanzee research is difficult to assess, and human trials are required
whether or not research proceeds using the chimpanzee during the course of vaccine
development.
It is important to note that there was a consensus among the committee that human
trials of candidate vaccines could be designed and performed ethically with or without
data from chimpanzee research.

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that can be linked to underlying genes, gene expression, or genetic processes; and (2) comparative studies across species to elucidate the origin
and potential impact of genetic variation. The sequencing of the chimpanzee genome (Mikkelsen et al., 2005) in addition to the mouse
(Waterston et al., 2002), the macaque (Gibbs et al., 2007), and other species, has shown that changes that set human beings apart from other species not only involve amino acid substitutions, but also to a large extent
relate to minor alterations in regulatory regions, gene transcription, and
gene expression (Marques-Bonet et al., 2009). However, the ability to
apply the new wealth of genomic and genetic information to health and
behavioral problems is impeded to the extent that developmental, physiological, behavioral, cognitive, and other phenotypic information is absent
for comparator species, especially the closest and in some ways most
informative taxon, the chimpanzee.
The development of advanced sequencing techniques provides access to another tool that investigators can use to further examine tissues
that are obtained either from biopsy or necropsy. For example, transcriptional assessment can be applied to tissues in chimpanzees with different
life histories and disease experience as well as to multiple tissues from
the same chimpanzee. Analysis of the resulting gene expression profiles
could greatly enhance our understanding of the biological pathways that
are activated among individuals that have been subjected to specific life
experiences and disease states. While such information is slowly becoming available from humans and other species, the systematic study of
gene expression in the current NIH-supported population of chimpanzees
may comprise an important source of biomedical and behavioral
knowledge. Moreover, the mechanisms underlying environmentally induced alterations in gene expression are also becoming better understood
and applied to chimpanzees. Specifically, epigenetic regulation of gene
expression through DNA methylation or histone modification can now
be readily evaluated in a wide variety of tissues and in blood. The general understanding of functional similarities and differences between
chimpanzees and human proteins will be informed by better understanding of the factors affecting epigenetic regulation of genes and the resulting patterns of gene expression in chimpanzees, as compared to humans.
Finally, insight through the examination of alternative splicing may also
yield valuable information. For example, 6-8 percent of the proteins they
examined exhibited profound differences in splicing between chimpanzees and humans and hypothesized that alternative splicing is an important source of the differences between humans and chimpanzees.

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Forkhead Box P2 Gene Function in Chimpanzees and Humans
Chosen here for case evaluation in comparative genomics is an investigation that uses material from chimpanzees and humans to evaluate
transcriptional regulation of the area of the central nervous system (CNS)
that appears to encode language development—the preeminent human
characteristic (Konopka et al., 2009). The human capacity to generate
spoken language and the ability to understand and apply language to
complex problems is a hallmark human feature, the origins of which remain relatively poorly known. Over the past several years, a number of
investigators have produced various types of data demonstrating that the
“forkhead box P2” or FOXP2 gene has important effects on the development of language skill (Enard et al., 2002). FOXP2 is a transcription
factor, a gene that codes for a protein that binds to DNA and functions by
turning on and turning off numerous other genes.
Furthermore, comparisons of the FOXP2 gene sequence in humans,
chimpanzees, and other primates indicate that the human FOXP2 gene
has undergone significant, rapid, and recent evolutionary change (Enard
et al., 2002). This pattern has led researchers to infer that changes occurring in FOXP2 in human ancestors—after their divergence from the ancestors of modern chimpanzees—may help explain the evolution of the
human capacity for language. Equally important from a biomedical perspective, mutations in FOXP2 have been associated with speech and language disorders (Lai et al., 2001; MacDermot et al., 2005).
Criteria 1: Studies Provide Otherwise Unattainable Insight
Using human neuronal cell lines that express either the human or
chimpanzee forms of FOXP2, the investigators examined the function of
the FOXP2 protein (Konopka et al., 2009). The results indicated that the
human form of the protein had significantly different effects on the expression of many other brain-expressed genes, compared with the chimpanzee form of FOXP2. In addition, the investigators examined RNA
isolated from both human and chimpanzee brains and showed that many
of the genes that were differentially regulated by human vs. chimpanzee
FOXP2 in the neuronal cell line were also differentially expressed in
normal intact brains. These data demonstrate that changes in the FOXP2
gene that occurred during human evolution (subsequent to our divergence from chimpanzees) significantly affect gene expression in the human brain, potentially underlying the obligatory nature of human

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symbolic abilities and language in comparison to the rudimentary abilities and opportunistic expression of the homologous skills in chimpanzees. In parallel, other investigators continue to examine the relationship
between FOXP2 and clinical speech and language disorders. Results confirm the hypothesis that the differences between chimpanzees and humans derive less from DNA sequence (i.e., amino acid substitutions)
than from differences in gene expression and regulation.
The study by Konopka et al. (2009) provides an informative example
of the unique insights that access to captive chimpanzee phenotypes,
genotypes, and tissue can provide on the gamut of research from comparative genomics to behavior and biomedical. No living animals were
required for this study, but it did require the following:
•

•
•

Well-defined genetic sequences from both humans and chimpanzees, which of course requires access to DNA from both species
as well as relatively complete information concerning the type
and source of genetic variation in each species;
Access to high-quality RNA samples from fresh chimpanzee
brains, which can then be compared with similar RNA samples
from human brains; and
Detailed information about the behavioral and cognitive capacities of chimpanzees.

This type of study fulfills the general requirement to produce fundamental knowledge. Moreover, it is clear that this type of study is only
possible because of the close phylogenetic relationship between humans
and chimpanzees, indicating that the material from the chimpanzees provides unique, otherwise unattainable information that not only elucidates
the origin of human symbolic communication, but sheds light on the
mechanisms that may contribute to developmental abnormalities in this
domain.
Criteria 2: All Experiments are Performed on Acquiescent Animals and
in a Manner that Minimizes Distress
Inasmuch as the study required access to resources that were originally collected from living animals (genetic material, behavioral and
cognitive phenotypes) or that required animals to have been alive (brain
tissue harvested appropriately from deceased animals for reasons unrelated to the study), the general criteria for species-appropriate housing,

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acquiescence to procedures, and minimal distress for manipulations
would have to be fulfilled by all animals while still alive. Importantly,
maintenance in complex, species-appropriate environments would be
particularly important for this type of investigation in order to maintain
the species-typical (“normal”) pattern of gene expression and gene regulation across the lifespan. Only in such circumstances is it likely that the
derived brain and ancillary tissue will comprise the appropriate controls
for the human tissues used in the same studies.
Finding
Given the information provided in the publication regarding the collection of material, the chimpanzee study used as this case example
meets the committee’s criteria regarding unattainable insight, acquiescence, and the minimization of pain and distress. Other examples of the
application of genomic tools to behavioral or neurobehavioral investigations include the collection of tissues (including blood) that can be sequenced to provide transcriptomes (gene expression profiles). These
transcriptomes, in turn, could be studied in relation to rearing experiences,
temperamental characteristics, neurobehavioral traits, and other
biobehavioral phenotypes to help characterize the relationship between
the chimpanzee genome and the life histories of individual animals. Each
such study would have to be assessed to determine whether it meets the
proposed criteria.
Altruism
Studying behavior of individual chimpanzees as well as groups of
animals provides insights into human behavior, thus informing scientific
understanding about the nature of humans. Through their investigation of
specific aspects of behavior, scientists are identifying characteristics in
chimpanzees that were once thought to be unique to humans, such as certain facets of intelligence and communication, and patterns of social relationships.
Altruism is among the most contentious areas in human behavioral
research. Although it has long been observed that people help each other,
sometimes at great risk to their own health or well-being, there is little
agreement concerning the evolutionary origin of this behavior and
whether it can be expected to occur in the absence of clear self-interest

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(Okasha, 2010). It is argued that studies of chimpanzees may be particularly relevant for addressing complex behaviors such as altruism because
of our shared evolutionary history and recent common ancestry. Even for
chimpanzees, however, disagreement remains over the degree to which
the animals are sensitive to the needs of conspecifics (Horner et al.,
2011).
Chosen here for a case evaluation is one study that attempts to determine whether chimpanzees actively choose to help others, and whether such help is spontaneous—and thus could be interpreted as reflecting
sensitivity to the needs of another animal—or is triggered by a solicitation from the partner (Horner et al., 2011). The study design involves
allowing chimpanzees to choose between two different tokens, a “selfish” token that provides a reward for the actor only, and a “prosocial”
token that rewards both the actor and a partner. Seven females were tested, each with three different partners. The actors demonstrated a significant overall bias for the prosocial token, but more so when the partner
either showed no reaction or engaged in neutral attention getting (not
directed at the actor); attempts to pressure the actor resulted in reduced
prosocial choice (Horner et al., 2011).
Criteria 1: Studies Provide Otherwise Unattainable Insight
The research objectives of the study question addressed clearly fall
within the broad NIH mission to “seek fundamental knowledge about the
nature and behavior of living systems” (NIH, 2011) and more specifically, meets the first criteria: to provide “otherwise unattainable insight into
evolution, normal and abnormal behavior, mental health, emotion, or
cognition.” The insights derive from the arguably close genetic relationship between chimpanzees and human beings and the substantial similarity in brain structure and complexity—a similarity that is much less
pronounced in monkeys (Sakai et al., 2011). The less complex brain
structures in other old worlds of monkeys result in a tendency toward a
simpler pattern of signaling and signal recognition. It was of particular
interest that, in this study, actors behaved prosocially toward their partners irrespective of relative social status, genetic relationship, or expectation of reciprocity. These results imply that human beings may have a
tendency to help other individuals unconditionally, at least when the help
can be given at no cost.

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Criteria 2: All Experiments Are Performed on Acquiescent Animals and
in a Manner That Minimizes Distress
In assessing the degree of acquiescence and distress on the part of
the subjects, the study reported that the seven adult female chimpanzees
“volunteered to participate and were willing to exchange tokens with an
investigator.” However, no details regarding the definition of “volunteer”
were given in the manuscript or the associated methodology. The study
did describe the conditions under which the animals were maintained.
Specifically, they were housed in a large outdoor grass enclosure with
climbing structures as part of a long-established social group comprising
11 females and one male. There were two associated buildings, one with
indoor sleeping quarters and a second building designed for cognitive
research testing. No details were provided on the dimensions of these
buildings.
Finding
This study involved temporary removal of animals from their usual
housing and social group to engage in a cognitive task paired with other
chimpanzees. The information provided suggests that chimpanzee use in
this study could meet all criteria if more complete descriptions of the
handling and housing were provided. Specifically, the investigators
would have to substantiate the statement that the animals “volunteered”
for the procedures, confirm that the indoor sleeping quarters were of sufficient size for the species, and demonstrate that the cognitive testing
apparatus would meet all enrichment requirements for this species.
This study exemplifies the numerous cognitive investigations that
have been done in chimpanzees. As a group, these studies have demonstrated that human cognitive abilities with respect to the manipulation of
the social environment extend to chimpanzees in a variety of domains
that include altruism, deception, and grief. Many such studies would be
similarly approvable under the proposed guidelines; in other instances
they might be limited if, for example, they provided unattainable insights
but did not meet the need for acquiescence and minimization of distress.

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Cognition
Joint attention occurs when one animal alerts another to the presence
of a stimulus by means of gestural or vocal communication. It is generally thought that a breakdown in the ability to initiate joint attention may
be a predictor for autism spectrum disorders or other neurodevelopmental disorders (Mundy et al., 2010). Unfortunately, knowledge of developmental mechanisms of joint attention are poorly understood because
some functional imaging techniques used in adults are difficult to administer to children while others, like positron emission tomography (PET),
cannot be administered without some risk to normal young subjects. The
chimpanzee has been used as a model organism to study the neurodevelopmental basis of joint attention and similar phenomena and to increase
the understanding of the development trajectory of human communicative phenomena. This is because, in humans, joint attention (including
both gestures and vocalization) is associated with hemispheric lateralization, particularly in the portion of the inferior frontal gyrus (IFG), termed
Broca’s area, and is thought to have evolved from a lateralized manual
communication system present in the common ancestor of humans and
chimpanzees (Corballis, 2002; Kingstone et al., 2000). Chosen here for
case evaluation is a PET study designed to determine whether chimpanzees possess a gesture and vocalization-activated brain region homologous with the IFG (Broca’s area), which in humans is most often
enlarged on the left side to indicate significant left-lateralized patterns of
activation during communication (Taglialatela et al., 2008). While it has
been previously shown that chimpanzees engage in joint communication
and exhibit structural asymmetry in the brain, it had not been demonstrated that the brain regions underlying joint attention were the same as
those underlying homologous communicative behaviors in humans. In
particular, it was not known whether the IFG and related cortical and
subcortical areas were preferentially activated during gestural or vocal
communication in the chimpanzee. The presence of similarly activated
underlying brain structures would suggest that chimpanzees could be
used to model human communication development.
Criteria 1: Studies Provide Otherwise Unattainable Insight
The forgoing description suggests that the study does fulfill the need
to provide fundamental knowledge gain. Moreover, because the chimpanzee and humans both uniquely share a highly convoluted and lateral-

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ized cerebral cortex and the ability to engage in joint attention, it is likely
to provide otherwise unattainable insight into the neurodevelopment of
communication and, by implication, communicative disorders. Furthermore, while the modern imaging modalities necessary to map neurodevelopment can be applied to both chimpanzees and adult human beings,
the application of these techniques to children is often limited by logistical and ethical considerations. Finally, even if all imaging techniques
(even those involving unacceptably high radiation exposure) could be
applied to children, the study of neurodevelopment would be arguably enhanced by the availability of a comparative model like the chimpanzee.
This study provided the first direct evidence that the neuroanatomical
structures underlying communicative signals in chimpanzees are homologous with those present in humans. Furthermore, chimpanzees engaging
in communicative gestures—like human beings—activated the left IFG
(Broca’s area) in conjunction with other cortical and subcortical brain
areas, providing strong evidence in support of the hypothesis that the
neurological substrates underlying language production in the human
brain were present in the last common ancestor of humans and chimpanzees.
Criteria 2: All Experiments Are Performed on Acquiescent Animals and
in a Manner That Minimizes Distress
Chimpanzees were initially separated from groupmates, but maintained within their home enclosure. The animals were then provided with
a sweetened drink that contained the radioligand 18F-fluorodeoxyglucose
(18F-FDG), which initiated a 40-minute uptake period, during which the
radioligand would bind to parts of the brain that were being activated by
the chimpanzee’s behavior. During the uptake period, the investigator
sitting outside the enclosure placed a favored food item just beyond
reach, a situation that predictably elicited both gestural and vocal signaling from subjects. Experimenters would periodically respond to subjects
with both vocal communication and small food rewards. At the end of
the 40-minute uptake period, chimpanzees received an intramuscular
injection of an anesthetic agent and were transported to the PET facility.
All animals had been previously trained with positive reinforcement to
present for such anesthesia. Following scanning, animals were allowed to
fully recover before being reintroduced to their social groups. It should
be noted that three chimpanzees were used in the study, and each animal
was scanned on two occasions—once following the gesture and vocaliza-

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tion task and separately following a control task that did not require
communicative interaction.
Review of the study indicates that it was conducted in a manner consistent with acquiescence. Animals voluntarily engaged in behavioral
testing during the awake part of the procedure (i.e., uptake) and, furthermore, were trained to present for anesthesia. As described in the study,
anesthesia persisted for about 50 minutes (transport to and from the PET
facility, PET scanning). Animals were allowed to recover (and
radioligands allowed to decay) for approximately 18 hours, after which
they were returned to their social group. It is important to note that this
study likely exposed the animals to more than “minimal” distress in that
animals were fasted for 5 hours prior to the procedure, sedated for at
least 50 minutes, and then were separated from their social groups to
allow recovery. The total time required for the manipulation was probably 28-32 hours. However, the effects of this amount of separation from
the social group and handling must be judged against the unique contribution made by the study and the small number of acquiescent animals
involved. It should be noted that a complete veterinary examination
would involve a similar if not longer period of fasting, social group separation, and anesthesia.
Finding
In view of the scientific benefits compared to the temporary negative
impacts on the animal subjects (separation and anesthesia), this study
could potentially meet all criteria for approval if sufficient additional
assurance were provided that the animals were maintained in speciesappropriate housing and groupings and that the number and duration of
procedures imposed on individual animals was minimized in a manner
consistent with criteria described earlier in this report.
FUTURE USE OF CHIMPANZEES IN BIOMEDICAL
AND BEHAVIORAL RESEARCH
As highlighted throughout this report, over many years scientific advances that have led directly to the development of preventive and therapeutic products for life-threatening or debilitating diseases and disorders
have been dependent on scientific knowledge obtained through experiments using the chimpanzee. In addition, many preliminary proof-of-

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concept experiments have been carried out in the chimpanzee; for example, development of human and humanized monoclonal antibody therapies have required preclinical testing in the chimpanzee (Iwarson et al.,
1985). The same has been the case for early evaluation of therapeutic
concepts based on RNAi, microRNA, and antisense RNA (e.g., for treating chronic HCV infection), and for evaluation of TLR7 antagonists
(e.g., for treating chronic HBV infection) (Lanford et al., 2011).
The National Institute of Allergy and Infectious Diseases at the NIH
has identified eight instances over the past two decades where research
on new (or newly recognized), emerging, and reemerging infectious diseases has called for use of the chimpanzee to answer crucial questions
pertaining to pathogenesis, prevention, control, or therapy. In five of these,
the chimpanzee is still being used.11 At the same time, as has been the
case rather often in the past, an important new, emerging, or reemerging
disease may present treatment, prevention, and/or control problems that
defy available alternative experimental approaches, including the most
novel, innovative approaches, and therefore may require use of the
chimpanzee—rare as this may be, this possibility cannot be discounted
over the long term. The committee recognizes that the limited number of
available animals and the potential need to perform experiments under
conditions of biocontainment could potentially constrain the value of the
chimpanzee during a public health emergency. The similarity in the
neuroanatomy between the human and the chimpanzee may make it a
model for neuropsychiatric disorders, for example, expressing human
risk genes via viral vectors or from optogenetic methods that exploit the
chimpanzee functional neuroanotomy.
However, in this case the past is not necessarily prelude—great progress is being made in developing alternatives to the chimpanzee; more
studies are using other non-human primates (Ben-Yehudah et al., 2010;
Couto and Kolykhalov, 2006; Pan et al., 2010; Suomi, 2006), genetically
modified (knock-out, knock-in) mice (Chen et al., 2011a; de Jong et al.,
2010; Dorner et al., 2011; Kneteman and Mercer, 2005; Lindenbach et
al., 2005; Ma et al., 2010; Ploss and Rice, 2009), and even in silico technologies (Hosea, 2011; Qiu et al., 2011; Valerio, 2011). In some instances, “preclinical studies” in humans, that is, expanded studies carried out

11
Encephalitozoon cuniculi; Helicobacter pylori; Hepatitis C (ongoing); Hepatitis E
(ongoing); Human herpesvirus 8 (ongoing); Human herpesvirus 6 (ongoing); Streptococcus, Group A; Staphylococcus aureus (ongoing) (NIAID, 2011).

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in the field during disease outbreaks, have served as an alternative to the
use of the chimpanzee.
Finding
The committee cannot predict or forecast future need of the chimpanzee animal model and encourages use of the criteria established in
this report when assessing the potential necessity of chimpanzees for future research uses.
CONCLUSIONS AND RECOMMENDATIONS
Animal models serve as a critical research tool in facilitating the advancement of the public’s health. The chimpanzee’s genetic proximity to
humans and the resulting biological and behavioral characteristics not
only make it a uniquely valuable species for certain types of research, but
also demand a greater justification for conducting research using this
animal model. As this report demonstrates, the committee’s conclusions
and recommendations are predicated on the advances that have been
made by the scientific community in developing and using alternative
models to the chimpanzee, such as studies involving human subjects,
other non-human primates, genetically modified mice, in vitro systems,
and in silico technologies. Having reviewed and analyzed contemporary
and anticipated biomedical and behavioral research, the committee offers
the following three conclusions and two recommendations.
Conclusion 1: Assessing the Necessity of the Chimpanzee for Biomedical
Research
Having explored and analyzed contemporary and anticipated biomedical research questions, the committee concludes:
• The chimpanzee has been a valuable animal model.
• Based on a set of principles that ensure ethical treatment of
chimpanzees, the committee established criteria to determine the
necessity for the use of chimpanzees in current biomedical or
behavioral research.
• While the chimpanzee has been a valuable animal model in past
research, most current use of chimpanzees for biomedical re-

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search is unnecessary, based on the criteria established by the
committee, except potentially for two current research uses:
o

•
•
•

•

Development of future monoclonal antibody therapies will
not require the chimpanzee, due to currently available technologies. However, there may be a limited number of monoclonal antibodies already in the developmental pipeline that
may require the continued use of chimpanzees.
The committee was evenly split and unable to reach consensus on the necessity of the chimpanzee for the development
of a prophylactic HCV vaccine. Specifically, the committee
could not reach agreement on whether a preclinical challenge
study using the chimpanzee model was necessary and if or
how much the chimpanzee model would accelerate or improve prophylactic HCV vaccine development.

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3. Forgoing the use of chimpanzees for the research in question will
significantly slow or prevent important advancements to prevent,
control, and/or treat life-threatening or debilitating conditions.
Animals used in the proposed research must be maintained either in
ethologically appropriate physical and social environments or in natural habitats. Biomedical research using stored samples is exempt
from these criteria.
Conclusion 2: Assessing the Necessity of the Chimpanzee for
Comparative Genomics Research
Having reviewed comparative genomics research, the committee
concludes the chimpanzee may be necessary for understanding human
development, disease mechanisms, and susceptibility because of the genetic proximity of the chimpanzee to humans. Furthermore, comparative
genomics research poses minimal risk of pain and distress to the chimpanzee in instances where samples are collected from living animals and
poses no risk when biological materials are derived from existing samples. Application of the committee’s criteria would provide a framework
to assess scientific necessity to guide the future use of chimpanzees in
comparative genomics research that requires samples collected from living animals.
Conclusion 3: Assessing the Necessity of the Chimpanzee for Behavioral
Research
Having explored and analyzed contemporary and anticipated behavioral research questions, the committee concludes that chimpanzees may
be necessary for obtaining otherwise unattainable insights to support understanding of social, neurological, and behavioral factors that include
the development, prevention, or treatment of disease. Application of the
committee’s criteria would provide a framework to assess scientific necessity to guide the future use of chimpanzees in behavioral research.

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Recommendation 2: The National Institutes of Health should limit
the use of chimpanzees in comparative genomics and behavioral research to those studies that meet the following two criteria:
1. Studies provide otherwise unattainable insight into comparative
genomics, normal and abnormal behavior, mental health, emotion, or cognition; and
2. All experiments are performed on acquiescent animals, using
techniques that are minimally invasive, and in a manner that
minimizes pain and distress.
Animals used in the proposed research must be maintained either in
ethologically appropriate physical and social environments or in natural habitats. Comparative genomics and behavioral research using
stored samples are exempt from these criteria.
The criteria set forth in the report are intended to guide not only current research policy, but also decisions regarding potential use of the
chimpanzee model for future research. The committee acknowledges that
imposing an outright and immediate prohibition of funding could cause
unacceptable losses to research programs as well as have an impact on
the animals. Therefore, although the committee was not asked to consider how its recommended policies should be implemented, it believes that
the NIH should evaluate the necessity of the chimpanzee in all grant renewals and future research projects using the chimpanzee model based
on the committee’s criteria.
In March 1989 the NIH chartered the Interagency Animal Model
Committee (IAMC) “to provide oversight of all federally supported
biomedical and behavioral research involving chimpanzees” (NIH,
unpublished). As indicated in its charter:
The IAMC review mechanism represents a commitment to the public and the U.S. Congress to promote the
conservation and care of chimpanzees when this species
is the best or possibly the only model for the conduct of
research to advance scientific knowledge and to address
questions that have significant impact on public health.
The IAMC shall review all federally-supported research protocols involving the use of chimpanzees before the initiation of the study. Prior to this review, the

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project must be reviewed and approved by intramural
scientific program staff or an extramural initial review
group and by the appropriate Animal Care and Use
Committee. The IAMC’s evaluation constitutes an additional level of scientific review, focusing on such factors
as the appropriateness of the animal model, appropriateness of the numbers of animals, the availability of the
animals, the degree of invasiveness of the procedures,
and any unnecessary duplication. (NIH, unpublished)
Appointment of the IAMC is evidence that the NIH has determined
that the conservation and care of chimpanzees requires additional oversight. Membership on the Interagency Animal Model Committee is restricted to federal employees from the Department of Health and Human
Services (including the NIH, CDC, and FDA), Department of Veterans
Affairs, and Department of Defense. The committee believes that assessment of potential future use of the chimpanzee would be strengthened and the process made more credible by establishing an independent
oversight committee that uses the recommended criteria and includes
public representatives as well as individuals with scientific expertise,
both in the use of chimpanzees and alternative models, in areas of research that have the potential for chimpanzee use.

Chimpanzees in Biomedical and Behavioral Research: Assessing the Necessity

A
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B
Commissioned Paper: Comparison of
Immunity to Pathogens in Humans,
Chimpanzees, and Macaques

The following paper was commissioned by the Committee on the Use of
Chimpanzees in Biomedical and Behavioral Research. The responsibility
for the content of this paper rests with the authors and does not necessarily represent the views of the Institute of Medicine or its committees
and convening bodies.
By: Nancy L. Haigwood, Ph.D.
Professor of Microbiology and Immunology
Director
Oregon National Primate Research Center
Christopher M. Walker, Ph.D.
Professor of Pediatrics
Nationwide Children’s Hospital
The Ohio State University

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INTRODUCTION
The purpose of this white paper is to compare genetic and functional
features of immunity and the response to infection in humans and major
nonhuman primate species currently used in biomedical research. The
search for appropriate disease models has been stimulated by the need to
understand the most intractable of the persistent and lethal pathogens, as
well as chronic diseases and conditions that are determined by the genetic makeup of the individual. Because the outcome of infection is governed by carefully coordinated innate and adaptive immune responses,
and pathogens have evolved strategies to evade these defenses, use of
animal models that recapitulate key features of human infection is critical. Successful nonhuman primate models closely emulate human immunity, inflammation, and disease sequelae. They can also provide a
critical pathway to clinical testing of risky prevention or treatment strategies for serious human diseases.
Some past successes of infectious diseases research in nonhuman
primates are described. However, the primary objective of the paper is to
identify conditions that either support or limit use of these animals for
the study of human viral, bacterial, or parasitic infections. A survey of
the published literature reveals that the common chimpanzee (Pan troglodytes) is the only great ape used in infectious disease research. With
few exceptions there is usually no alternative, because lower species are
not permissive for infection or fail to replicate key features of disease.
Most studies involve very small numbers of chimpanzees to ensure safe
translation of vaccines or therapeutics to humans, or provide incontrovertible evidence for basic mechanisms of immune control and evasion
that cannot be obtained in human subjects. Various monkey species, primarily the Asian macaques (Macaca species), have served as models for
infection with human viruses and microbes. Alternatively, monkey pathogens like the simian immunodeficiency viruses (SIV) provide a reliable
model of human infection with closely related viruses like human immunodeficiency virus (HIV). Infection studies with human and monkey viruses have facilitated advances in vaccine development and studies of
immunity and pathogenesis relevant to humans.
Sequencing of the human, chimpanzee, and macaque genomes has
provided unprecedented insight into the evolutionary relationship between these species, especially for genes that regulate host defense and
susceptibility to infection. Here we also provide examples of gene families involved in immunity that have been largely conserved since specia-

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APPENDIX B

tion, and others that have undergone rapid evolution because of selective
pressure by infectious diseases. How these adaptive changes might affect
modeling of human infectious diseases in monkeys and great apes is discussed. Contemporary examples of primate infectious disease models
that replicate most if not all features of human infection and immunity
are provided. Where infection models are not perfectly matched in humans and nonhuman primates, differences have provided insight into key
features of the relationship between the pathogen and its human host.
Finally, several practical advantages of nonhuman primate models
are also reviewed. The include the ability to (1) infect with clonal or genetically modified pathogens, (2) modify the immune response to identify protective mechanisms, (3) sample at the earliest times after infection,
often before symptoms are apparent in humans, and (4) access organs or
tissues that are the primary site of infection. The latter is particularly important because blood, which is often the only compartment available for
human sampling, may not adequately reflect immunity at the site of infection. Advances in adapting the most sophisticated technologies to
nonhuman primates, including methods to monitor immunity, and understand molecular aspects of infection using genomic and proteomic approaches, has the potential to provide new insight into vaccination and
infection with known and emerging pathogens.
CHIMPANZEES
Historical and Current Examples of Human Infectious Disease
Research in Chimpanzees
Chimpanzees have been used for over 100 years to model human viral, bacterial, and parasitic infections. This long history has revealed that
chimpanzees are often uniquely permissive for infection with some medically important human pathogens. These animals can also provide a
more faithful model of human disease than lower nonhuman primates.
Studies in chimpanzees, particularly with hepatotropic viruses, have provided critical insight into host defense mechanisms and facilitated development of vaccines that have changed global public health. Yet for other
pathogens key features of immunity and infection outcome differ between humans and chimpanzees. In these instances, the host-pathogen
interaction is influenced by adaptations that are species-specific despite a
strikingly close genetic relationship.

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The promise and limitations of chimpanzees as an infectious disease
model were first recognized in a 1904 publication from Albert Grunbaum
who transmitted the Eberth-Gaffky bacillus (Salmonella typhi) to two
animals (Grunbaum, 1904). The bacillus, isolated 10 years earlier, was
the suspected cause of enteric fever. Efforts to satisfy Koch’s third postulate by transmission of disease to rats, rabbits, and monkeys had failed.
Infection of chimpanzees was successful, but with much milder disease
symptoms than expected. The author noted “the virulence of my cultures
was not sufficient to produce a fatal result in the two instances in which
they were given the opportunity to do so” (Grunbaum, 1904). That the
chimpanzee might not be suitable for S. typhi vaccine development was
highlighted in a 1914 publication (Nichols, 1914). The author, a proponent of a killed vaccine, critiqued an earlier study where such an approach had failed. “The authors found that a whole killed vaccine did not
protect chimpanzees. But they used tremendous infecting doses—the
contents of a whole Kolle flask. The problems must be settled, as some
of them already have been settled, by actual experience with large numbers of men kept under close observation” (Nichols, 1914).
Infectious disease research involving chimpanzees published in the
last 30-40 years fits into three broad categories. They include (1) identification and characterization of infectious agents that are serious public
health threats; (2) characterization of protective immunity and how it is
subverted; and (3) development of strategies to prevent or treat human
infections. All published experimental infection studies used human
pathogens and not closely related (and thus potentially different) chimpanzee pathogens as a model. Here, factors that determine the suitability
of chimpanzees for research on infectious diseases are reviewed. Malaria, respiratory syncytial virus (RSV), HIV, and the hepatitis viruses are
used as case studies.
Malaria
Malaria vaccine research is made difficult by complexities of the
parasite life cycle and selection of antigens to either interrupt transmission of infection or protect from disease after a mosquito bite (Good and
Doolan, 2010). That irradiated P. falciparum sporozoites prevent disease
was established several decades ago, but this approach is not easily
scaled for human vaccination (Hoffman and Doolan, 2000). A small pilot
study demonstrating protection of chimpanzees by a recombinant liver
stage antigen derived from the sporozoites (Daubersies et al., 2000,

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APPENDIX B

2008) laid the foundation for a recent human clinical trial of this concept
(ClinicalTrials.gov NCT00509158). Nevertheless, malaria is exceptional
because human challenge studies are permissible and studies in lowerorder species can provide guidance for vaccine development. Many malaria trials that are either underway or completed involved parasite challenge of vaccinated human volunteers followed by co-artemether
eradication therapy if necessary (as an example see Porter et al., 2011).
Recent studies have also included sophisticated analyses of humoral and
cellular immune responses with goal of identifying protective correlates
in human volunteers (Good, 2011). While chimpanzees have been used
sparingly to date, there is increasing concern that no successful vaccine
has emerged from the concepts tested to date. If progress requires identification of new antigens and a better understanding of immunity, especially in the liver (Good, 2011), the place of the chimpanzee in malaria
research may be reconsidered.
Chimpanzees have also been critically important for the in vivo generation of malaria parasites that are recombinants between drug-resistant
and drug-sensitive strains in order to map drug resistance genes and
thereby better understand the metabolism of these pathogens and to develop improved drugs. Several studies that used parasites generated by
this approach have been published recently (Hayton et al., 2008;
Nguitragool et al., 2011; Sa et al., 2009).
Respiratory Syncytial Virus
RSV was first isolated from captive chimpanzees with upper respiratory tract disease (Blount et al., 1956) but was quickly identified as a
human virus (Chanock and Finberg, 1957; Chanock et al., 1957). It is
now recognized as the most important viral agent of severe respiratory
tract disease in infants and children worldwide (Hall et al., 2009; Nair et
al., 2010). RSV is also an important cause of morbidity and mortality in
the elderly and in profoundly immunosuppressed individuals. Protection
of vulnerable infants and young children from severe airway disease by a
licensed monoclonal antibody against the RSV F protein, as well as the
protection in the general population afforded by prior infection, suggests
that active vaccination is also feasible (Graham, 2011). Progress over the
past 4 decades was slowed by an unfortunate clinical trial of a formalin
inactivated RSV vaccine that worsened disease and resulted in two
deaths upon natural infection with the virus (Kapikian et al., 1969).
There is a general consensus that the vaccine failed to induce potent neu-

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tralizing antibody responses, provoked heightened lymphoproliferative
responses, and was associated with eosinophilia and immune complex
deposition in airways. Rodent and monkey models have demonstrated
Th2 responses and eosinophilia using formalin-inactivated vaccines, but
the precise mechanisms of immunopathogenesis remain undefined (reviewed in Graham, 2011). With the failure of this killed vaccine, development of live-attenuated RSV vaccines was initiated.
Chimpanzees are the only experimental animal in which RSV replication and pathogenicity approach that of humans. Small numbers of
chimpanzees were used to demonstrate the safety of live-attenuated vaccines as well as identifying candidates that were sufficiently attenuated to
move forward into clinical trials (e.g., Clinicaltrials.gov NCT00767416)
(Crowe et al., 1993, 1994; Teng et al., 2000; Whitehead et al., 1999).
Importantly, the body temperature of the chimpanzee is the same as that
of humans. Other available nonhuman primates have higher body temperatures and so chimpanzees are uniquely suited for pre-clinical evaluation of temperature-sensitive vaccine candidates, which comprise all of
the candidates evaluated in clinical trials to date. In addition, the chimpanzee experiments added to a body of evidence that both live attenuated
vaccines and vectored vaccines are not associated with enhanced disease.
A series of clinical trials have been initiated in infants and young children to evaluate safety, attenuation, and immunogenicity of several live
RSV vaccines (for instance, see ClinicalTrials.gov NCT00767416). It is
too soon to know if live RSV vaccines that are sufficiently attenuated to
be well tolerated in young infants (Karron et al., 2005) will be sufficiently immunogenic to prevent severe RSV disease. Alternate approaches
involving recombinant viral vectors (such as attenuated parainfluenza
virus type 3; see ClinicalTrials.gov NCT00686075), virus-like particles
(ClinicalTrials.gov NCT01290419), and subunit proteins are at various
stages of development and evaluation. RSV subunit vaccines are considered unsuitable for use in RSV-naïve individuals, based on studies in
mice, cotton rats, and African green monkeys. However, the evolutionary
distance relative to humans, reduced permissiveness to RSV replication,
and lack of disease may limit the predictive value of these models
(Graham, 2011). Until the significant medical need for an RSV vaccine is
fully met, it is difficult to exclude the possibility that chimpanzees will be
required to answer questions about mechanisms and duration of immune
protection and disease potentiation.

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APPENDIX B

The Human Immunodeficiency Virus
Susceptibility of chimpanzees to persistent HIV infection was first
reported in 1984, a little more than 1 year after discovery of the virus
(Alter et al., 1984). Successful infection of two animals, and persistence
of lymphadenopathy for several weeks in one of them, suggested that the
chimpanzee would be valuable for further studies of acquired immune
deficiency syndrome (AIDS) (Alter et al., 1985). This study, and all other early studies of immunity and vaccine development, used viruses like
HIVIIIb and HIVSF2 that adapted in culture to use CXCR4 as a co-receptor
for cell entry. These viruses did initiate infection in chimpanzees, but
viremia was usually low or short-lived and immunodeficiency was not
observed (with one notable exception described below). Several studies
of the early studies with CXCR4 adapted viruses nonetheless provided
insight into the nature of antiviral immunity in infected chimpanzees
(Nara et al., 1987), including the development of neutralizing antibodies
(Prince et al., 1987), proliferative responses, and lack of CD4+ T cell impairment (Eichberg et al., 1987). Important advances were made in understanding mucosal routes of HIV-1 transmission using chimpanzees
(Fultz et al., 1986), as well as the now better-appreciated issue of
superinfection (Fultz et al., 1987). Some success in protecting animals
from infection with the CXCR4-dependent HIV strains was achieved by
active and passive vaccination. Sterilizing immunity was induced by
immunization with recombinant subunit envelope glycoproteins, but only
with the CXCR4-utilizing virus HIVIIIB matched to the envelope
immunogen (Berman et al., 1988). The vaccine was not fully protective
when a different strain belonging to the same subtype, HIVSF2, was used
(El-Amad et al., 1995). Passive transfer of HIVIG at a higher dose eventually showed protection against HIVIIIB (Prince et al., 1991), as did one
of the first neutralizing monoclonal antibodies directed against the HIV
envelope (Emini et al., 1990). The interpretation of vaccine and antibody-based protection work in chimpanzees was complicated by the observation that chimpanzees were mostly resistant to infection with
primary human HIV isolate that required the CCR5 chemokine receptor
for cell entry. This discovery brought pause to the vaccine field, since
none of the vaccines in testing could elicit neutralizing antibodies against
the primary isolates that required CCR5 for infection. Later attempts to
block infection using a human monoclonal against a primary HIV-1 challenge were also less successful, though they showed some effect in reducing acute phase viremia (Conley et al., 1996).

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Notably, one chimpanzee did develop immunodeficiency after more
than a decade of subclinical infection with two prototype strains of
CXCR4-adapted HIV (Novembre et al., 1997). Isolation of a pathogenic
virus from this animal sparked a debate on the role of chimpanzees in
HIV vaccine research. Specifically, it was proposed that a pathogenic
virus could facilitate a direct test of vaccines designed to slow CD4+ T
cell loss and immunodeficiency, if not infection (Cohen, 1999; Letvin,
1998). Vaccinated chimpanzees were never challenged with this virus in
the face of persuasive ethical and scientific arguments (Cohen, 1999;
Prince and Andrus, 1998). From the scientific perspective, there was
considerable doubt about whether very rapid CD4+ T cell loss observed
after transmission of the virus to new animals was representative of human disease. Moreover, because immunodeficiency was not a consistent
finding, there were also practical concerns with design of a study involving two or three animals per group. These experimental infections with
the pathogenic HIV strain were perhaps the last conducted at a primate
research facility in the United States. No new HIV infection studies in
chimpanzees have been published in the past decade.
Studies on the origin of human HIV infection are beginning to yield
insight into a host-virus relationship so finely tuned that it cannot be recapitulated in an animal with 99 percent genetic identity. It is now apparent that HIV originated from a chimpanzee simian immunodeficiency
virus (SIVcpz) introduced into human populations by zoonotic infection
at least three times since the beginning of the 20th century (Keele et al.,
2009a). Most simian retroviruses, including those from monkeys, are
restricted from growth in human cells by species-specific factors (see
section below on Monkey-human models of infection). SIVcpz is no exception, as Vpu and Nef proteins had to adapt to neutralize human
tetherin, a protein that is induced by interferon and restricts virus release
from infected cells (Lim et al., 2010; Sauter et al., 2009). Adaptations
like this one may explain attenuation of HIV infectivity for chimpanzees
and perhaps limit its value as a model for vaccine development.
The Hepatitis Viruses
Chimpanzees are currently used to study the host response to four
hepatitis viruses (HAV, HBV, HCV, and HEV) and to develop or refine
approaches for prevention and treatment of the liver disease that they
cause. Prevention and treatment of transmissible hepatitis in humans has
been a public health priority for over 60 years. Progress toward isolation

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APPENDIX B

of the agent(s) responsible for the disease burden was slow, in part because hepatotropic viruses are fastidious and not easily propogated in cell
culture. By the 1960s there was strong clinical, epidemiological, and
immunological evidence for two distinct forms of transmissible hepatitis
in humans (Krugman and Giles, 1972). Type A (or infectious) hepatitis
had a short incubation period and was self-limited. Type B (or serum)
hepatitis had a longer incubation period and was characterized by the
prolonged presence of the Australia antigen (hepatitis B surface antigen;
HBsAg) in serum. Use of chimpanzees in hepatitis research predated the
discovery of the viruses that caused type A and B hepatitis. Sporadic
outbreaks of liver disease in chimpanzee colonies with occasional zoonotic transmission indicated that the animals might be susceptible to infection with human viruses (Maynard et al., 1972a). Transmission of type A
(Dienstag et al., 1975; Maynard et al., 1975) and B (Barker et al., 1973;
Maynard et al., 1972b) hepatitis to chimpanzees facilitated characterization of both viruses and rapid development of diagnostics and highly effective vaccines. Chimpanzee research provided critical proof that HBV
infection was preventable by vaccination with HBsAg purified from the
serum of human carriers (Buynak et al., 1976a, 1976b; Purcell and Gerin,
1975), and for the transition to a safer recombinant subunit vaccine
(McAleer et al., 1984). Attenuated and inactivated vaccines were also
shown to prevent HAV infection of chimpanzees (Feinstone et al., 1983;
Provost et al., 1983; Purcell et al., 1992). The principle that a vaccine can
prevent disease when administered as post-exposure prophylaxis was
also established using HAV-infected chimpanzees (Purcell et al., 1992).
Universal childhood vaccination against HAV and HBV is now recommended in the United States.
Chimpanzees were also critically important to the discovery of the
agent causing a third major form of human hepatitis. Studies published in
1975 concluded that unidentified type C hepatitis virus(es) were responsible for post-transfusion hepatitis in subjects not infected with HAV or
HBV (Feinstone et al., 1975; Prince et al., 1974). The infectious nature
of non-A, non-B hepatitis was not established by experimental transmission of liver disease to uninfected humans, an approach used to define
features of type A and B hepatitis in the highly controversial
Willowbrook experiments (Krugman, 1986). Instead, evidence that the
disease was caused by a small, enveloped RNA virus was obtained by
physico-chemical analysis of patient serum that transmitted persistent
hepatitis to chimpanzees (Alter et al., 1978; Bradley et al., 1983, 1985;
Tabor et al., 1978). Serum that was titrated and serially passaged in

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chimpanzees provided the pedigreed material from which the HCV genome was eventually cloned as described in 1989 (Choo et al., 1989).
All four hepatitis viruses remain significant public health problems
today. A box summarizing research objectives of contemporary hepatitis
virus research using chimpanzees is provided (Box 1). As described in
detail below, HAV, HBV, HCV, and HEV all cause robust infection in
chimpanzees. These viruses can cause the same spectrum of liver disease
observed in humans, although in both species most infections tend to
clinically mild and/or slowly progressive.

BOX 1
Major Uses of Chimpanzees in Infectious Disease Research
•

Characterize and identify new infectious agents, especially those that
cannot be propagated in lower species or cell culture.

•

Define mechanisms of protective innate and adaptive immunity and
pathogen evasion strategies. This is particularly important in settings
where early phases of acute infection are not easily identified in
humans, or infected tissues are not accessibly for studies of immunity.

•

Establish that new concepts for vaccination or therapy of infection are
safe and effective before translation to humans.

•

Determine if reagents critical to development of therapeutics like clonal
viruses or parasites replicate in a host closely related to humans.

Enteric Hepatitis Viruses
HAV and HEV cause acute hepatitis and self-limited infection in
humans and chimpanzees. Although liver disease may be somewhat
milder in chimpanzees, the kinetics and magnitude of virus replication,
onset of liver disease, and histopathological changes in the liver are similar to those in HAV-infected humans (Dienstag et al., 1975, 1976). The
course of HEV infection in chimpanzees is variable, ranging from low
viremia with no obvious liver disease to high viremia with biochemical
and histological evidence of hepatitis (Li et al., 2006; McCaustland et al.,
2000). This may be similar to the spectrum of disease in HEV-infected
humans (McCaustland et al., 2000). HAV and HEV infections are preventable by vaccination. The efficacy of a subunit HEV vaccine was ap-

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APPENDIX B

101

proximately 90 percent in two large human trials in Nepal and China, but
there is uncertainty about the durability of protective immunity as currently formulated and how (or if) it will be deployed where needed
(Shrestha et al., 2007; Wedemeyer and Pischke, 2011; Zhu et al., 2010).
Thus it is likely that endemic and epidemic HEV will remain a cause of
serious liver disease in developing countries (Aggarwal, 2011). HEV
immunity and pathogenesis are still very poorly understood (Aggarwal,
2011). For HAV, socioeconomic development accompanied by improved
sanitation and opportunity for vaccination has changed epidemiology in
regions where the virus is still endemic, as illustrated by a recent outbreak in South Korea (Kim and Lee, 2010; Kwon, 2009). Under these
circumstances, HAV infection shifts from the first to the second and third
decades of life with an associated increase in the severity of disease. This
situation has highlighted a gap in knowledge about mechanisms of immunity and hepatocellular injury caused by HAV. Very recent studies in
chimpanzees provided insight into patterns of innate immunity and host
gene expression immediately after infection with HAV and HEV, with
the goal of understanding the pathogenesis of these infections and how
they compare to responses elicited by HCV that often establishes a persistent infection (Lanford et al., 2011; Yu et al., 2010a). Follow up studies of adaptive immunity to these viruses in animals should be
anticipated. Similar studies in humans will be difficult, if not impossible,
because infections with these small RNA viruses are often not symptomatic for several weeks and access to liver may be challenging as there is
typically no medical need for liver biopsy.
HBV Worldwide, approximately 500 million people are infected with
HBV. Hepadnaviruses are widespread in nature and chimpanzees do harbor indigenous strains of HBV that can be distinguished from human
viruses based on genomic signatures despite overall identity of about 90
percent (Barker et al., 1975a, 1975b; Dienstag et al., 1976; Guidotti et
al., 1999; Hu et al., 2000; Rizzetto et al., 1981). Chimpanzees are nevertheless highly susceptible to challenge with human HBV. Chimpanzees
develop persistent and resolved infections after challenge with the virus
(Barker et al., 1975a, 1975b). The incubation period preceding symptoms
is long and biochemical evidence of acute hepatitis is associated with
parenchymal inflammation, as in man. The magnitude and general pattern of viremia and antigenemia during the acute and chronic phases of
infection are also similar between the species (Barker et al., 1975a,
1975b; Kwon and Lok, 2011). Severe progressive hepatitis and cirrhosis

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observed in some humans appears to be uncommon in chimpanzees. Implementation of universal HBV immunization will gradually reduce the
number of human infections in future decades, but there is a current need
for therapies to control this chronic condition. Nucleoside analog inhibitors of the HBV polymerase that suppress production of infectious virus
have been available for years but do not cure infection. Because the HBV
genome cannot be eradicated from the liver, most individuals require
life-long therapy (Kwon and Lok, 2011). The problem of HBVresistance to direct-acting antivirals is increasing, and will probably accelerate in regions where treatment practice and availability of highquality pharmaceuticals of required potency are inadequate (Kwon and
Lok, 2011). Immunotherapy to reactivate effective immunity against
HBV is an alternative (Rijckborst et al., 2011). A finite course of type I
interferon can reverse immune tolerance in about 30 percent of chronically infected patients, conferring long-term control of HBV infection
(Rijckborst et al., 2011). As discussed below, new and perhaps more effective approaches to reverse immune tolerance are being considered for
chronic viral hepatitis.
Contemporary research in HBV-infected chimpanzees addresses
questions that are highly translational to humans. As for HCV, the animals provide a way to develop titered pools of monoclonal HBV for vaccine and related studies (Asabe et al., 2009). These animals were also
used to determine if resistance mutations that arise during antiviral therapy facilitate escape from vaccine protection (Kamili et al., 2009). In this
study, chimpanzees vaccinated with a commercial HBV vaccine were
challenged with a virus containing mutations in key neutralization
epitopes of HBsAg caused by development of lamivudine in the viral
polymerase gene that is encoded in an overlapping but alternate reading
frame (Kamili et al., 2009). Lamuvidine-resistant variants now circulate
in some human populations, so this experiment addressed an important
public health problem.
HCV For HCV, there is no vaccine to prevent infection and therapies
remain inadequate despite recent progress in developing direct-acting
antivirals that target key replicative enzymes of the virus. It should be
emphasized that acute infections sometimes resolve spontaneously and
chronic infections can be cured. For these reasons, vaccination to prevent
persistence is more realistic than for HIV, even though both viruses present similar challenges in their adaptability to immune pressure. Similarly, the goal of effective therapy is to eradicate the virus rather than

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simply control chronic infection as in HIV and HBV. Chimpanzees are
the only species other than humans with known susceptibility to HCV
infection. No chimpanzee homolog of HCV has been found and closely
related viruses that consistently cause a similar pattern of resolving and
persistent infection have not been described in other species. Only chimpanzees have the correct combination of four entry receptors and other
cellular co-factors required to recapitulate key features of human infection. Woodchucks and old- and new-world monkeys tested to date are
not susceptible to infection (Bukh et al., 2001). HCV infection of a tree
shrew (Tupaia belangeri) has been reported, but viremia was intermittent
and several orders of magnitude less than that measured in chimpanzees
and humans (Amako et al., 2010). HCV infection can either resolve
spontaneously or persist in humans and chimpanzees. The typical pattern
of virus replication is identical, with high levels of viremia for at least 712 weeks followed by a decline that is usually associated with a spike in
serum transaminases (Abe et al., 1992; Thimme et al., 2002; Walker,
2010). Virus can fluctuate at low levels for several weeks or months before the infection resolves or persists (Walker, 2010). One study reported
a lower rate of chronic infection in chimpanzees (40 percent) than humans (60-70 percent) (Bassett et al., 1998), although there is not unanimity on this point. It is difficult in a retrospective chart review to exclude
the possibility that some animals thought to be naïve at the time of HCV
challenge were already immune because of prior exposure to unscreened
human blood products. At least some of the difference may also be explained by over-estimation of virus persistence in humans because acute
resolving infections that are clinically silent or mild are missed. Differences related to the young of age of infection in most chimpanzees, and
the dose or strain of virus used for experimental challenge, are also possible. If the rate of persistence is lower, it has had no apparent impact on
interpretation of studies on immunity to HCV in chimpanzees, or relevance of the findings to human infection (reviewed below). Liver disease
is typically mild in persistently infected chimpanzees, as it is in most
humans with chronic hepatitis C. More serious liver disease may become
evident after several decades. Late-stage disease, including hepatocellular carcinoma, has been observed in some animals more than 30 years
after HCV or HBV infection. It should be emphasized that sub-clinical
hepatitis over a course of many years falls within the spectrum of hepatitis observed in many humans, and is not uncommon in those without risk
factors for rapid progression like male sex, older age, and alcohol intake.
Objectives of current chimpanzee research are directly relevant to human

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health. Highly translatable studies include the first evidence that interferon-free control of HCV infection is possible with combinations of directacting antivirals (Olsen et al., 2011), and that interference with a cellular
microRNA can prevent HCV replication (Lanford et al., 2010). The latter
represents an entirely new approach to control of virus infections. More
basic studies focused on the balance between innate and adaptive immunity in HCV infection outcome (Barth et al., 2011), and patterns of
host gene expression in liver before infection is clinically evident in humans (Yu et al., 2010b).
In summary, whether chimpanzees are required for progress in understanding and controlling human infectious diseases is highly dependent on several factors, including the availability of valid alternatives,
intricacies of the relationship between the host and each pathogen, and
the objective of the research. Here, malaria, RSV, HIV and the hepatitis
viruses were used as case studies to illustrate these points. To summarize:
•

•

Malaria provides an example where there are alternatives to
chimpanzee research, including experimental infection of humans, lower primates, and rodents. The animal model may retain
value for testing new vaccine concepts, identification of candidate antigens, and characterization intrahepatic immunity, especially if current strategies to protect humans from infection are
inadequate.
For other pathogens like RSV, the chimpanzee provides the only
faithful model of human disease even though lower species are
permissive for infection. This has been critical for development
of candidate RSV vaccines that have the potential to cause harm.
The example of HIV illustrates how an animal model can fail despite a very close genetic relationship to humans. Adaptation of
SIVcpz to humans after it crossed the species barrier apparently
attenuated its replication and pathogenicity for chimpanzees, the
species from which it originated. A second very important point
that emerged from the HIV experience is that the objectives of
vaccination will determine utility of the animal model. If the
goal of vaccination is to prevent serious progressive disease (rather than infection), it must be carefully balanced against ethical
considerations and any scientific limitations of the model.
Hepatitis virus research in the chimpanzee has a track record of
success that began almost half a century ago. It continues to the
present day. As described in more detail later in this paper, proof

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that humoral and/or cellular immunity protect against HCV infection was generated from chimpanzee studies before the initiation of vaccine trials in humans. As an example, chimpanzees
studies within the past decade documented the critical need for T
lymphocytes to control HCV infection (Grakoui et al., 2003;
Shoukry et al., 2003), and that a vaccine based on this principle
could dramatically alter primary viremia (Folgori et al., 2006).
These experiments were direct antecedents of current human
clinical trials (ClinicalTrials.gov NCT01070407). Publications
within the last 18 months addressed important public health concerns surrounding HBV escape variants and vaccination, and
tested new concepts for control of chronic hepatitis C virus infection. As noted above, liver disease caused by chronic hepatitis
B and C is usually at the mild end of the spectrum observed in
humans, but to date this has not been a barrier to successful development of vaccines or therapeutics that target the viruses.
Comparative and Evolutionary Immunology in Humans
and Chimpanzees
Humans and chimpanzees diverged approximately 5-7 million years
ago. In the 19th century paleontology and comparative anatomy were
used to study kinship between the species, but the advent of serology
provided a new avenue for investigation. Landsteiner and Miller summarized these studies in a 1925 publication that documented distinct differences between humans, chimpanzees, and orangutans in patterns of
hemagglutination by anti-erythrocyte sera (Landsteiner and Miller,
1925). It was nonetheless concluded that chimpanzees and humans were
closely related as serology revealed that “the arthropoid apes do not rank
in the genealogical tree between lower monkeys and man.” Evolution of
the immune system remains an important approach to probe the relationship between the species. Publication of the draft genome sequence of a
common chimpanzee (Pan troglodytes) 80 years after the Landsteiner
study facilitated a comparative analysis with the human genome
(Mikkelsen et al., 2005). The genomes diverged by approximately 1 percent when estimated polymorphism was excluded. A total of 13,454 pairs
of human and chimpanzee genes with unambiguous 1:1 orthology were
identified (Mikkelsen et al., 2005). Alignment revealed that the most rapidly diverging gene clusters in both species were associated with taste,

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olfaction, reproduction, and immunity. With regard to immunity, rapid
diversification of chemokine ligands, cytokine biosynthesis, human leukocyte antigen (HLA), and immunoglobulin-like receptors could be discerned even at the relatively close evolutionary distance of humanchimpanzee divergence. Over the past 30 years much has been learned
about chimpanzee and human immunogenetics through studies of rapidly
evolving genes in the major histocompatibility complex (MHC) and killer cell immunoglobulin-like receptor (KIR) family. Similarities and differences in genes that regulate immunity are reviewed in this section.
How these studies of gene evolution in chimpanzees have facilitated and
provided insight into infectious disease research is also discussed.
The Major Histocompatibility Complex
Immunogenetic differences between humans and chimpanzees were
first explored in the 1960s when mixed leukocyte cultures (Bach et al.,
1972) and isoantisera (Balner et al., 1967) were used to define antigenicity of chimpanzee leukocytes. This interest in transplantation biology led
to initial characterization of the chimpanzee histocompatibility complex
that is now designated Patr (Pan troglodytes). During this era experimental transplantation of chimpanzee liver to pediatric patients suffering
from biliary artersia was undertaken (Giles et al., 1970). Contemporary
immunogenetic research involving the chimpanzee has focused on the
evolutionary relationship with man (Lienert and Parham, 1996). The
HLA and Patr gene complexes are remarkably similar considering the
genetic polymorphism at class I and II loci (Lienert and Parham, 1996).
Humans and chimpanzees have orthologous MHC class I A, B, and C
loci. Remarkably, there are no species-defining characteristics amongst
the highly polymorphic alleles at these loci (Lienert and Parham, 1996).
For instance, it is not possible to distinguish HLA-A from Patr-A alleles
based on genetic signature. Class II loci are similarly conserved, as humans and chimpanzees express DP, DQ, and DR gene products (de
Groot et al., 2009). Chimpanzee and human class I genes are functionally
identical. Detailed studies of peptide binding to chimpanzee and human
class I molecules demonstrated remarkable overlap in the pool of viral
epitopes presented to T cells (Mizukoshi et al., 2002; Sidney et al.,
2006). As noted below, complete characterization of Patr haplotype in
virus-infected chimpanzees has facilitated adaptation of state-of-the-art
reagents for monitoring T cell immunity. Finally, specific class I MHC
alleles have been associated with infection outcome in HIV- and HCV-

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infected humans. Some of these protective alleles appear to have functional orthologs in the chimpanzee, as a subset of Patr class I alleles were
shown to bind highly conserved HIV gag epitopes associated with protection from AIDS (de Groot et al., 2010).
The KIR Gene Family
Natural killer (NK) cells are involved in regulation of pregnancy and
host defense. With regard to host defense, cytolytic activity and production of effector cytokines by NK cells is tightly controlled by the interaction of activating and inhibitory receptors with their ligands, the class I
MHC molecules (Jamil and Khakoo, 2011; Lienert and Parham, 1996;
Parham, 2008). Comparison of human and chimpanzee class I ligands
over the past 3 decades has stimulated recent interest in evolution of NK
receptors that might influence the outcome of infection. Two primary
groups of NK receptors have been described. The NKG2 family is relatively non-polymorphic and conserved between humans and chimpanzees. The other family, comprised of KIRs, is highly polymorphic and
rapidly evolving as observed in the draft genome sequence of the chimpanzee (Mikkelsen et al., 2005). Humans and chimpanzees each have 10
variable KIR genes but only two, designated 2DL5 and 2DS4, are common between the species. In humans, but not chimpanzees, KIR genes
are organized into two haplotypes proposed to roughly correlate with
host defense (haplotype A) and reproduction (haplotype B) functions
(Abi-Rached et al., 2010). Evolution may have also altered the functional
profile of human KIR gene products, as species-specific mutations that
reduce avidity of activating KIR for HLA class I, while retaining highavidity inhibitory KIR, have been found (Abi-Rached et al., 2010). It is
apparent that these evolutionary changes over the past 7 million years
were driven by selection pressure from infectious diseases and possibly
the physiological demands of reproduction in humans versus chimpanzees.
KIR gene diversity between the species may influence the outcome
of chimpanzee infections with human pathogens. Resolution of human
HCV infections has been associated with homozygous expression of the
KIR2DL3 receptor and its specific HLA-C ligand (Khakoo et al., 2004).
A KIR haplotype association with HBV infection, and a specific protective effect of KIR2DL3, has also been reported (Gao et al., 2010). It is
important to emphasize that these associations were identified in large
population studies and the effect is not sufficiently strong to have practi-

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cal predictive value for individuals. Overall, inhibitory and activating
functions of the KIR genes are conserved in humans and chimpanzees.
Given the complexity and redundancy of compound KIR:HLA genotypes
on NK responsiveness, it is unlikely that KIR genetics have a material
impact on typical studies of immunity or vaccine protection involving
small populations of humans or chimpanzees.
T Cell Receptor Genetics
T cell recognition is mediated by the heterdimeric T cell αβ receptor
(TCRαβ) that recognizes antigens presented by MHC class I or II complexes. TcRβ chain diversity is generated by the rearrangement of V, D,
J, and C regions. The random insertion of non-germline-encoded nucleotides at the junctions of these rearranged segments provides additional
diversity and is the main site of Ag recognition (complementarity determining region [CDR3]). The human TcRVβ repertoire consists of 54
functional TcRVβ genes belonging to approximately 25 families based
on DNA sequence similarities. Partial characterization of the chimpanzee
TCR repertoire revealed 42 TcRVβ genes that could be aligned with
known human genes (Jaeger et al., 1998; Meyer-Olson et al., 2003,
2004). All functionally rearranged human TcRVβ families were represented in the chimpanzee TcRVβ repertoire. No evidence of new TcRVβ
families was found in the chimpanzee, and some genes were identical
between the species (Meyer-Olson et al., 2003, 2004). These data indicate a high degree conservation of the TcRVβ repertoire in humans and
chimpanzees, and suggest complexity of the T cell repertoire responding
to highly mutable viruses like HCV is similar.
Innate Immunogenetics
Innate immune defenses are a potentially important determinant of
infection outcome in humans and chimpanzees. This was recently documented in human HCV infection, where a chronic outcome of infection
and response to therapy was strongly influenced by a polymorphism in
the non-coding region of the IL-28β gene. Whether the same IL-28β polymorphisms exist in the chimpanzee is not yet known, but seems likely
given that the range of infection outcomes is identical with humans. Most
information on coding sequence differences in innate genes has derived
from comparison of evolutionary pressures on key gene families since
separation of humans and chimpanzees from a common ancestor

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(Barreiro and Quintana-Murci, 2010). These studies have provided insight into natural selection of human and chimpanzee defense genes by
infectious diseases. Loss of genes that regulate innate immunity from the
chimpanzee but not the human genome has been described. For instance,
three genes (IL1F7, IL1F8, and ICEBERG) that appear to be deleted
from the chimpanzee genome are involved with regulation of proinflammatory responses. ICEBERG is an inhibitor of IL-1β and its loss
may indicate a species-specific modulation of inflammasome function,
perhaps to reduce sepsis risk (Mikkelsen et al., 2005). Relatively little is
known about how deletions or even coding sequence differences in innate genes (which are usually minor) alter immune responsiveness in
these species. Using the toll-like receptors as an example, natural selection studies have documented that six chimpanzee TLR genes fit within
the range of haplotypes found in European-American, African-American,
and Indian human populations (Mukherjee et al., 2009). Despite this similarity, the modal human haplotypes are many mutational steps away
from the chimpanzee haplotypes indicating species-specific adaptation to
pathogens (Mukherjee et al., 2009). From a practical standpoint, the TLR
genes from both species are very close in sequence. For instance, chimpanzee and human TLR4 gene sequences differ at only three amino positions (Smirnova et al., 2000). Differences in patterns of gene expression
were observed in primary monocytes stimulated with the TLR agonist
lipopolysaccharide (Barreiro et al., 2010). A difference in the number of
responding genes in human (335) versus chimpanzee (273) monocytes
was observed. Many of the activated genes common to both species were
regulated by the transcription factor NFκB and involved in host defense
(Barreiro et al., 2010). Others were species-specific, and fell into gene
families related to apoptosis (for humans) or SIV control (chimpanzees)
(Barreiro et al., 2010). The impact of differences in innate gene coding
sequences to the study of specific pathogens in the chimpanzee is unclear, but might be greatest for viruses that originated in the animals and
adapted to a new human host. As noted above, HIV strains that adapted
to interfere with human tetherin may lose their ability to replicate efficiently in chimpanzee CD4+ T cells, or to infect via the CCR5 coreceptor because of species-specific differences in regulation of gene
expression (Wooding et al., 2005).
In summary, comparison of the chimpanzee and human genomes has
revealed remarkable conservation of genes; about 30 percent are identical and single base pair substitutions account for about half of the genetic
change (Mikkelsen et al., 2005). At the same time, selective pressure

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against genes associated with immunity is apparent, and almost certainly
attributable to infectious diseases that uniquely afflict each species. It is
likely that most of these coding differences have limited impact on the
value of the chimpanzee as a model for most infectious diseases because
of functional redundancies common to immune pathways. An important
exception may be a virus like HIV that targets the immune system and
only recently adapted to humans after zoonotic transmission from chimpanzees, the intended animal model.
The high degree of protein sequence homology between the species
has practical significance for studies of immunity and evaluation of therapeutics like monoclonal antibodies. A body of published literature has
documented that most antibodies against cluster of differentiation (CD)
antigens that define lymphocyte subsets, differentiation status, and function are fully cross-reactive for human and chimpanzee mononuclear
cells. Most importantly, some of these molecules (and others not associated with immunity) are considered targets for monoclonal antibody
therapy of human diseases. Examples are provided below. Advantages of
chimpanzees as a pre-clinical model for monoclonal antibody development have been summarized elsewhere (VandeBerg et al., 2006), but
include increased probability of detecting unintended effects against proteins that are orthologous to the primary target, similar binding affinities
that might alter cellular responses to a therapeutic antibody, and identical
pharmacokinetics of human and humanized antibodies in humans and
chimpanzees but not lower primate species.
Functional Immunology and Vaccine Research in Humans
and Chimpanzees
Evolutionary studies have revealed similarities and differences in
immune response genes between the species. How different coding sequences in immune response genes alters infection and immunity in a
chimpanzee versus a human is difficult to predict and probably pathogenspecific. Infection of chimpanzees with the hepatitis C virus illustrates
the strengths and limitations of studying immunity to a human virus in
chimpanzees. Non-A, non-B hepatitis (hepatitis C) was first studied in
chimpanzees to ask fundamentally important questions unrelated to immunity. For instance, the ability to transmit non-A, non-B hepatitis from
humans to chimpanzees indicated an infectious etiology of disease. It
also facilitated physico-chemical characterization of the agent as a small,

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enveloped RNA virus and provided a pedigreed stock of infectious serum
for molecular cloning of the HCV genome as noted above. The observation that some animals, like humans, developed chronic hepatitis C while
others spontaneously cleared the virus provided a unique opportunity to
identify protective immune responses that might be relevant to humans.
In this section, functional adaptive immune responses elicited by infection with HBV and HCV in chimpanzees and humans are compared.
Value of the animals for vaccine development is also highlighted. Limitations of the model, and examples of experimental approaches that can be
taken in chimpanzees but not humans are described.
Adaptive CellularIimmunity
Detailed studies of cellular immunity to HBV and HCV have provided insight into mechanisms of protection from persistence and how these
responses fail.
Chimpanzees offer at least three distinct advantages for this research:
(1) The first few weeks of HBV and HCV infection are clinically silent
and so critical events that shape the adaptive immune response and infection outcome are very difficult to study in humans; (2) animals can be
challenged with well-defined HCV quasispecies and even clonal HCV
genomes to facilitate studies of virus adaptation to the host and immune
selection pressure; and (3) the liver can be sampled by percutaneous needle biopsy from the earliest times after infection, so that patterns of innate and adaptive gene expression can be studied.
It is important to emphasize that the tools for measuring cellular immunity in chimpanzees are as sophisticated as those available for human
studies. Antibodies to key differentiation, regulatory, and effector molecules expressed by human T cells cross-react with the equivalent chimpanzee molecules. Virus-specific T cell responses in chimpanzees can be
very precisely quantified by functional assays that measure production of
effector cytokines or killing. As noted above, evolutionary studies of the
chimpanzee Patr complex provided insight into MHC class I and II restriction of the T cell response to hepatitis viruses in chimpanzees. This
work on the Patr complex also facilitated development of soluble class I
and II molecules (tetramers) for direct visualization of virus-specific T
cells in the blood and liver of chimpanzees infected with HCV and HBV.
These chimpanzee reagents are produced by an NIH-funded facility that
established to provide human and murine class I and II tetramers. In
summary, there are no technical disadvantages, and several distinct ad-

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vantages, to the study of antiviral T cell immunity in chimpanzees versus
humans.
Patterns of virus replication and T cell immunity are identical in humans and chimpanzees infected with HCV and HBV (Cooper et al.,
1996; Guidotti et al., 1999; Rehermann, 2009; Thimme et al., 2001,
2002, 2003; Walker, 2010). For instance, HCV replicates at high levels
for 8-12 weeks before the onset of CD4+ helper and CD8+ cytotoxic T
cell responses that are associated with a spike in biochemical markers of
hepatitis and initial control of viremia (Rehermann, 2009; Walker, 2010).
In some humans and chimpanzees, the T cell response is sustained and
the infection is terminated within a few days or weeks. In others, the
CD4+ T cell response fails and the virus persists. Failure of the HCVspecific CD4+ T cell response before apparent resolution of infection is
the best predicator of a chronic course of infection. Importantly, mechanisms of acute phase CD4+ T cell failure remain unknown (Rehermann,
2009; Walker, 2010). HCV-specific CD8+ T cells are present in the liver
at high frequency for decades but provide no apparent control of virus
replication. Infection of chimpanzees with viruses of known sequence
was essential to show that some of the HCV epitopes targeted by these
CD8+ T cells acquired escape mutations that prevent recognition of infected cells (Bowen and Walker, 2005). Other long-lived intrahepatic
CD8+ T cells target intact epitopes but lack effector functions
(Rehermann, 2009; Walker, 2010). Based on these observations, current
research in chimpanzees has two goals. The first goal is to facilitate development of vaccines that skew the outcome of HCV infection from
persistence to resolution. The second goal is to determine the defect that
underlies CD4+ and CD8+ T cell failure in chronic hepatitis C (and B),
and to test approaches to reverse exhaustion.
Vaccine Research
Very early studies demonstrated that spontaneous resolution of HCV
infection in a chimpanzee did not protect from liver disease when the
animal was re-exposed to the same infectious inoculum (Farci et al.,
1992; Prince et al., 1992). It was concluded that anti-HCV immunity was
weak and that vaccine development would be difficult. Subsequent studies revealed that this was not necessarily the case. While some second
infections in naturally immune animals do persist, the majority of infections are very rapidly controlled (Walker, 2010). As noted above, primary
HCV infections typically do not resolve for 3-4 months, but most second

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infections clear within days, and are associated with an accelerated
memory T cell response. The chimpanzee model was essential to prove
the importance of memory CD4+ and CD8+ T cells to protection from
persistence. Animals that had successfully resolved two infections were
treated with monoclonal antibodies directed against CD4 or CD8 to temporarily deplete these subsets before a third challenge with HCV. In the
absence of CD4+ T cells, the virus persisted and CD8+ T cells (that were
not depleted) selected for virus variants with escape mutations in class I
epitopes (Grakoui et al., 2003). Depletion of CD8+ T cells in a second set
of immune chimpanzees prolonged a subsequent infection; termination
of the infection coincided with recovery of these effector cells (Shoukry
et al., 2003).
Together, these studies demonstrated that sterilizing immunity provided by antibodies is not necessarily required for HCV protection.
Instead, they indicated that induction of T cell immunity to prevent persistence (but not infection) may be a realistic goal for vaccination.
Indeed, the T cell depletion studies in chimpanzees led directly to the
design of a recombinant adenovirus vector that expressed the nonstructural proteins of HCV that are predominantly targeted by the
cellular immune response (Folgori et al., 2006). Structural proteins, including envelope glycoproteins that are the targets of neutralizing antibodies, were not incorporated into the vaccine. Chimpanzees vaccinated
with this vector had dramatically lower levels of primary HCV viremia
than mock-vaccinated controls, and all cleared the infection (Folgori et
al., 2006). This vaccine is now in human clinical testing for prevention
and treatment of HCV infection (see ClinicalTrials.gov NCT01070407,
NCT01094873, and NCT01296451). It should be noted that these vaccines developed in Europe by IRBM (Merck) and Okairos were evaluated in chimpanzees at primate facilities in the United States.
The contribution of antibodies to vaccine-mediated protection
against HCV also cannot be minimized, as indicated by a recent metaanalysis of chimpanzee vaccine studies (Dahari et al., 2010). Active vaccination with recombinant subunit vaccines comprised of the HCV E2
envelope glycoprotein protected chimpanzees from virus challenge.
Proof of protection by these vaccines was obtained in chimpanzees before initiation of phase I and II testing in humans. Finally, chimpanzees
were used to test post-exposure prophylaxis with anti-HCV antibodies, a
potentially important approach to infection control in the setting of needlestick injury (Krawczynski et al., 1996). These antibodies substantially

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modified the course of acute hepatitis C, but did not prevent persistence
of the virus.
Therapeutics
The last decade has brought tremendous progress in understanding
mechanisms of T cell evasion by persistent viruses. Studies in murine
models of virus (LCMV) persistence have demonstrated that functionally
impaired virus-specific T cells express the inhibitory molecule PD-1.
Antibody-mediated interruption of the PD-1 interaction with its ligand at
least partially restores T cell function and leads to accelerated control of
virus replication (Barber et al., 2004). It is now clear that exhausted T
cells in humans and chimpanzees persistently infected with HCV and
HBV express multiple inhibitory receptors including PD-1 that put a
brake on effector function (Boni et al., 2007; Golden-Mason et al., 2007;
Penna et al., 2007; Raziorrouh et al., 2010). Interruption of ligand binding by inhibitory PD-1, CTLA-4, and TIM-3 receptors on HCV-specific
CD8+ T cells restores function in cell culture assays (Boni et al., 2007;
Golden-Mason et al., 2007; Penna et al., 2007; Raziorrouh et al., 2010).
Initial studies in persistently infected chimpanzees indicate that PD-1
blockade can have a dramatic effect on viremia in some but not all animals (C. Walker, unpublished). Similar studies have been completed in
humans (ClinicalTrials.gov NCT00703469) but the results have not been
released. Based on studies in the animal model, it might be predicted that
the human trial had some successes but more failures.
There is a continuing need for chimpanzees to develop nextgeneration therapeutics against persistent viruses, especially those that
cannot be eradicated from infected cells (Callendret and Walker, 2011).
Very recent cell culture studies have indicated that blockade of one inhibitory receptor may not be adequate to fully restore function the HBV
or HCV specific T cells (McMahan et al., 2010; Nakamoto et al., 2009).
Blockade of multiple pathways is feasible, but the approach carries risk
as these pathways were designed to temper unwanted or dangerous immune responses (Callendret and Walker, 2011). Also, studies in mice
indicate blockade of one of more than inhibitory pathway in combination
with vaccination might potentiate activity against persistent viruses (Ha
et al., 2008). In considering these strategies for human use, two considerations are paramount:

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(1) Most humans with chronic hepatitis are relatively healthy and so
combinations of blocking antibodies and vaccines carry more
risk than studies in patients with advanced stages of cancer. Under these circumstances, a nonhuman primate model like the
chimpanzee is important for progress.
(2) Antiviral therapy for chronic hepatitis C will become more effective with the advent of small molecules antivirals. It is too soon
to know if there is a place for immunotherapy with vaccines
and/or blocking antibodies in hepatitis C, although the propensity of the virus to develop resistance is remarkable and a perhaps
a significant barrier to availability and use of the multiple drug
cocktails in developing countries. There is a significant need for
this type of therapy in chronic hepatitis B, where direct-acting
antivirals do not eradicate the infection and it is necessary to
break immune tolerance for long-term control of virus replication. Chimpanzees will remain important to advance this concept.
The Chimpanzee in an Era of New and Emerging Technologies for
Studying Immunity
Chimpanzee infection studies continue to have value beyond proofof-concept studies to validate new preventive or therapeutic strategies.
New technologies offer great promise in unraveling molecular mechanisms underlying the failure of immunity in acute and persistent infections with viruses like HAV, HBV, and HCV. It is now possible to probe
the innate and adaptive immune responses, and how they are coordinated, a level of resolution not possible a few short years ago. Genes that are
expressed in virus-specific T cells that successfully control infection or
become exhausted can be identified with new technologies (Haining and
Wherry, 2010). Chimpanzees may be integral to the future of this work
that could provide new targets for intervention in acute and persistent
infections. Human genomic and proteomic technologies are directly
adaptable to the chimpanzee, and isolation of antiviral T cells to high
purity is possible. Perhaps most importantly, the chimpanzees provide
unique access to paired blood and liver specimens at very early time
points after virus exposure when there are no symptoms but the outcome
of infection is probably determined. It is likely that molecular characterization of antiviral T cells in liver at the earliest stages of infection will
identify and validate therapeutic targets relevant to humans.

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MACAQUES AS MODELS FOR HUMAN DISEASE
In this section, we address host factors in macaque models for human
diseases, macaque immunogenetics, and understanding the roles of innate and adaptive responses in macaque models for the development of
vaccines and immunotherapies. With 93 percent sequence identity with
humans, Macaca species that predominate in Asia are the most widely
utilized nonhuman primates in biomedical research. The three most
commonly utilized in biomedical research today are M. mulatta (rhesus),
M. nemestrina (pigtailed) and M. fascicularis (crab-eating or longtailed);
and within the genus the rhesus macaque is by far the most frequently
studied. The landmark work by Landsteiner and Wiener in 1937 to define
Rh factors in blood, allowing blood typing, was an early example of the
contributions that this species has made to medical research (Landsteiner
and Wiener, 1937, 1941). Efforts since then have been focused on developing multiple models for understanding human disease states. Macaques share many similarities with humans and chimpanzees in their
hematology, reproductive biology, neurological development, behavior,
immunogenetics, and immune responses to pathogens. Much of this subsequent research has focused on models in the rhesus macaque, due to
their relative ease of breeding in captivity and high adaptability to novel
environments. These models include (references are representative examples and not comprehensive in nature): reproduction, including stem
cell research (Ben-Yehudah et al., 2010; Schatten and Mitalipov, 2009;
Tachibana et al., 2009), bone marrow transplantation and hematopoietic
stem cell gene therapy (Donahue and Dunbar, 2001), aging (Messaoudi
et al., 2006), metabolic diseases and their sequelae such as diabetes
(Grove et al., 2005), brain and neurological development (Sarma et al.,
2010; Soderstrom et al., 2006; Voytko and Tinkler, 2004), behavioral
(Bethea et al., 2004; Sabatini et al., 2007; Stevens et al., 2009) including
addiction (Barr et al., 2010), and infectious diseases (Daniel et al., 1985;
Haigwood, 2009; Hansen et al., 2010; Messaoudi et al., 2009) including
virus-associated malignancies (Messaoudi et al., 2008). There has also
been some work to understand autoimmunity and arthritis (collageninduced arthritis and spontaneous arthritis) in macaques, reviewed in
Vierboom and ’t Hart, 2008. With the advent of array technologies to
examine multiplex responses to disease, it will be increasingly possible
to identify the roles of innate and adaptive immunity in the macaque
models for human disease models. Models for aging and immune senescence have been developed using rhesus macaques that are 18 years and

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older. These animals are characterized by a progressive loss of naïve T
cells and an accumulation of memory type T cells with age. The models
can be used to examine therapeutic approaches to reinstating naїve T
cells, such as IL-7 therapy (Aspinall et al., 2007) and caloric restriction
(Messaoudi et al., 2006). At this time, one of the best probes for understanding host immunity is to utilize pathogens that elicit similar responses to infection in humans and macaques. To introduce this subject, we
provide a brief review of host restriction factors and infectious disease
models for human disease in the macaque.
Host Factors in Macaque Models for Human Diseases
Host Interactions with Pathogens at the Cellular Level
A major distinction for macaques compared with chimpanzees is that
their greater genetic distance from humans results in lack of susceptibility to certain human pathogens. Viral agents and intracellular pathogens
utilize host cellular receptors and intracellular molecules such as the nucleic acid polymerases and transcription machinery for replication and
propagation. In order to assure priority treatment when inside the cells,
these organisms or viruses utilize specific proteins encoded in their genomes to interfere with basic cellular activities such as host protein production. In contrast, extracellular bacterial and protozoan parasites (at
least in some stages of their life cycles) replicate independently of the
human cell and thus are more capable of establishing infection in a wider
range of hosts. Typically pathogens are adapted to certain hosts, a property termed “host range” that is conferred by a number of factors. For
viruses, it has become clear that there are specific restriction elements
that interact with portions of the virus to limit replication or assembly.
Concomitantly, viral proteins can confer resistance to restriction elements in “spy versus spy” interplay at the molecular level, such as Nef
from HIV-1 or SIV (Schmokel et al., 2009). No fewer than four different
host-pathogen mechanisms have been identified to limit the cytopathic
effects of HIV and SIV alone, summarized in a recent review (Lifson and
Haigwood, in press) and publication on the latest factor to be discovered
(Laguette et al., 2011; St Gelais and Wu, 2011). Generally speaking, viruses with larger genomes such as those from the herpesvirus family are
better equipped to stave off the antiviral effects of the host, with multiple
pathways for downregulation of various host proteins, including those

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that are critical for immune responses such as MHC Class I proteins
(Hansen et al., 2010). The process of adaptation of viruses during
zoonoses is one of accruing sufficient mutations to overcome these host
factors, and one of the best examples of recent zoonoses that have had a
major impact upon human health is the transmission of HIV-1 and HIV-2
to humans (Gao et al., 1999; Hahn et al., 2000). A well-adapted virus is
one that can peacefully coexist with the host in the absence of pathogenic
effects, an example being SIV in African nonhuman primates (sooty
mangabeys, African green monkeys, and mandrills) (Pandrea et al.,
2006; Sodora et al., 2009). Understanding the immunological differences
between pathogens that are recently acquired and poorly adapted, compared with those that are established and benign, may yield important
information about both the host and the virus (Silvestri, 2009). The consequence of this host range restriction is that certain types of infectious
disease and immune-based research can only be performed in chimpanzees or in humans, and not in macaques. In this section, we provide examples of macaque models for major human diseases that utilize either
the same microbe or species-specific pathogens that are related to the
human pathogens.
Pathogenic Models for Human Diseases Using the Same Organism
Due to the physiological and genetic similarities of humans and macaques, many human pathogens can infect and cause disease in macaques, and the degree of adoption for experimental usage is dependent
upon several factors such as length and severity of the disease, as well as
similar pathologic outcomes to humans. An example is tuberculosis,
which is highly infectious in macaques and represents a good model for
acute and latent infection as well as re-activation and progressive disease
(Chen et al., 2009; Lewinsohn et al., 2006). Other models include acute
infections that are typically resolved in humans, such as measles
(McChesney et al., 1997; Permar et al., 2007; Zhu et al., 1997), potentially severe acute respiratory syndrome (SARS), (Miyoshi-Akiyama et al.,
2011), Ebola (Sullivan et al., 2006), monkeypox (Estep et al., 2011), and
dengue virus (Onlamoon et al., 2010; Smits et al., 2010). The considerable work that goes into model development for these agents includes the
production and in vivo titration of infectious challenge stocks, in some
cases necessitating testing many different sources to find the right balance of infectiousness and pathogenicity, the development of key assays
for monitoring disease sequelae and the progression of infection short of

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necropsy, and the development of reagents that are appropriate for monitoring innate and adaptive immunity in vivo (discussed below). In addition, experiments using these agents require special containment to
reduce biohazardous exposure to humans and other nonhuman primates.
However, significant progress has been made not only in understanding
correlates of protection from challenge in some cases but also in developing human vaccines that show some promise, discussed with examples
in the section below on vaccines. Obvious advantages of these models
include the ability to identify virulence genes and to perform more frequent and more invasive sampling, with the judicious use of serial sacrifice studies to examine tissues in more depth.
Pathogenic Models for Human Diseases Using Closely Related But
Distinct Organisms
When host range limits the infectivity of certain agents, closely related pathogens that are adapted for Macaca species can sometimes be
found. These include: simian adenoviruses, simian varicella virus (SVV)
as a model for varicella zoster virus (Messaoudi et al., 2009), rhesus cytomegalovirus (CMV) as a model for human CMV (Hansen et al., 2010),
and SIV and chimeric simian/human immunodeficiency virus (SHIV) as
a model for HIV-1 (Lifson and Haigwood, in press). Because the HIV-1
and SIV Envelope proteins do not elicit cross-protective neutralizing antibodies, testing of human monoclonal antibodies or HIV Env-based vaccines for protection was not possible with SIV. Therefore chimeric
viruses were made consisting of the SIV backbone and a “swapped”
HIV-1 env gene and these viruses were passaged in vivo in macaques to
obtain more pathogenic strains. Originally, SHIVs were tropic for
CXCR4 and caused rapid loss of CD4+ T cells in the periphery
(Reimann et al., 1996), but then CCR5-utilizing isolates with slower
pathogenesis were successfully constructed and shown to be transmitted
by mucosal routes in adult (Harouse et al., 2001) and newborn macaques
(Jayaraman et al., 2007). Despite their appeal, these models have potentially more limitations that must be kept in mind in interpreting the results. The specific agent (genetically or phenotypically characterized),
the host, or that particular combination can each contribute to differences
in disease outcomes. All of the caveats noted in the section above hold in
this case, and in addition there is the potential for difficulty in translating
the findings from macaque-specific pathogens to their human homologs.
Nonetheless, these models can be and have been highly instructive in

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establishing certain basic principles that would have been difficult or
impossible to determine by experimentation in humans or in chimpanzees, as summarized in Table 1. Although many of these concepts have
since been proven in clinical studies, it can be argued that the timing of
the discovery of the concept in the macaque accelerated understanding and
exploration in human studies. Furthermore, many of the findings could not
be directly tested in humans for ethical or safety reasons.
TABLE 1 Examples of Lessons Learned from Macaque Models for
Human Diseases
Human
Pathogen
HIV-1

Macaque
Pathogen
SIV

Concept Revealed
Mucosal routes of infection require
greater doses than parenteral for
productive infection after a single
challenge; influenced by hormonal
status

References
(Hirsch and Lifson,
2000; Sodora et al.,
1997)

SIV

Timing of tissue distribution using
serial sacrifice; earliest events in
infection

(Milush et al., 2004)

SIV

Multiple low dose mucosal challenge with can mimic the transmission dose and composition, similar
to sexual mucosal acquisition of
HIV-1 in humans of a few variants
to seed the infection

(Keele et al., 2009b)

SIV,
SHIV

Relatively more rapid pathogenesis
in newborns compared with adults

(Baba et al., 1995,
Jayaraman et al.,
2007; Marthas et al.,
1995)

SIV

Early loss of GALT

(Smit-McBride et al.,
1998)

SIV

Neurotropic strains of SIV and
HIV-2

(Van Rompay and
Haigwood, 2008)

Superinfection definitively
Demonstrated

(Yeh et al., 2009)

Differential pathogenesis conferred
by the same viruses in different
macaque species

(Polacino et al.,
2008; Sodora et al.,
2009)

SIV,
SHIV

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APPENDIX B
Human
Pathogen
Human
CMV

Macaque
Pathogen

Ebola
virus

Concept Revealed
Mechanisms of superinfection revealed

References
(Hansen et al., 2010)

Demonstration that antibodies are a
correlate of protection but are not
sufficient for protection

(Sullivan et al., 2009)

Macaque Immunogenetics
Due to the more extensive use of the Indian-origin rhesus macaque,
this was the first of the macaque genomes to be sequenced. The draft
DNA sequence of an Indian-origin female rhesus was completed in 2007
and compared with the human and chimpanzee genomes (Gibbs et al.,
2007); the Chinese rhesus macaque genome was just published in 2011
(Fang et al., 2011). This three-way comparison study gave some of the
first insight to inform an understanding of mutational mechanisms that
have, during the last 25 million years, shaped the biology of the three
species. Prior work had focused on specific regions of the genome that
encode gene members of the immune system, as noted below.
Major Histocompatibility Complex
MHC loci in rhesus macaques have been explored and compared,
with a great deal of progress in the rhesus macaque. Class I alleles are
termed Mamu (for Macaca mulatta) (Doxiadis et al., 2007; Otting et al.,
2007); in contrast to humans only two MHC class I loci are found, A and
B, with at least two expressed B loci, indicating a duplication of the B
locus. Macaques have three MHC class II loci: DP, DQ, and DR. Haplotype diversity can result from crossing over events, since rhesus macaques have several class I alleles on each chromosome. Comparison of
rhesus and human class I and class II evolution shows that the class I
alleles are not shared between the species (Boyson et al., 1996), although
similar epitope binding motifs are shared by macaque and human MHC
class I molecules (Loffredo et al., 2009). MHC class I haplotype can
clearly affect disease progression in SIV infection, in that certain MHC
haplotypes affect the ability to control viral replication in vivo (Bontrop
and Watkins, 2005; Goulder and Watkins, 2008). Mamu-A*01 animals
typically show better control of infection in vaccine studies (Pal et al.,
2002), and haplotypes B*08 and B*17 are associated with elite control of

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viremia (Loffredo et al., 2008; Yant et al., 2006). There also appears to
be an effect of class I haplotype upon antiretroviral drug effectiveness
(Wilson et al., 2008). Certain MHC class I alleles in humans also appear
to be associated with better control of viremia and disease outcomes, reviewed in Goulder and Watkins, 2008.
The KIR Gene Family
As noted above in the section on chimpanzees, MHC class I molecules are ligands for the KIRs, which are expressed by natural killer cells
and T cells. As with chimpanzee KIRs, the interactions between these
molecules contribute to both innate and adaptive immunity, and combinations of MHC class I and KIR variants influence resistance to infections, susceptibility to autoimmune diseases and complications of
pregnancy, and outcomes of transplantation (Parham, 2005). The genes
encoding the KIRs all arose recently from a single-copy gene during the
evolutions of simian primates, after which the KIR and MHC class I
genes co-evolved. The genes have been sequenced in rhesus, humans,
chimpanzees, gorillas, gibbons, orangutans, and marmosets (Sambrook et
al., 2006), and in Mauritian cynomolgous macaques (Bimber et al.,
2008). There has been a recent comprehensive rhesus macaque KIR data
set developed (Moreland et al., 2011) and an overview of MHC/KIR coevolution (Parham et al., 2010), emphasizing rapid evolution of KIR sequences, in large part due to evolutionary pressure from infectious pathogens. Of note, the old-world monkeys have been recently described as
being the species most likely to provide useful and informative models
for human disease.
T Cell Receptor Genetics
The diversity of T cell receptor (TCR) alpha and beta chains is created by somatic recombination of germ-line genes, as described above.
Several studies have examined TCRs in chimpanzees and macaques
(Jaeger et al., 1993). Macaques that are not infected display a diverse T
cell repertoire characterized by a Gaussian distribution of betaCDR3
lengths (Currier et al., 1999). T cell repertoire analysis has revealed a
dominance of T cells expressing specific V-beta segments during chronic
infection (such as SIV infection). Rhesus CMV infection led to polyclonal CD4+ T cells that changed over time and chronic infection to reveal a
skewed hierarchy dominated by two or three clonotypes (Price et al.,

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2008). These kinds of comparisons aid in understanding the role of T
cells in controlling infection and how these types of changes compare
with natural progression of aging, for example (summarized in
Messaoudi et al., 2011).
Antibody Gene Families
In macaques as in humans, the diversity of B cell receptors (BCR)
and the soluble forms, or antibodies, that result, is generated by somatic
recombination as with the TCR. The immunoglobulin loci for antibodies
are similarly arranged in the rhesus macaque as in humans, and the antibodies have the same structures, with clear homologs identified for IgG
and IgA classes and for subclasses of IgG (Scinicariello et al., 2004).
There are differences, as would be anticipated with the time since speciation, but remarkable functional and genetic conservation.
CD Genes
Elegant comparative studies examining the relative proportions and
cell surface markers of human versus macaque cells have been described
and are summarized in a recent review (Messaoudi et al., 2011). The
strong conservation of these molecules has allowed detailed studies on
immune cell ontogeny, homing, survival, proliferation, and death that
also have opened the field of immune senescence in the macaque. As
noted in the sections below, the roles of specific cells in disease have
been studied in vivo by transient depletion of subsets.
Innate Immunogenetics
CD16+ and CD56+ NK subsets are largely similar in function and
distribution in humans and macaques. The distribution of NK cells in
blood and tissues differs somewhat in macaques, where CD16 predominates in the blood, and CD16 negative cells positive for CD56 can be
found in tissues (Reeves et al., 2010). Prior studies had suggested that
NK cells might not play a strong role in the containment of SIV; the role
of NK cells in control of SIV still uncertain but certainly cannot be discounted. Macaques are appropriate models in which to address questions
in acute infection, which is a phase of the infection that is very difficult
to identify and thus study in humans. There are new data that have identified the macaque counterpart of mucosal NK cells producing IL-22

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(Reeves et al., 2011), as previously identified in humans. These studies
emphasize the importance of performing studies in macaques where
greater access to mucosal samples is possible.
Monitoring and Understanding the Roles of Innate and Adaptive
Responses in Macaque Models for the Development
of Vaccines and Immunotherapies
Flow cytometric analysis of macaque immune-related cells using
murine anti-human CD antibodies that were developed to bind to human
cell surface markers demonstrates the strong immunological conservation of the vast majority of these surface molecules. This attribute of
shared receptor recognition is not surprising knowing the genetic conservation of the species, and it has meant that the nuances of antigen presentation and the respective roles of B and T cells in macaque immunity is
now a well-established area of research. A recent review provides an
overview and examples of the staining and separation of these subsets in
rhesus macaques (Messaoudi et al., 2011). The relative contribution of
specific types of cells in innate and adaptive immune responses in the
outbred Macaca species has been made possible by infusion studies using murine monoclonals directed at human CD8, CD4, CD16, CD20 (or
other cell surface markers of interest) to transiently deplete specific subsets of lymphocytes in vivo. These studies have demonstrated the relative
contribution of CD4+ and CD8+ T cells, B cells, and NK cells to the control of specific pathogens at different time points during infection, with
examples in the sections that follow.
Stimulating Innate Responses
As in humans, the mediation of innate responses includes neutrophils, NK cells, dendritic cells (DC), and macrophages. Recognition of
microbes depends upon the detection of pathogen-associated molecular
patterns (PAMPs) by pattern recognition receptors, which fall into two
families, toll-like receptors (TLR) and RIG-I-like RNA helicases (RLH).
DCs and NKs have been well characterized in the rhesus. The major two
subsets, myeloid (mDC) and plasmacytoid (pDC) types, are identified
with the same surface markers and share functionality and cytokine response following viral infection. These two types of DCs express the
same TLRs as human DCs, which differ drastically from murine DCs,

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and thus help establish the macaque as an excellent species in which to
evaluate TLR ligands as adjuvants (Rhee and Barouch, 2009).
Magnitude and Quality of T Cell Responses
In the T cell realm, there has been significant development work to
understand and to quantify specific T cell subsets in the blood and effector sites (Pitcher et al., 2002; Walker et al., 2004), aided by advances in
sampling methodologies that provide repeated sampling opportunities at
effector sites such as the lung, for example. The functional diversity of
the T cell response in macaques, as in humans, can now be measured via
“staining” for multiple cytokines simultaneously. Intracellular cytokine
staining (ICS) is a commonly utilized technique, where cells are stimulated with antigens (virus, lysates, purified antigens, or peptides) and
then treated to block cytokine secretion, then labeled for each cytokine
with a different-colored tag, and enumerated on a flow cytometer. Much
of this work has been stimulated by interest in HIV pathogenesis and
subsequently SIV infections, as these viruses destroy CD4+ T cells in the
gut and peripheral blood compartments, with concomitant negative effects on T cell help; the rapidity of destruction varies with the strain. The
time course of longitudinal development of T cell help (CD4+ T cells)
and cytotoxic cells (CD8+ T cells) in response to SIV or SHIV infection
is similar to that of HIV-1 in humans. In acute SIV infection, CD8+ T
cells were shown to be very important for viral control (Schmitz et al.,
1999). More recent studies have further elucidated the impact of CD4
and CD8 T cells, in experiments that clearly show that CD8+ T cell removal during this timeframe results in rapid disease progression due to
unchecked viremia (Okoye et al., 2009); the depletion also resulted in
proliferation of CD4 T cells, particularly effector memory cells. Antiviral
CD8+ T cells have also been implicated in controlling vaginal infection
upon exposure to a highly virulent SIVmac239 after vaccination with
SHIV89.6, an infectious but non-pathogenic strain (Genesca et al., 2009).
Antibodies and Affinity Maturation
The development of antibody responses is dependent upon the effective antigen presentation and, for some diseases, persistence of antigens.
Antibody response kinetics are indistinguishable in macaques and in humans, but it has been easier to perform longitudinal studies to examine
the maturation of the response with more frequent time points (Cole et

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al., 1997). Antibodies increase in avidity with time of exposure to antigen and the quality of the response depends upon the form of the antigen.
Many persistent pathogens utilize various methods for immune evasion,
including antigenic variation of their surface proteins to elude recognition B cells and thus to prevent containment by antibodies. SIV and
SHIV have served as excellent models for longitudinal studies of antibody development, including neutralizing antibodies, which typically
increase in magnitude and breadth with time (Hirsch et al., 1998; Kraft et
al., 2007), as is seen in humans infected with HIV-1 (Mahalanabis et al.,
2009; Sather et al., 2009). Antibody responses directed to HIV or SIV
Envelope typically are robust and directed to hydrophilic, hypervariable
regions; responses to conserved regions (such as those required for receptor and coreceptor binding) arise later and do not appear in all subjects (Li et al., 2007). Variation and post-translational modifications such
as N-linked glycosylation in the SIV Envelope protein have been shown
to lead to escape (Rudensey et al., 1998). There is now extensive molecular and sequence data of both viral variants and antibodies that HIV
and SIV infection leads to similar B cell responses in humans and macaques, respectively. The development of binding and neutralizing antibodies occurs over the same time frame and requires extensive affinity
maturation from the germ line antibody genes (Moore et al., 2011).
Monoclonal antibodies from SIV-infected macaques have been instructive in understanding the neutralizing epitopes targeted (Cole et al., 2001;
Glamann et al., 1998; Robinson et al., 1998), although no extraordinarily
powerful monoclonal antibodies have yet been isolated with properties
similar to those found in HIV+ subjects who are elite neutralizers (DoriaRose et al., 2009; Walker et al., 2010; Wu et al., 2010). Contributions by
CD20-positive cells in SIV infection were evaluated and shown to be
limited to the chronic phase, with no apparent effect on early viremia
(Schmitz et al., 1999, 2003). A recent clinical report showed that an
HIV-positive subject with lymphoma who was treated with anti-CD20
(Rituximab) to reduce his B cells had a transient increase in plasma virus
and a reduction in the level of neutralizing antibodies. These data were
interpreted as evidence for contributions to viral control by neutralizing
antibodies during the chronic stage of HIV-1 infection, consistent with
the data on SIV-infected macaques treated with anti-CD20 (Huang et al.,
2010). Depletion studies have been highly informative in other diseases,
such as measles (Permar et al., 2003, 2004). A comparison of B cell depletion during the acute phase of infection in this model alone or in combination with CD8+ T cell depletion clearly showed that the antibodies

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played a limited role in the control of measles viremia, while the CD8
effector T cells were critically important for limiting viremia and rash
production.
Vaccine Approaches in Macaques
Macaque vaccine experiments performed over the last 25 plus years
have accrued a large body of data about relative immunogenicity of various vaccine approaches, and these experiments have also allowed correlates of vaccine protection to be determined in many cases. In the
sections below, we have attempted to summarize briefly the status of
research in five major pathogens, to introduce the major concepts under
investigation and the importance of these models to the discovery of effective vaccines for diseases that are emerging, or re-emerging due to
persistence in the host, such as tuberculosis. Approaches for vaccines
depend upon the desired type of immunity required for protection. Protein formulations are often processed through endocytic pathways that
stimulate CD4+ T helper 2 (TH2) cell responses and promote antibody
production. By contrast, vaccines that allow synthesis of foreign proteins
within cells lead to processing of antigens through the proteasome, a process that more effectively elicits CD8+ T cell responses, while also eliciting antibody responses. Some gene-based vaccines have the potential to
generate broad responses because of their ability to target antigenpresenting cells (APCs) directly, which is a property of certain viral vectors. The quality and range of vaccine-induced immune responses can
therefore be influenced by the specificity of viral vectors for different
APC targets.
With the advent of molecular tools for genetic manipulation and the
identification of virulence factors, it has been possible to utilize this
knowledge to build recombinant vectors to precisely excise unwanted
genes and to express one or more vaccine antigens in their place. Advances in the development of safer, more attenuated viral vectors utilized
for one major disease, smallpox, were the genesis of recombinant poxvirus-based vectors that persist in the human vaccine armamentarium
today. These viral vectors are attractive because they stimulate innate
and adaptive immunity and persist long enough to provide a strong antigen pool to boost B cells, much as the currently licensed live attenuated
vaccines. The ability to challenge in macaques prior to testing in humans
provides a measure of confidence that the immune responses elicited by

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the new vaccines are effective against diseases that closely model human
pathologies.
As with model development to study pathogenesis, it is also true that
the use of related pathogens as “vectors” for vaccine delivery has also
necessitated understanding the host range of the various vectors for humans and for macaques. Thus there has been an intensive search for nonpathogenic viruses that can replicate equally and stimulate similar levels
of immunity directed to the foreign antigen(s) in both species. Current
investigations with viral vectors include Vesicular stomatitis virus, Sendai virus, adenoviruses (chimpanzee, human, and macaque), poxviruses
(various levels of attenuation and species specificity) and herpesviruses
(including cytomegalovirus, and adenovirus-associated virus vectors), to
name a few. Due to cellular targeting via receptors, replication capacity,
and the inclusion of cofactors such as cytokine genes, some vectors are
better at stimulating specific arms of the immune response; combinations
can work additively and possibly synergistically.
In addition to viral vectors, other promising approaches in use include DNA delivered by a variety of routes (intramuscular, intradermal,
via microneedles, and with electroporation to enhance uptake) (Yin et al.,
2010). DNA vaccines showed impressive protection in a mouse influenza
model (Ulmer et al., 1993) but have been much less immunogenic in macaques and humans with SIV or SHIV immunogens and viral challenge
(Doria-Rose et al., 2003; Rosati et al., 2005; Yin et al., 2010), albeit there
was significant improvement in immunogenicity with added cytokine
genes (Barouch and Letvin, 2000) and with electroporation to enhance
intramuscular uptake (Patel et al., 2010) and with improved vector design
(Kulkarni et al., 2010). DNA vaccine immunogenicity is also greatly enhanced by protein boosting (Malherbe et al., 2011; Vaine et al., 2008).
DNA vaccines have recently shown some promise for influenza vaccines
in humans (Smith et al., 2010). They are attractive because they can deliver multiple antigens that can express genes in vivo to assemble noninfectious virus-like particles or native proteins that are difficult or
impossible to produce by recombinant methodologies. They can be delivered multiple times without inducing anti-vector immunity that limits
the effectiveness of viral vectors.
Another noteworthy area of active research in nonhuman primate
models is the development of protein immunogens and improved adjuvants. Novel adjuvants are needed to stimulate both innate and adaptive
responses, and with a better understanding of TLR binding it may be
possible to direct responses more effectively, while increasing the magni-

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tude of the response. In addition to whole virion approaches to preserve
native structures (Frank et al., 2002; Johnson et al., 1992; Lifson et al.,
2002; Warfield et al., 2007b; Willey et al., 2003), novel and native scaffold approaches are being modeled to present epitopes out of context on
the surface of heterologous proteins (Guenaga et al., 2011; van Montfort
et al., 2011; Zolla-Pazner et al., 2011), often in multimeric arrays that B
cells prefer (De Berardinis et al., 1999).
HIV/SIV
The overwhelming body of literature on HIV vaccines in macaques
has been summarized a number of times in several recent reviews
(Haigwood, 2009) and chapters and thus the committee is encouraged to
avail themselves of the detailed information summarized in a recent review (Lifson and Haigwood, in press). Many vaccines have focused on
SIV only, while some have also included HIV Envelope for SHIV challenge. These studies have provided key observations about the immune
responses elicited and how these have correlated with protection from
infection. A critical example of this is the T cell-focused vaccines based
on a non-replicating recombinant human adenovirus (Ad5) expressing
SIV Gag, Pol, and Nef. A simiar SIV Gag vaccine had an effect on plasma viremia, reducing it 1 or 2 log10 using a less pathogenic X4 SHIV
challenge virus (Shiver et al., 2002). When these SIV vaccines expressing Gag, Pol, and Nef were tested using the most pathogenic challenge
(SIVmac239), there was no evidence of control of viremia post infection
(Casimiro et al., 2010), the result found in the STEP clinical trial
(Buchbinder et al., 2008). However, until there is a definitively positive
human vaccine trial with correlates of immunity, we will not know for
certain which of these macaque infection models and/or which immune
responses are predictive of protection (Haigwood, 2009; Morgan et al.,
2008). At this stage in vaccine development, the field awaits with great
interest the ongoing immunological analysis of the RV144 trial, which
showed modest, transient efficacy in a subset of the trial participants,
those with lowest risk of exposure (Rerks-Ngarm et al., 2009). A few key
lessons from this field are highlighted below:
Combination vaccines show more promise than single entities
Combination vaccines—prime-boost—with multiple antigens that stimulate T-cell and B-cell responses generally have been found to be consistently more immunogenic and more effective in resisting challenge or

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controlling viremia than single approaches, but even these experiments
had different outcomes depending upon the challenge virus. Early success with highly immunogenic yet risky vaccinia virus led to the testing
of attenuated poxviruses such as Modified Vaccinia Ankara (MVA) and
the avian poxvirus ALVAC. For SIV and SHIV, there are many examples of combination poxvirus vaccines that include one or more vectors
with or without DNA or a recombinant protein, and these have shown
different degrees of viral control upon challenge, depending upon the
virus used for the challenge (Doria-Rose et al., 2003; Hel et al., 2002; Pal
et al., 2006; Patterson et al., 2003). The recent RV144 trial was designed
with an avian poxvirus prime, followed by a ALVAC plus Env protein
boost. This vaccine has shown some modest and transient protection in
humans (Rerks-Ngarm et al., 2009)—was it predicted by macaque experiments? Because no exact replica of the RV144 design was tested, a
closely similar experiment based on SIV immunogens is in progress in
macaques at this writing so that comparisons can be made.
New vectors to stimulate effector T cell memory Current promising
SIV vaccines based on rhCMV have demonstrated an impressive ability
to control viremia to nearly undetectable levels in approximately half of
the macaques challenged with SIVmac239 (Hansen et al., 2009, 2010,
2011). The mechanism of this vaccine is the persistence of the vector,
which is apparently years at least, and the very strong induction of effector T cells against the SIV gene products. Further research is underway
to understand the bimodal effect of the vaccine (all-or-none effects on
virus loads) as well as to combine this approach with other vaccines that
could stimulate central memory, such as adenovirus vectors, and antibodies, such as recombinant adjuvanted proteins. To move this approach into
the clinic, it will require making HIV antigens in an attenuated hCMV
vector, since hCMV is a high-risk infection for fetuses and immunecompromised humans.
Immunity to adapted viruses may provide clues for non-adapted
infection Because both HIV-1 and HIV-2 are derived from naturally
occurring SIVs, understanding the immune responses in the host to
which they are adapted could yield clues as to whether immunity in the
non-adapted host contributes to pathogenesis (Silvestri, 2009). SIV not
only replicates well in its natural host (sooty mangabeys, Cercocebus
atys) (Sodora et al., 2009), but there is also evidence for loss of gut CD4
T cells; thus the idea has been proposed that these cells may not be the

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major source of plasma virus, even though they are an early target for
destruction (Lay et al., 2009). These studies suggest that inflammation
induces CCR5 expression as a co-factor for pathogenesis, as CD4+ cells
that are also CCR5+ are greatly reduced in blood and tissue in the naturally infected hosts (Pandrea et al., 2007). Immune activation in pathogenic infection with SIV and HIV has been shown to be related to
enhanced microbial translocation, which is related to CCR5 expression
and can be partially controlled by antiretroviral treatment (Brenchley et
al., 2006); translocation is reduced in the sooty mangabeys and is likely
to be a similar story with the other highly adapted viruses in African
green monkeys (Pandrea et al., 2006).
Improved challenge models to better mimic low-dose mucosal exposure
Studies in macaques have extended early findings in chimpanzee models
for HIV-1 that passive transfer of antibodies (monoclonals or IgG from
infected animals) can be delivered by intravenous, intramuscular, or subcutaneous routes to directly demonstrate a role for antibodies in blocking
infection (reviewed in Lifson and Haigwood, in press). These studies
have informed the magnitude and breadth of antibodies that may be necessary for a fully effective prophylactic vaccine, but much of this work
was based on high-dose mucosal challenges, in order to achieve infection
of all control animals after a limited number (1-2) of challenges. A very
important advance to our understanding has been furthered by the use of
low-dose challenge models that more closely resemble human transmission (Keele et al., 2008). These newer studies indicate that much lower
doses than previously tested can be effective in preventing viral acquisition upon repeated low-dose challenge (Hessell et al., 2009a, 2009b).
The use of repeated low-dose challenge in vaccine studies increases the
expense and time needed to obtain answers but may provide more realistic assessment of the types and magnitude of immunity needed for more
typical human sexual exposure to HIV-1.
Gene therapy as proof of principle for antibody-mediated protection
One of the most innovative uses of the SIV/macaque model was to directly prove that neutralizing antibodies expressed in vivo could prevent
infection. This question was critically important to address because work
prior to this point had suggested that only extraordinarily high levels of
antibodies would be effective in preventing infection. Gene therapy and
adenovirus associated virus (AAV) expressing an SIV neutralizing monoclonal sFv were utilized to prevent intravenous infection by SIV

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(Johnson et al., 2009). Not all macaques were able to resist infection, and
this appeared to correlate with the persistent expression of the antibody
in vivo. This experiment could have failed completely, or could have
caused major pathogenic consequences in vivo, and thus was an excellent use of the SIV macaque system to test proof of principle. If the problems can be overcome, this may see further development.
Tuberculosis
Tuberculosis (TB) is a major threat worldwide, particularly with ~2
billion people latently infected. Identifying immune mechanisms that
control the initial infection and prevent reactivation remain critical goals
(summarized in Lin and Flynn, 2010). Examples of the contributions of
macaques to understanding these issues includes a demonstration of the
role of T cells in disease control via a CD8 depletion study in BCGvaccinated macaques that were infected with M. tuberculosis (Chen et
al., 2009). Diedrich et al. (2010) used cynomolgus macaques with latent
TB co-infected with SIVmac251 to develop the first animal model of
reactivated TB in HIV-infected humans to better explore these factors.
All latent animals developed reactivated TB following SIV infection,
with a variable time to reactivation (up to 11 months post-SIV). Reactivation was independent of virus load but correlated with depletion of
peripheral T cells during acute SIV infection (Diedrich et al., 2010). Further studies on SIV and TB co-infection indicate that events during acute
HIV infection are likely to include distortions in proinflammatory and
anti-inflammatory T cell responses within the granuloma that have significant effects on reactivation of latent TB. In this study, mycobacteriaspecific multifunctional T cells were better correlates of Ag load (i.e.,
disease status) than of protection (Mattila et al., 2011).
Smallpox and Monkeypox
Smallpox and monkeypox are closely related orthopoxviruses that
differ in their pathogenicity for humans. Although less infectious and the
cause of less mortality, monkeypox is still a problem for humans when
zoonotic transmissions take place. Due to the eradication of smallpox,
vaccines can no longer be tested in humans for the prevention of the infection and thus nonhuman primate (macaque) studies are necessary for
licensing. MVA has shown strong protective effects in M. fasicularis
(Earl et al., 2004) and was shown to be more effective than the standard

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smallpox vaccine. Protection correlated with the more rapid immune response to MVA, potentially related to the higher dose of MVA that can
be tolerated safely (Earl et al., 2008). Another group showed by depletion studies that B cells are essential for protection in this model
(Edghill-Smith et al., 2005), and went on to develop a DNA/protein approach that shows promise of being a safe and effective vaccine (Heraud
et al., 2006).
Yellow Fever Virus
Although there is a vaccine for yellow fever virus (YFV-17D) in use
since 1945 that was originally developed in the macaque, it is not a fully
efficacious vaccine, and severe adverse events have been reported that
may be related in some cases to impaired innate responses (Pulendran et
al., 2008). The vaccine elicits long-lived persistent T (Akondy et al.,
2009) and B cell responses (Poland et al., 1981), and systems biology has
been applied to determine correlates of protective immunity (Querec et
al., 2009). To test for improved vaccines, there is currently a model for
yellow fever using the YFV-Dakar strain of virus that has previously
been characterized as viscerotropic and capable of being lethal in rhesus
macaques (Monath et al., 1981). Following challenge with YFV-Dakar,
unvaccinated animals demonstrated fever, lymphocytopenia, and fulminant viscerotropic disease with multi-organ failure, resulting in death
within 4-6 days after infection. Histological analysis of the liver demonstrated widespread neutrophil infiltration, councilman bodies, and severe
tissue necrosis, which correlated well with ALT (alanine aminotransferase). In contrast, animals that were vaccinated can show protection
against lethal challenge and there is evidence that novel inactivated vaccines may protect against viremia, at least below detection (<50 genome
copies/mL of serum) (M. Slifka, personal communication). Whether these new vaccines will offer improved safety profiles along with broad efficacy in humans remains to be determined.
Ebola Virus
The acute hemorrhagic filoviruses Ebola and Marburg cause infections with very high mortality rates in humans and nonhuman primates.
Several approaches have been tested in macaques, with a primary focus
on Ebola virus (EBOV). These have included DNA-prime-adenovirus
boost with glycoprotein and nucleoprotein, either in a prolonged

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(Sullivan et al., 2000) or shortened regimen (Sullivan et al., 2003). Although effective, preexisting adenovirus immunity may limit the utility of
this approach. Other approaches tested have included live attenuated
vaccines based on vesicular stomatitis virus (VSV) (Jones et al., 2005),
as well as parainfluenzavirus (Bukreyev et al., 2010) and virus-like particles (Warfield et al., 2007a, 2007b). Discordant results of vaccine efficacy studies between mice and nonhuman primates have been observed
with Ebola vaccines and have underscored the importance of examining
this question. Although IgG titers are correlated with protection from
EBOV challenge, passive antibody transfer was not fully effective in
protection in macaques, demonstrating that protection is multifaceted.
This subject is summarized in an excellent recent review that lays out the
argument for using the “animal rule” for vaccine approval (Sullivan et
al., 2009). Ultimately, the development of a vaccine for humans based on
a replication defective Ad5 platform has shown significant promise and
good immunogenicity (Ledgerwood et al., 2010).
CONCLUSIONS AND FUTURE USES OF NONHUMAN
PRIMATE MODELS, INCLUDING THE CHIMPANZEE
•

•

Chimpanzees have been essential for the study of human pathogens that do not infect lower species or reproduce key features of
human disease. It is difficult to exclude the possibility that
emerging infectious diseases will have a similar highly-restricted
host range and thus be difficult to model in lower primates.
There are as yet no vaccines for many of the human infectious
diseases that have benefited from chimpanzee studies, including
HCV, RSV, and malaria. All three remain important public
health problems and there are high hurdles to successful vaccine
development. These hurdles include a poor understanding of
how to (1) vaccinate against highly mutable viruses that establish
persistence (e.g., HCV), (2) safely balance vaccine immunogenicity with attenuation (e.g., RSV), and (3) select antigens for
vaccination against a parasite with a complex life cycle and
poorly understood strategies for immune evasion (e.g., malaria).
It should be emphasized that even for an existing successful vaccine, unexpected adaptation of a virus like HBV can create vaccine escape variants. The chimpanzee model has in the recent

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•

135

past, and may again in the future, be important to test the threat
that such adaptations present to public health.
Monoclonal antibodies and other biologicals designed to modulate inflammation and immunity in infectious and non-infectious
diseases are routinely assessed for off-target effects in chimpanzees. The chimpanzee is valuable for these pre-clinical studies
because unexpected cross-reactivity with orthologous proteins is
more likely to be revealed. Humanized monoclonal antibodies
are also less likely to elicit a neutralizing humoral response in
chimpanzees when compared with more distant non-human primate species. This use of the animal model should accelerate as
new targets for intervention are identified. Antibodies against T
cell activating and inhibitory receptors that might modulate immune function in autoimmunity, cancer, and infectious diseases
provide a prime example. For instance, combinations of inhibitory receptor blocking antibodies may be useful to restore immunity in chronic hepatitis B, but the animal model will be important
to assess effectiveness and risk in a disease that is often subclinical and slowly progressive.
The very close genetic relationship between humans and chimpanzees affords the opportunity to define the molecular pathogenesis of infections caused by viruses, microbes, and parasites
that afflict humans. Genomic and proteomic technologies can be
applied to understand host responses over the course of acute and
(where relevant) persistent infection in primary target tissues.
These tissues are often not available from humans because biopsies are not medically indicated. Also, critical aspects of innate
and adaptive immune responses may be missed in humans because early stages of the infection are asymptomatic. Thus,
chimpanzees provide a means to define immune responses at
time points and locations that are inaccessible in humans.
The close similarity of the macaque and human immune systems
and the susceptibility of Macaca species to many human pathogens have together afforded opportunities to explore systematic
comparison of multiple approaches for vaccine design, delivery,
and comparative analyses of immunogenicity and responses to
challenge. Furthermore, the relative availability of macaques for
experimentation has allowed the discrimination of the contributions of different arms of the immune response by passive trans-

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•

fer of antibodies or transient depletion of specific subsets of
cells.
Having access to a broad range, or “full spectrum” of nonhuman
primates has been enormously useful in order to understand how
pathogens affect different species, in order to gain an understanding of the interplay between the host and the pathogen. Disease models differ in robustness depending on which species is
used, so it is critical to have multiple species available. Understanding control in a species that has adapted to a virus may
yield insights into novel therapeutics.
“Failure” of an imperfect model can lead to a better understanding of the host-pathogen relationship. Mismatched outcomes between humans and animals, once understood, can provide insight
into the pathogenesis of infection in humans. They can also lead
to important refinements in a nonhuman primate model so that it
better reflects the situation in humans. An example is high- versus
low-dose mucosal challenge with SIV and SHIV in macaques.
There was very strong resistance to changing challenge modalities based on the cost of requiring many more animals per group,
time, manpower and virus stocks needed to deliver daily challenges for weeks or months, and statistical complications due to
different times of acquisition. When it was demonstrated that
typical sexual transmission of HIV generally results in a single
or few founder viruses, then there was a stronger scientific rationale for the lower-dose challenges that are typically used today. This has led to encouraging news that protection from this
type of challenge and indeed protection in humans may be more
attainable, based on the amounts of antibodies needed for protection in macaques.

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APPENDIX B

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Information-Gathering Agendas

May 26, 2011
Keck Center, Room 109
500 Fifth Street, NW
Washington, DC 20001
BACKGROUND AND OVERVIEW
Session Objectives: Obtain a better understanding of the background to
the study and the charge to the committee. Receive a briefing from NIH
about existing areas of science where chimpanzee research is supported.
Hear from stakeholders about the use of chimpanzees in research, as
specifically related to the committee’s charge.
1:00 p.m.

Welcome and Introductions
JOHN STOBO, Committee Chair
Senior Vice President
Health Sciences and Services
University of California System

1:10 p.m.

Background and Charge to the Committee
SALLY ROCKEY
Deputy Director for Extramural Research
National Institutes of Health
167

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1:30 p.m.

ASSESSING THE NECESSITY OF THE CHIMPANZEE

Committee Discussion with Sponsor
JOHN STOBO, Committee Chair
Senior Vice President
Health Sciences and Services
University of California System

2:15 p.m.

NIH-Supported Chimpanzee Biomedical Research
HAROLD WATSON
Deputy Director
Division of Comparative Medicine
National Center for Research Resources, NIH

2:35 p.m.

Discussion with the Committee

2:45 p.m.

BREAK

3:15 p.m.

NIH-Supported Chimpanzee Behavioral Research
RICHARD NAKAMURA
Scientific Director
National Institute of Mental Health, NIH

3:35 p.m.

Discussion with the Committee

3:45 p.m.

Panel Discussion: Is there a continued need for
chimpanzee research?
JOHN PIPPIN
Senior Medical and Research Adviser
Physicians Committee for Responsible Medicine
JARROD BAILEY
Science Director
New England Anti-Vivisection Society

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APPENDIX C

KEVIN KREGEL
Professor, Departments of Integrative
Physiology and Radiation Oncology
University of Iowa
Chair, Animal Issues Committee
Federation of American Societies for
Experimental Biology
4:15 p.m.

Discussion with the Committee

4:45 p.m.

ADJOURN

__________________________________________________________
August 11, 2011
Keck Center, Room 100
500 Fifth Street, NW
Washington, DC 20001
Meeting Objectives:
•
•
•
8:00 a.m.

To obtain background data on the current use of
chimpanzees in biomedical and behavioral research.
To explore potential alternative models to chimpanzees.
To seek public comment about the scientific need for
chimpanzees in biomedical and behavioral research.
Welcome and Meeting Objectives
JEFFREY KAHN, Committee Chair
Director and Professor
Maas Family Endowed Chair in Bioethics
Center for Bioethics
University of Minnesota

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ASSESSING THE NECESSITY OF THE CHIMPANZEE

SESSION I: THE CHIMPANZEE
Session Objectives: Understand chimpanzee behavior and genetics and
their role in biomedical research. Compare chimpanzees both to other
models and to humans. Explore the usefulness of the chimpanzee as a
model for biomedical and behavioral research, specifically for
understanding human diseases and disorders. Discuss what scientific
alternatives exist should the chimpanzee no longer be an available
model.
JAY KAPLAN, Session Chair
Professor of Pathology (Comparative Medicine),
Translational Science and Anthropology
Wake Forest University Primate Center and
Wake Forest Translational Science Institute
Wake Forest School of Medicine
8:10 a.m.

Chimpanzee Behavior
FRANS DE WAAL
C.H. Candler Professor of Primate Behavior
Department of Psychology
Emory University

8:30 a.m.

Chimpanzee Genetics
JEFFREY ROGERS
Associate Professor
Department of Molecular and Human Genetics
Baylor College of Medicine

8:50 a.m.

Chimpanzee Biomedical Research
ROBERT PURCELL
Chief, Hepatitis Viruses Section
Laboratory of Infectious Diseases
National Institute of Allergy and Infectious
Diseases

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APPENDIX C

9:10 a.m.

Panel Discussion with Committee
• What scientific alternatives exist should the
chimpanzee no longer be an available model?

9:40 a.m.

BREAK
SESSION II: BEHAVIORAL RESEARCH

Session Objective: Review current use of chimpanzees for behavioral
research. Explore alternative models also used in this research area.
ROBERT SAPOLSKY, Session Chair
Professor of Biology, Neurology and
Neurological Sciences
Stanford University
9:50 a.m.

PANELISTS [15 min/talk]
Chimpanzee Social Behavior and Communication
WILLIAM HOPKINS
Professor
Department of Psychology
Agnes Scott College
Chimpanzee Learning and Memory
CHARLES MENZEL
Senior Research Scientist
Language Research Center
Georgia State University
Potential for Non-Human Primates in Behavioral
Research
MARK MOSS
Professor and Chair
Department of Anatomy and Neurobiology
Boston University

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ASSESSING THE NECESSITY OF THE CHIMPANZEE

Chimpanzee Research in Zoos and Sanctuaries
BRIAN HARE
Assistant Professor
Department of Evolutionary Anthropology
Duke University
10:50 a.m.

Panel Discussion with Committee
• What scientific alternatives exist should the
chimpanzee no longer be an available model?
• How long would it take for science to catch up
if the chimpanzee were no longer available?
SESSION III: PUBLIC COMMENT

Session Objectives: Seek public comment from interested stakeholders
about the continued and potential future need for chimpanzees in
biomedical and behavioral research.
NOTE: To accommodate requests, speakers will be strictly limited to 3
minutes.
JEFFREY KAHN, Committee Chair
Director and Professor
Maas Family Endowed Chair in Bioethics
Center for Bioethics
University of Minnesota
11:20 a.m.

Public Comments
ALICE RA’ANAN
Director of Government Affairs and Science
Policy
The American Physiological Society
ANNE DESCHAMPS
Science Policy Analyst
Federation of American Societies for
Experimental Biology

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173

APPENDIX C

JUSTIN GOODMAN
Associate Director
People for the Ethical Treatment of Animals
LAURA BONAR
Program Director
Animal Protection of New Mexico
STEPHEN ROSS
Assistant Director, Lester Fisher Center for the
Study and Conservation of Apes
Lincoln Park Zoo
RAIJA BETTAUER
Bettauer BioMed Research
PAMELA OSENKOWSKI
Director of Science Programs
National Anti-Vivisection Society
SUE LEARY
President
Alternatives Research & Development
Foundation
THEODORA CAPALDO
President/Executive Director
New England Anti-Vivisection Society/Project
Release & Restitution
ERIC KLEIMAN
Research Director
In Defense of Animals
RYAN MERKLEY
Associate Director of Research Policy
Physicians Committee for Responsible Medicine
MATTHEW BAILEY
Vice President
National Association for Biomedical Research

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ASSESSING THE NECESSITY OF THE CHIMPANZEE

JOSEPH ERWIN
Consulting Primatologist
KATHLEEN CONLEE
Director of Program Management
The Humane Society of the United States
BETH CATALDO
Director
Cetacean Society USA
CATHY LISS
President
Animal Welfare Institute
DAVID DEGRAZIA
Professor of Philosophy
George Washington University
C. JAMES MAHONEY
Research Professor
New York University School of Medicine
12:20 p.m.

LUNCH
SPECIAL LECTURE

1:00 p.m.

Chimpanzees in Biomedical and Behavioral Research
JANE GOODALL (via video conference)
Founder
Jane Goodall Institute

1:30 p.m.

Discussion with Committee

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APPENDIX C

SESSION IV: HEPATITIS
Session Objectives: Review the role of chimpanzees in hepatitis research.
Explore alternative models also used in this research area.
DIANE GRIFFIN, Session Chair
Professor and Chair
Department of Molecular Microbiology and
Immunology
Johns Hopkins Bloomberg School of Public
Health
1:40 p.m.

PANELISTS [15 min/talk]
The Current State of Hepatitis Research
ROBERT LANFORD
Scientist
Department of Virology and Immunology
Texas Biomedical Research Institute
The Next Drug for Hepatitis B and C
CHRISTOPHER WALKER
Professor of Pediatrics
Nationwide Children’s Hospital
The Ohio State University
Cellular and Molecular Technique Advances in
Hepatitis Research
STANLEY LEMON
Professor of Medicine
Division of Infectious Diseases
University of North Carolina School of Medicine

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ASSESSING THE NECESSITY OF THE CHIMPANZEE

Humanized Mice for the Study of Human
Infectious Diseases
ALEXANDER PLOSS
Research Assistant Professor
Laboratory of Virology and Infectious Disease
The Rockefeller University
From Chimpanzee to Human—Translational Research
in Viral Hepatitis
EUGENE SCHIFF
Leonard Miller Professor of Medicine
Director, Schiff Liver Institute/Center for Liver
Disease
University of Miami Medical School
2:55 p.m.

3:40 p.m.

BREAK
SESSION V: INFECTIOUS DISEASES

Session Objectives: Review the role of chimpanzees in infectious disease
research. Explore alternative models also used in this research area.
JOHN BARTLETT, Session Chair
Professor
Department of Medicine
Johns Hopkins University School of Medicine
4:00 p.m.

PANELISTS [15 min/talk]
The Role of Chimpanzees in HIV Research
NANCY HAIGWOOD
Professor of Microbiology and Immunology
Director
Oregon National Primate Research Center

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APPENDIX C

The Role of Chimpanzees in RSV Research
PETER COLLINS
Director
RNA Viruses Section
National Institute of Allergy and Infectious
Diseases
Current Experimental Models for Malaria Vaccine
Development
ANN-MARIE CRUZ
Program Officer, Research and Development
PATH Malaria Vaccine Initiative
Monoclonal Antibody Therapeutics
THERESA REYNOLDS
Director
Safety Assessment
Genentech
Alternative Models for Infectious Disease
Research
ROBERT HAMATAKE
Director of HCV Biology
GlaxoSmithKline
5:15 p.m.

6:00 p.m.

ADJOURN

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ASSESSING THE NECESSITY OF THE CHIMPANZEE

August 12, 2011
Keck Center, Room 100
500 Fifth Street, NW
Washington, DC 20001
Meeting Objectives:
•
•
•

To obtain background data on the current use of chimpanzees
in biomedical and behavioral research
To explore potential alternative models to chimpanzees
To seek public comment about the scientific need for
chimpanzees in biomedical and behavioral research
SESSION VI: POTENTIAL FUTURE NEEDS

Session Objectives: Explore potential future needs for chimpanzees in
biomedical and behavioral research. Consider emerging threats and novel
technologies.
EDWARD HARLOW, Session Chair
Special Assistant to the Director
National Cancer Institute
8:30 a.m.

PANELISTS [15 min/talk]
Surveying the Future of Chimpanzee Research
THOMAS J. ROWELL
Director
New Iberia Research Center
University of Louisiana at Lafayettte
Is Chimpanzee Research Critical to the Health
Security of the United States?
JOSEPH BIELITZKI
Associate Director
Office of Research and Commercialization
University of Central Florida

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179

APPENDIX C

The Role of Chimpanzees in Biodefense Research—
DoD Perspective
JAMES SWEARENGEN
Director (retired)
Comparative Medicine Veterinarian
National Biodefense Analysis and
Countermeasures Center
The Role of Chimpanzees in Biodefense Research—
NIH Perspective
MICHAEL KURILLA
Director
Office of Biodefense Research Affairs
National Institutes of Health
9:45 a.m.

Discussion with the Committee
• In the event of a public health emergency,
what would the consequences be if there were
no chimpanzees available for biomedical
research?
• What would the impact be if chimpanzees
were unavailable for testing during drug
development and research?
• How long would it take for science to catch up
if the chimpanzee were no longer available?

10:45 a.m.

ADJOURN

Chimpanzees in Biomedical and Behavioral Research: Assessing the Necessity

D
Committee Biographies

Jeffrey Kahn, Ph.D., M.P.H. (Chair), is the Robert Henry Levi and
Ryda Hecht Levi Professor of Bioethics and Public Policy at the Johns
Hopkins University Berman Institute of Bioethics. Prior to joining the
faculty at Johns Hopkins in 2011, Dr. Kahn was director of the Center
for Bioethics and the Maas Family Endowed Chair in Bioethics at the
University of Minnesota, positions he held from 1996 to 2011. Earlier in
his career, Dr. Kahn was director of the Graduate Program in Bioethics
and assistant professor of bioethics at the Medical College of Wisconsin,
and associate director of the White House Advisory Committee on Human Radiation Experiments. Dr. Kahn works in a variety of areas of bioethics, exploring the intersection of ethics and public health policy,
including research ethics, ethics and genetics, and ethical issues in public
health. He has served on numerous state and federal advisory panels, and
speaks nationally and internationally on a range of bioethics topics. He
has published more than 100 articles in the bioethics and medical literature, and is a coeditor of the widely used text Contemporary Issues in
Bioethics, about to enter its eighth edition. From 1998 to 2002, he wrote
the biweekly column “Ethics Matters” for CNN.com. Dr. Kahn earned
his B.A. in Microbiology from the University of California, Los Angeles
(UCLA), his M.P.H. from Johns Hopkins University, and his Ph.D. in
Philosophy/Bioethics from Georgetown University.
John G. Bartlett, M.D., is an internationally renowned authority on
AIDS and other infectious diseases. In 1970, he joined the faculty at
UCLA. He later moved to the faculty of Tufts University School of Medicine, where he served as associate chief of staff for research at the Boston VA Hospital. In 1980 he moved to Baltimore as professor of
181

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ASSESSING THE NECESSITY OF THE CHIMPANZEE

medicine and chief of the Division of Infectious Diseases at Johns Hopkins University School of Medicine. For 27 years, he has been a leader
for the School of Medicine’s worldwide efforts to understand, prevent,
and treat AIDS. He received the prestigious 2005 Maxwell Finland
Award for scientific achievement from the National Foundation for Infectious Diseases. Dr. Bartlett was the first to direct clinical trials in Baltimore of new treatments that prevent HIV from replicating, and he
pioneered the development of dedicated inpatient and outpatient medical
care for HIV-infected patients. In 1984, when AIDS was still in its infancy, he helped start a small clinic within the Moore Clinic to serve a small
group of gay men with AIDS, which along with providing research data
about how the disease spread, grew to become the centerpiece of the
Johns Hopkins AIDS Service. It is now the largest program for HIV care
in Maryland. Dr. Bartlett cochaired the national committee that drafted
the first and all subsequent treatment guidelines for HIV-infected patients. He counsels numerous medical societies and health ministries
around the world on infectious diseases in general and on AIDS specifically. Bartlett’s research interests have dealt with anaerobic infections,
pathogenic mechanisms of Bacteroides fragilis, anaerobic pulmonary
infections, and Clostridium difficile-associated colitis. Since joining
Hopkins in 1980, his major interests have been HIV/AIDS, managed care
of patients with HIV infection, pneumonia (community acquired), and,
most recently, bioterrorism. Clinically his interests include HIV primary
care, general infectious diseases, HIV and hemophilia, and HIV managed
care. He received his undergraduate degree from Dartmouth University
and earned his M.D. at Upstate Medical Center in Syracuse, New York.
He then completed residency training in Internal Medicine at the
Brigham and Women’s Hospital in Boston and the University of Alabama at Birmingham. Dr. Bartlett also completed Fellowship training in
Infectious Diseases at UCLA and at the Wadsworth Veterans Administration Hospital.
H. Russell Bernard, Ph.D., is the founder and current editor of the journal Field Methods, and has served as editor for the American Anthropologist and Human Organization. He has also served as the chair of the
Board of Directors for the Human Relations Area Files. A member of the
National Academy of Sciences (NAS), Dr. Bernard has been a recipient
of the Franz Boas Award from the American Anthropological Association as well as the University of Florida Graduate Advisor/Mentoring
Award. His teaching interests focus on research design and the systemat-

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183

ic methods available for collecting and analyzing field data. He has
taught both within the United States and in Greece, Japan, Germany, and
England. Dr. Bernard received his B.A. in Anthropology/Sociology from
Queens College, New York, his M.A. in Anthropological Linguistics
from the University of Illinois, and his Ph.D. in Anthropology from the
University of Illinois.
Floyd E. Bloom, M.D., is a past chair of the American Association for
the Advancement of Science (AAAS), former editor in chief of the journal Science, and former chair of the Department of Neuropharmacology
at the Scripps Research Institute in La Jolla, CA. A member of the National Academy of Sciences (NAS), he is the recipient of numerous prizes for his contributions to science, including the Janssen Award in the
Basic Sciences, the Pasarow Award in Neuropsychiatry, and the Institute
of Medicine’s (IOM’s) Rhoda and Bernard Sarnat International Prize in
Mental Health. He has also been named a member of the Royal Swedish
Academy of Sciences and a member of the IOM. Dr. Bloom’s more than
600 publications include the seminal work, The Biochemical Basis of
Neuropharmacology and The Dana Guide to Brain Health. In an important call-to-arms for healing the U.S. health care system, published
June 13, 2003, in Science and based on his Presidential Lecture at the
2003 AAAS Annual Meeting, he describes how events of the 20th century have produced a system that cannot incorporate or implement new
knowledge for the diagnosis or treatment of disease. Dr. Bloom earned
his B.A. from Southern Methodist University and his M.D. from the
Washington University School of Medicine.
Warner C. Greene, M.D., Ph.D., is director and Nick and Sue Hellmann Distinguished Professor of Translational Medicine of the Gladstone Institute of Virology and Immunology (GIVI), a research center
that is affiliated with the University of California, San Francisco, and
dedicated to fundamental studies of modern virology and immunology
with a focus on HIV and AIDS. Dr. Greene graduated from Stanford
University with a B.A. and Washington University School of Medicine
with an M.D. and a Ph.D. He completed internship and residency training in medicine at the Massachusetts General Hospital. After serving as a
senior investigator at the National Cancer Institute (NCI) and a Howard
Hughes Medical Institute investigator and professor of medicine at Duke
University, Dr. Greene moved to San Francisco in 1990 to become the
founding director of the Gladstone Institute of Virology and Immunolo-

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gy. He is also a professor of medicine, microbiology, and immunology at
UCSF. The ongoing research in Dr. Greene’s laboratory focuses on the
molecular basis for HIV pathogenesis, transmission, and latency and the
biochemical mechanisms underlying the regulation and action of the NFkB/Rel family of eukaryotic transcription factors. The lab also studies
HIV Env-mediated fusion and its role in the transmission of HIV virions
across the female genital mucosa. Dr. Greene’s laboratory is also exploring how CD4 T cells die during HIV infection and devising new approaches to interdict this death pathway. Dr. Greene is the author of more
than 330 scientific papers. He is a member of the IOM and a Fellow of
the AAAS. He is also currently president-elect of the Association of
American Physicians. In 2007 he became president of the Accordia
Global Health Foundation, whose mission to build a healthy Africa
where every individual can thrive. Accordia is specifically focused on
overcoming the burden of infectious disease on the continent by creating
innovative program models that strengthen health capacity, building centers of excellence, and strengthening medical institutions. With Paul
Volberding, Dr. Greene also directs the UCSF–GIVI Center for AIDS
Research and is a member of the executive committee of the AIDS Research Institute at UCSF.
Diane E. Griffin, M.D., Ph.D., has been the principal investigator on a
variety of grants from the National Institutes of Health (NIH), the Bill &
Melinda Gates Foundation, and the Dana Foundation. She is the author
or coauthor of many scholarly papers and articles and is past president of
the American Society for Virology, Association of Medical School Microbiology Chairs, and American Society for Microbiology. She is a
member of the NAS, American Academy of Microbiology, and the IOM.
Dr. Griffin began her career at Johns Hopkins as a postdoctoral fellow in
Virology and Infectious Disease. After completing her postdoctoral
work, she was named an assistant professor of Medicine and Neurology.
Since then, she has held the positions of associate professor, professor,
and now professor and chair. She has also served as an investigator at
Howard Hughes Medical Institute. Dr. Griffin’s research interests include alphaviruses, acute encephalitis, and measles. Alphaviruses are
transmitted by mosquitoes and cause encephalitis in mammals and birds.
She has identified determinants of virus virulence and mechanisms of
noncytolytic clearance of virus from infected neurons. She is also working on the effect of measles virus infection and immune activation in response to infection on the immune system. In Zambia, she and her

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colleagues are examining the effect of HIV infection on measles and
measles virus vaccination. They have discovered that measles suppresses
HIV replication and are identifying the mechanism of this suppression.
Vaccine studies are defining the basis for atypical measles, and a new
vaccine to induce immunity in infants under the age of 6 months is under
development using a rhesus macaque model. Dr. Griffin earned a Biology degree from Augustana College, followed by an M.D. and a Ph.D.
from Stanford University. She completed her residency in Internal Medicine at Stanford University Hospital.
Edward Harlow, Ph.D., a distinguished molecular biologist, is an internationally recognized leader in cancer biology who is best known for his
discoveries regarding the control of cell division and critical changes that
allow cancer to develop. He is a professor of Biological Chemistry and
Molecular Pharmacology at Harvard Medical School and a Special Assistant to the Director at the National Cancer Institute. Previously he
served as Chief Scientific Officer of Constellation Pharmaceuticals, a
Cambridge MA biotechnology company that specializes in making anticancer drugs that target the unusual transcriptional regulatory states
found in tumor cells. He served as Scientific Director for the Massachusetts General Hospital Cancer Center and was Associate Director for Science Policy at the National Cancer Institute, where he helped direct U.S.
cancer research planning. Dr. Harlow has received numerous scientific
honors, including election to the National Academy of Sciences and the
Institute of Medicine, appointment as Fellow of the American Academy
of Arts and Sciences, and receipt of the American Cancer Society’s highest award, the Medal of Honor. Dr. Harlow has served on a number of
influential advisory groups, including the Board of Life Sciences for the
National Research Council, External Advisory Boards for UCSF, Stanford, UCLA, and NYU Cancer Center, and Scientific Advisory Boards
for the Foundation for Advanced Cancer Studies and numerous biotechnology and pharmaceutical companies, including Onyx, Alnylam, 3V
Biosciences, and Pfizer Pharmaceuticals. He received his B.S. and M.S.
from the University of Oklahoma and his Ph.D. at the Imperial Cancer
Research Fund in London.
Jay R. Kaplan, Ph.D., is professor of Pathology (Comparative Medicine), Translational Science, and Anthropology at Wake Forest School of
Medicine. He is also serves as head of the Section on Comparative Medicine (Department of Pathology) and director of the Wake Forest Primate

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Center. He moved to the Wake Forest University School of Medicine in
1979 to study the effects of behavioral stress on susceptibility and resistance to coronary artery atherosclerosis in a monkey model of human
heart disease. His current research with monkeys focuses on the behavioral and genetic factors that influence the quality of premenopausal
ovarian function, and in turn, on the effect of ovarian function on risk for
coronary heart disease and osteoporosis. This research has demonstrated
that much of the postmenopausal trajectory for atherosclerosis and bone
loss is established premenopausally, suggesting that primary prevention
of postmenopausal disease should begin in the decades prior to menopause. His achievements include more than 150 peer-reviewed publications, the Irvine H. Page Arteriosclerosis Award for Young Investigators
from the American Heart Association, the Presidency of the Academy of
Behavioral Medicine Research, and the awarding of numerous grants
from the NIH. He currently serves as principal investigator of the grant
that supports a large pedigreed and genotyped colony of vervet monkeys.
He also reviews for numerous journals and for the NIH. He has served as
a member of the National Academies Institute for Laboratory Animal
Research and as a member of the Animal Resources Review Committee
of the National Center for Research Resources. Most recently, Dr.
Kaplan became a member of the Society for Women’s Health Research
Interdisciplinary Studies in Sex Differences Fund for Cardiovascular
Disease Network. He received his B.A. in economics from Swarthmore
College. He then earned an M.A. and a Ph.D. in biological anthropology
from Northwestern University, where his research involved behavioral
observations of free-living rhesus monkeys on Cayo Santiago Island,
Puerto Rico.
Margaret S. Landi, V.M.D., is vice president of Global Laboratory Animal Science (LAS) for Glaxo SmithKline Pharmaceuticals and Chief of
Animal Welfare and Veterinary Medicine for GSK Research and Development. In this capacity, she is responsible for promoting animal welfare
and providing a high standard of technical and professional assistance to
the company’s research and development community. Dr. Landi is a
Diplomate in the American College of Laboratory Animal Medicine
(ACLAM) and is a past president of the organization. Besides serving on
the ACLAM Board of Directors, she has served on the Council of the
Institute of Laboratory Animal Research (ILAR), a part of the National
Academy of Science. While on the Council, she was editor-in-chief of
the ILAR Journal. She serves currently on the Board of Trustees for the

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Scientists Center for Animal Welfare, the National Association for Biomedical Research, and Americans for Medical Progress. Dr. Landi has
received Distinguished Alumni Awards from both the University of
Pennsylvania and William Paterson University. She has been awarded
the Charles River Prize and the Pennsylvania Veterinary Medical Association’s Veterinarian of the Year Award. In 2010, she was the recipient
of the Harry Rowsell Award from the Scientists Center for Animal Welfare. Dr. Landi has published and presented papers on a number of topics
related to laboratory animal medicine, welfare, and science. Her recent
area of work is in the application of global principles for laboratory animals in an international arena where laws, cultures, regulations, and policies differ.
Frederick A. Murphy, D.V.M., Ph.D., is a professor in the Department
of Pathology at the University of Texas Medical Branch (UTMB), Galveston. He is dean emeritus and distinguished professor emeritus of the
School of Veterinary Medicine at the University of California, Davis
(UCD). He is also distinguished professor emeritus at the School of Medicine, UCD. Earlier, he served as the director, National Center for Infectious Diseases, Centers for Disease Control and Prevention (CDC), and
before that as director of the Division of Viral and Rickettsial Diseases at
CDC. At UTMB, Dr. Murphy is a member of the Institute for Human
Infections and Immunity (and its executive board), the Center for Biodefense and Emerging Infectious Diseases, the Galveston National Laboratory, the Center for Tropical Diseases, and the McLaughlin Endowment
for Infection and Immunity (and member of its executive board). Dr.
Murphy’s professional interests include the virology, pathology, and epidemiology of highly pathogenic viruses/viral diseases: (1) Rabies: longrunning studies leading to the identification of more than 25 viruses as
members of the virus family Rhabdoviridae, identification and characterization of the first rabies-like viruses, and major studies of rabies pathogenesis in experimental animals, including the initial descriptions of
infection events in salivary glands and in muscle; (2) Arboviruses: longrunning studies of togaviruses and bunyaviruses with the initial proposal
for the establishment and naming of the virus family Bunyaviridae, and
characterization of “reo-like” viruses culminating in the establishment
and naming of the virus genus Orbivirus; (3) Viral hemorrhagic fevers:
long-running studies leading to the initial discovery of Marburg and Ebola viruses, and characterization of several other hemorrhagic fever viruses, culminating in the establishment and naming of the virus families

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Arenaviridae (e.g., Lassa virus) and Filoviridae (Marburg and Ebola viruses), and elucidation of the pathology and pathogenesis of the diseases
in humans, monkeys, hamsters, and guinea pigs caused by these exceptionally virulent agents; and (4) Viral encephalitides: long-running studies of the pathogenesis of neurotropic viruses in experimental animals,
including alphaviruses, flaviviruses, bunyaviruses, enteroviruses,
paramyxoviruses, herpesviruses, and others. He has been a leader in advancing the concept of “new and emerging infectious diseases” and “new
and emerging zoonoses.” Most recently his interests have included the
threat posed by bioterrorism. Dr. Murphy has a B.S. in bacteriology and
a D.V.M. from Cornell University, and a Ph.D. in comparative pathology
from UCD.
Robert Sapolsky, Ph.D., is a professor of biology, neurology and neurological sciences, and neurosurgery at Stanford University. He has focused his research on issues of stress and neuronal degeneration, as well
as on the possibilities of gene therapy strategies for protecting susceptible neurons from disease. Currently, he is working on gene transfer techniques to strengthen neurons against the disabling effects of
glucocorticoids. Dr. Sapolsky also spends time annually in Kenya studying a population of wild baboons in order to identify the sources of stress
in their environment, and the relationship between personality and patterns of stress-related disease in these animals. More specifically, he
studies the cortisol levels between the alpha male and female and their
subordinates to determine stress level. Dr. Sapolsky has received numerous honors and awards for his work, including the prestigious MacArthur
Fellowship genius grant in 1987, an Alfred P. Sloan Fellowship, and the
Klingenstein Fellowship in Neuroscience. He was also awarded the National Science Foundation Presidential Young Investigator Award and
the Young Investigator of the Year Awards from the Society for Neuroscience, International Society for Psychoneuro-Endocrinology, and Biological Psychiatry Society. In 2007, he received the John P. McGovern
Award for Behavioral Science, awarded by the AAAS. In 2008, he received the Wonderfest’s Carl Sagan Prize for Science Popularization.
Sapolsky received his B.A. in biological anthropology summa cum laude
from Harvard University and his Ph.D. in neuroendocrinology from
Rockefeller University.
Sharon F. Terry, M.A., is president and chief executive officer of the
Genetic Alliance, a network transforming health by promoting openness

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as process and product, centered on the health of individuals, families,
and communities. She is the founding executive director of PXE International, a research advocacy organization for the genetic condition
pseudoxanthoma elasticum (PXE). Following the diagnosis of their two
children with PXE in 1994, Ms. Terry, a former college chaplain, and her
husband founded and built a dynamic organization that enables ethical
research and policies and provides support and information to members
and the public. Along with the other coinventors of the gene associated
with PXE (ABCC6), she holds the patent for the invention, and with the
assignment of all rights to PXE International, is its steward. She
codirects a 33-lab research consortium and manages 52 offices worldwide for PXE International. Ms. Terry is also a cofounder of the Genetic
Alliance Biobank. It is a centralized biological and data repository catalyzing translational genomic research on genetic diseases. The BioBank
works in partnership with academic and industrial collaborators to develop novel diagnostics and therapeutics to better understand and treat these
diseases. She is at the forefront of consumer participation in genetics research, services, and policy and serves as a member of many of the major
governmental advisory committees on medical research, including the
Health Information Technology Standards Committee for the Office of
the National Coordinator for Health Information Technology, liaison to
the Health and Human Services Secretary’s Advisory Committee on Heritable Disorders and Genetic Diseases in Newborns and Children, and the
National Advisory Council for Human Genome Research, National Human Genome Research Institute (NHGRI), NIH. She serves on the
boards of GRAND Therapeutics Foundation, Center for Information &
Study on Clinical Research Participation, The Biotechnology Institute,
National Coalition of Health Professional Education in Genetics, and
Coalition for 21st Century Medicine. She is on the steering committees
of the Genetic Association Information Network of the NHGRI, the
CETT program, and the EGAPP Stakeholders Group; the editorial boards
of Genetic Testing and Biomarkers and Biopreservation and Biobanking,
and the Google Health and Rosalind Franklin Society Advisory Boards.
She is chair of the Coalition for Genetic Fairness, which was instrumental in the passage of the Genetic Information Nondiscrimination Act. She
is a member of the IOM Roundtable on Translating Genomic-Based Research for Health. In 2005, she received an honorary doctorate from Iona
College for her work in community engagement and haplotype mapping;
in 2007 received the first Patient Service Award from the UNC Institute
for Pharmacogenomics and Individualized Therapy; and in 2009 received

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the Research!America Distinguished Organization Advocacy Award.
She has recently been named as an Ashoka Fellow and won the Clinical
Research Forum’s 2011 Public Advocacy Award.

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