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Guiding Limited Use of Chimpanzees in Research

Bruce M. Altevogt,1* Diana E. Pankevich,1* Andrew M. Pope,1* Jeffrey P. Kahn2*
Institute of Medicine, National Academies, Washington, DC 20001, USA. 2Berman Institute of Bioethics, Johns Hopkins University, Baltimore, MD 21205, USA. *Responsibility for the content of this article rests with the authors and does not necessarily represent the views of the Institute of Medicine, its committees, and its convening activities.
1

J. P. Kahn was chair of the IOM committee (1).

Author for correspondence. E-mail: baltevogt@nas.edu Research on chimpanzees is contentious, expensive, and of increasingly limited necessity. Over the past 10 years, there have been only 110 projects involving chimpanzees sponsored by the National Institutes of Health. Close to half of these projects were used for hepatitis research; the remaining studies were in fields including comparative genomics, neuroscience and behavioral research, and infectious diseases such as respiratory syncytial virus (RSV). NIH requested that the Institute of Medicine (IOM) and National Research Council convene an expert committee to assess the current and future scientific necessity of chimpanzee use as a research model in publicly funded biomedical and behavioral research. The committee developed a set of uniform principles around what constitutes necessary use of chimpanzees, because of the lack of existing criteria (1). The knowledge gained must be necessary to advance the publics health; 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 the animals used in the proposed research must be maintained in either ethologically appropriate physical and social environments or natural habitats. comparative genomics and behavioral research met the criteria developed or could meet the criteria if minor modifications in study protocols were made to address questions of acquiescence, pain, and distress. Some studies did not specify the type of housing or how often and by what mode anesthesia was provided to the animal. In general, for behavioral research, the committee would not find it acceptable for an animal to be provided general anesthesia through a dart gun or for animals not to be housed in social settings. It encouraged studies relying on examinations or sample gathering performed as part of regular veterinary care. Examples of minimally invasive research include behavioral observation and noninvasive interventions that can only be performed on anesthetized animals, e.g., magnetic resonance imaging scans of the brain. The committee recommended that these be performed in conjunction with regular veterinary exams and care that would otherwise require general anesthesia of individual animals. The committees criteria for behavioral and genomics studies were additionally motivated by the view that research involving animals that are stressed or otherwise affected by their environment are less likely to yield meaningful, consistent, and useful results. In addition to the principles described above, one additional criterion was specific to biomedical research: 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. The committee concluded that, although the chimpanzee has been a valuable animal model in the past, by its criteria, most current use of chimpanzees for biomedical researchincluding RSV vaccine, therapeutic hepatitis C (HCV) vaccine, and HCV antiviral drug developmentis not currently warranted, except for two limited research uses: for monoclonal antibodies and in prophylactic HCV vaccines. Production of monoclonal antibodies after immunization in other species or through in vitro synthetic methods is equally powerful for the generation of such reagents. Further, there are currently four methods in use that lessen the need for

Necessity of Chimpanzees for Research

Criteria specifically aimed at comparative genomics and behavioral research were as follows: (i) studies provide otherwise unobtainable insight into comparative genomics, normal and abnormal behavior, mental health, emotion, or cognition, and (ii) all experiments are performed on acquiescent animals, using techniques that are minimally invasive and in a manner that minimizes pain and distress. Acquiescence is defined as situations in which animals do not refuse or resist research-related interventions and that do not require threats for participation; for instance, animals are often trained to present their arms for the purpose of blood draws. The committee found that much of the current

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safety tests in chimpanzee: (i) genetic engineering of the target protein in rodents, (ii) selection of antibodies that recognize target epitopes shared across species, (iii) selection of multiple antibodies that can serve as surrogates for responses, and (iv) testing low levels in humans (2). However, not all antibodies under development were derived with the newer technologies; studies based on these antibodies may require continued use of chimpanzees to avoid substantially slowing research or preventing important advancements. For these specific cases, continued use of chimpanzees should be assessed against the committees criteria for biomedical research, although the expectation is that, within 5 years, chimpanzees will not be used in monoclonal antibody research. The greatest number of projects using the chimpanzee over the past 10 years has been for hepatitis research. Development of antiviral drugs and therapeutic vaccines for HCV does not necessitate use of the chimpanzee because of the emergence of other animal models and the ability to ethically perform safety and efficacy studies in humans. However, the challenges associated with developing prophylactic HCV vaccines may continue to necessitate the chimpanzee. Progress is being made in the development of various mouse models that can be infected with HCV, but these do not allow evaluation of the human protective immune response. Although challenge studies for HCV prophylactic vaccine development cannot be performed in humans, studies in consenting individuals at high risk for natural HCV infection can be ethically done provided that these vaccines are first shown to be safe and immunogenic in experimental animals, such as mice and nonhuman primates. The committee could not reach consensus on whether preclinical studies examining the safety of candidate prophylactic vaccines necessitate the chimpanzee, or if the development of a prophylactic HCV vaccine would be slowed by bypassing preclinical chimpanzee research and going directly into human trials. Research relying on existing blood or tissue samples would be exempt from the criteria, as no interaction with living chimpanzees would be required. Finally, the committee stressed that chimpanzees used for any research must be maintained in ethologically appropriate environments accredited by Association for Assessment and Accreditation of Laboratory Animal Care, for example, Primadomes or corrals with environmental enrichment, outdoor caging with access to shelter, and indoor caging (1).

Discussion
The committee was charged specifically to develop criteria for chimpanzee use; therefore, it would not be appropriate to apply these criteria to assess the necessity of other nonhuman primates in research. The necessity of other research animals

should continue to be assessed using current regulations and guidelines. The Interagency Animal Model Committee (IAMC) currently provides an additional review by the NIH to ensure the appropriateness of using the chimpanzee and the number of animals, as well as the degree of invasiveness of the research. However, only federal employees are members. The assessment would be strengthened and the process made more credible by establishing an independent oversight committee that builds on the IAMC and that uses the recommended criteria. It should include public representatives, as well as individuals with scientific expertise in the use of chimpanzees and alternative models and in areas of research in which chimpanzees might be used. This is similar to the working groups of the Advisory Committee to the NIH Director. The committee was not tasked with assessing the use of the chimpanzee by the private sector; however, many of the biomedical research areas assessed by the committee are also being pursued by industry. Adoption of the committees criteria by industry could ensure that the private sector limits its use of chimpanzees to areas of clear necessity. The request for the IOM report originated with the U.S. Congress, which for the past three sessions has been considering legislation that would ban research using the chimpanzee and other great apes [Great Ape Protection Act (GAPA) of 2010 (111th Congress, second session) and Great Ape Protection and Cost Savings Act (GAPCSA) of 2011 (112th Congress, first session)]. Similarly, in 2010, the European Union banned the use of all great apes, including chimpanzees, in research. However, a safeguard clause in the EU ban allows use of great apes for research that is broadly defined as addressing a life-threatening, debilitating condition that endangers human beings provided the purpose cannot be achieved by the use of other species or alternative methods (3). The EU Directive provides no additional information by which researchers or member states should base their decisions. There has been no biomedical research involving great apes in the EU since 1999 (4, 5). Both the committees criteria and the EU directive are in contrast to the approach proposed in GAPSCA, which would prohibit any research that may cause death, injury, pain, distress, fear, or trauma (H.R.1513.IH and S.810.IS). The proposed legislation does not include an analysis in support of the proposed prohibition, though its findings and purpose focus on the welfare and protection of the animals. The committee did consider ethics in its analysis, which informed its approach in responding to the NIH charge to assess the necessity of the chimpanzee in contemporary and future research (1). Given the information available to the committee through its research and provided by relevant federal agencies, it will be very difficult to defend the necessity of nearly all current

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biomedical research on chimpanzees. The most difficult assessment will be in cases of prophylactic vaccine development research in which the chimpanzee is the only nonhuman animal model. Even those cases are likely to see the need for chimpanzees diminish as alternative models become available. However, a new, emerging, or reemerging disease or disorder may present challenges to treatment, prevention, and/or control that defy nonchimpanzee models and technologies and thus may require their future use. Therefore, an outright ban on biomedical chimpanzee research would not be appropriate. Since 1997 the NIH has instituted a moratorium on government sponsored breeding of chimpanzees (6); however, very limited breeding of chimpanzees for research purposes is still under way through the support of the private sector. The moratorium presents a challenge for conducting future research, should it be justified, because of the aging chimpanzee population (7), the very small number of research-naive animals, and the time it takes for chimpanzees to mature. The cost of maintaining a chimpanzee is $44/day, and with an average lifespan of 40 to 45 years, this can reach over $642,400 per animal over the course of their lifetimes (there has been a moratorium on euthanasia of chimpanzees since 1995) (8). Should there be a public health emergency requiring the chimpanzee, it will likely not be possible to quickly breed and expand the population. Therefore, the number and demographics of animals maintained for any potential research use will need to be carefully considered. The committees review and assessment highlighted not only the issues and challenges of chimpanzee research, but also the importance of other animal research models. Although the necessity of chimpanzees in research is quickly declining, animal research remains a critical tool in protecting and advancing the publics health. References and Notes 1. IOM, Chimpanzees in Biomedical and Behavioral Research: Assessing the Necessity (National Academies Press, Washington, DC, 2011). 2. K. Chapman et al., MAbs 1, 505 (2009). 3. European Union, Directive 2010/63/EU of the European parliament and of the council of 22 September 2010 on the protection of animals used for scientific purposes. Official Journal of the European Union, No. L 276/33 (20 October 2010). 4. European Parliament, Declaration of the European Parliament on primates in scientific experiments, adopted 25 September 2007. 5. G. Vogel, ScienceNOW, 1 May 2001; http://news.sciencemag.org/sciencenow/2001/05/0101.html. 6. National Center for Research Resources, NIH, Chimpanzee management program;

www.ncrr.nih.gov/comparative_medicine/chimpanzee_ma ngement_program/. 7. J. L. VandeBerg, S. M. Zola, Nature 437, 30 (2005). 8. U.S. Department of Health and Human Services, Archived, Costs for maintaining humane care and welfare of chimpanzees; http://grants.nih.gov/archive/grants/policy/air/cost_for_car ing_housing_of_chimpanzees_20110609.htm. Published online 15 December 2011; 10.1126/science.1217521

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