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National Research Council (US) Committee on Long-Term Care of Chimpanzees. Chimpanzees in Research: Strategies for Their Ethical Care, Management, and Use. Washington (DC): National Academies Press (US); 1997.

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Chimpanzees in Research: Strategies for Their Ethical Care, Management, and Use.

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2RESEARCH NEEDS

Chimpanzees have been used in biomedical research to gain an understanding of various diseases that result in substantial morbidity and mortality. The value of chimpanzees in studies designed to make it possible to prevent or treat diseases is due in large part to their genetic similarity to humans. In the case of some infectious diseases, such as hepatitis B, chimpanzees are the only nonhuman species that can be infected with the causative microorganism. Furthermore, some important therapies for diseases not caused by microorganisms have been developed only because they were evaluated in chimpanzees when other species proved to be unsuitable or provided suboptimal results. Because situations like these are likely to arise in the future, chimpanzees should continue to be available for research protocols that benefit human health and well-being. Furthermore, the possibility of a national emergency due to a new infectious agent that presents a major hazard to human health and for which no obvious prophylaxis or therapy is available is a compelling reason to maintain a population of chimpanzees for biomedical research.

VALUE OF PAST STUDIES WITH CHIMPANZEES

An important perspective on future research needs for chimpanzees can be gained from an evaluation of the results of previous studies. Over the last 20 years, chimpanzees have been used as experimental models of humans in several research fields, including infectious disease, reproduction, language, and behavior. The contributions with the greatest effect on human health have come from infectious-disease research that focused on the development of vaccines and new classes of therapeutic agents. Instances in which the use of chimpanzees was considered either critical or a prerequisite to introducing an agent into humans include development and safety testing of vaccines for hepatitis B virus (HBV) and identification of the hepatitis C virus (HCV) both of which had enormous benefit to humankind; and development of novel inhibitors of neutrophil elastase. Those and other examples warrant additional discussion to emphasize the value of chimpanzees as an experimental model of human health problems.

INFECTIOUS DISEASE

Experimental infection of chimpanzees as animal models in biomedical research has involved such diverse microorganisms as mycoplasma species, the filarial nematode Onchocerca volvulus, numerous viruses, and unconventional agents associated with subacute degenerative diseases of the central nervous system (such as spongiform encephalopathies, including kuru and Creutzfeldt-Jakob disease). Major contributions to human health have resulted from the use of chimpanzees in studies to control transmission of and disease induced by the hepatitis viruses, respiratory syncytial virus, and human immunodeficiency virus (HIV).

Early research on HBV was hindered by the inability to propagate it in tissue culture. Because chimpanzees are the only nonhuman primates susceptible to infection with HBV, they were critical to the development of a vaccine by providing a source of virus and viral antigens and by making it possible to evaluate the safety and the effectiveness of candidate vaccines. The benefits of HBV vaccination to humanity can be characterized as not only controlling an important disease but also presenting a potential approach to controlling the transmission of disease from mother to child, thereby eliminating a major problem for mankind, particularly in Asia, but also in the United States. Even though hepatitis B is relatively rare in the United States, the major vaccine-recommending bodies, including the American Academy of Pediatrics and the Immunization Practices Advisory Committee, now recommend universal hepatitis B vaccination of newborns. This is important because about 75% of newborns who acquire it from their mothers become chronic carriers, which provides the potential for lifelong transmission of the disease, lifelong carriage of the virus in an active replicating form, and an increase by a factor of 200 in the relative risk of developing hepatocellular carcinoma, compared with a noninfected person. The latter possibility makes this the first vaccine against a form of cancer. That enormous long-term benefit to humanity represents the harvest that we will continue to reap from the research on hepatitis B that was carried out in chimpanzees.

Although the exact number of chimpanzees used in the successful development of a vaccine against HBV is not known, institutions reporting past exposures of chimpanzees to specific agents indicate that 195 animals that they now house, including those also exposed to HCV and HIV, participated in hepatitis virus research (Table 2.1). That number substantially underestimates the total used, because of normal attrition and the fact that many chimpanzees housed at New York University's Laboratory of Experimental Medicine and Surgery in Primates (LEMSIP) were not counted but are known to have been used in HBV studies.

TABLE 2.1. Chimpanzees Exposed to All Hepatitis Viruses and HIV at Six Research Facilities.

TABLE 2.1

Chimpanzees Exposed to All Hepatitis Viruses and HIV at Six Research Facilities.

Infection of chimpanzees with the hepatitis A, C, and delta viruses also provided important models for gaining an understanding of disease. HCV virus is a bloodborne pathogen that can establish a chronic infection and lead to cirrhosis or hepatocellular carcinoma. It is rapidly evolving, and already 1-2% of people in the United States are infected (Purcell 1994). Using molecular biological techniques and plasma samples from a chimpanzee chronically infected with HCV, previously called non-A, non-B (NANB) hepatitis virus, Choo and others (1989, 1990) successfully identified the causative agent of the infection. That would not have been possible without the clearly documented titration and transmission studies that were performed in chimpanzees. A successful vaccine for hepatitis C remains elusive because of the extensive genetic diversity of the virus. Chimpanzees continue to be important in the search for a solution to this problem (Lemon and Thomas 1997).

Respiratory syncytial virus (RSV) is an RNA virus that causes annual epidemics of upper and lower respiratory disease, primarily in infants and young children; some of these infections can be life-threatening. Only the chimpanzee develops disease symptoms comparable with those observed in infected humans, particularly the more-severe lower respiratory infections. As with the hepatitis viruses, that fact has made the use of chimpanzees critical for evaluating RSV vaccine efficacy. A temperature-sensitive, attenuated RSV mutant has been used in vaccine trials, and chimpanzees were required for two reasons: to determine whether the attenuated viruses revert to wild-type and thereby cause disease, and to determine whether antibodies induced by immunization will enhance disease on exposure to infection with wild-type RSV.

As with HBV and HCV, the only animal species initially tested that could be infected with AIDS-patient material, or with the virus itself after it was isolated, was the chimpanzee (Francis and others 1984; Gajdusek and others 1985). This primate species remains the only one (except humans) that can be persistently infected with multiple HIV-1 strains by both intravenous and mucosal routes. That chimpanzees can be infected with HIV strains representing different subtypes is critical because of the unprecedented genetic diversity of strains circulating worldwide (WHO Network for HIV Isolation and Characterization 1994). That diversity (and data obtained in studies with chimpanzees) indicates that a vaccine based on only one HIV subtype will have limited protective value, so it will be necessary to test different combinations of antigens to identify the ones that together induce the broadest cross-reactivity. This is even more important in light of the high costs associated with the current successful advances in the treatment of AIDS; these costs will limit their use not only in the United States, but especially in poorer nations. Thus, the formulation of clinically effective, inexpensive vaccines is likely to be the best long-term solution to this global problem.

Although only one of about 200 chimpanzees infected with HIV-1 has so far succumbed to an AIDS-like disease, several animals that have been infected for a long time exhibit decreased CD4:CD8 lymphocyte ratios. Virus isolated from the chimpanzee that died of AIDS elicited a rapid decline in CD4+ cells in all of three chimpanzees experimentally infected with this HIV variant (Fultz unpublished data; Novembre and others 1997). Thorough evaluation of immune responses and virus-host interactions in these infected animals, compared with chimpanzees infected with other, less pathogenic isolates, might provide new insights into HIV pathogenesis. In addition, chimpanzees have been and will continue to be important in studies to develop HIV vaccines and to evaluate their immunogenicity and protective efficacy against infection.

Although HIV infection of chimpanzees has not been an ideal model of disease, at least 198 chimpanzees have been used to date in HIV-related studies; this number reflects only HIV-1-infected animals now held at various institutions, excluding animals exposed at LEMSIP of which the committee has no knowledge (Table 2.1).

XENOBIOTICS

Chimpanzees have been used as a final step in the evaluation of new therapeutic agents before their administration to humans. Evaluation of xenobiotics is generally brief and presents little or no potential hazard to the well-being of the chimpanzee. However, such studies can be essential in justifying the introduction of a xenobiotic to humans. A specific example is the development of novel inhibitors of the enzyme elastase, which is present at high concentrations in human neutrophils and has been implicated in tissue destruction associated with inflammatory diseases, such as those of the upper respiratory tract, including cystic fibrosis, bronchiectasis, and emphysema. The inhibitors are much less potent in lower species, only by using chimpanzees was it possible to validate their use in human trials (Mumford and others 1995), where its remarkable potency was confirmed.

FUTURE NEEDS FOR CHIMPANZEES

Chimpanzees have not been a universally satisfactory model for human diseases. The reason (given the close genetic relationship of chimpanzees to humans) is not clear, but one reason is probably the lack of research in basic biology and medicine in chimpanzees. The cost of using chimpanzees has prevented research on all but high-visibility diseases such as AIDS and hepatitis B research. Their contribution to hepatitis B is direct and substantial; to AIDS research it is still unknown. In sum, the committee concluded that the chimpanzees have contributed to human health research and would likely do so in the future and that without sustaining a small “core population” it is unlikely that there will ever be another captive US research population. The committee's approach to these problems is to recommend a central management structure (ChiMP, see chapter 5) that can vigorously manage the population to reduce the number in research and breeding, reduce the cost, and encourage basic research. Given the unpredictable nature of emerging threats to human health, it is not possible to predict the total requirement for chimpanzees in the future. Table 2.2 shows some projected future needs, as indicated by a limited survey of investigators at NIH and elsewhere, and includes emerging health threats to mankind that could best be met by research with chimpanzees. If, as exemplified by experience with HIV and hepatitis, some of the emerging threats will involve long periods of disease latency or chronicity that will require commitment of multiple chimpanzees over periods of years. Tables 2.2 and 2.3 provide some guidance as to the numbers of chimpanzees that are required to meet such needs. Chapter 4 provides two models by which to meet the needs. The tables do not take into account needs for chimpanzees that individual investigators or organizations were not prepared to disclose. Thus, chimpanzees will be required in the future for continuation of the research discussed above and to address problems associated with aging and unforeseen health conditions.

TABLE 2.2. Projected Future Needs for Chimpanzees in Biomedical Research (Government Only).

TABLE 2.2

Projected Future Needs for Chimpanzees in Biomedical Research (Government Only).

TABLE 2.3. Some Present Uses of Chimpanzees in Biomedical Research.

TABLE 2.3

Some Present Uses of Chimpanzees in Biomedical Research.

KNOWN INFECTIOUS AGENTS

The future use of chimpanzees will be critical in ensuring progress in controlling diseases associated with a number of specific agents that have been identified. The most efficient way to prevent infectious disease is prophylactic vaccination. Because of the complexity of the immune system and the diversity of virus-host interactions, there is no suitable substitute for a live animal in the testing of vaccine efficacy. We present here four important examples of such need for chimpanzees.

HEPATITIS

Even though a vaccine for HBV is in wide use and much progress has been made in developing an effective HCV vaccine, additional work is required for the latter (Lemon and Thomas 1997). In addition to HCV, the former NANB hepatitis viruses are known to include an enterically transmitted virus, designated hepatitis E, which has been transmitted to cynomolgus macaques, as well as to chimpanzees. Because there is evidence that more hepatitis viruses exist, and most hepatitis viruses grow poorly or not at all in tissue culture, chimpanzees will probably continue to be an important resource in efforts to control this diverse group of viruses.

Conceivably, the number of chimpanzees required for safety and efficacy testing of vaccines for several such viruses will be comparable with that for the development of HBV vaccines.

RSV

RSV is an RNA virus for which subunit vaccines are being tested in chimpanzees. However, a major problem is associated with the use of chimpanzees for RSV studies: like humans, chimpanzees become naturally infected with this virus when very young. Unless enough RSV-negative older animals are available, this research probably will require a recurring supply of animals less than about 3-yr-old. It is projected that 18-24 infant or older RSV-seronegative chimpanzees per year will be needed for at least the next 3 yr for studies with live attenuated vaccines. The use of young animals and the associated breeding would be obviated by screening all animals, particularly the older ones, for RSV seropositivity.

HIV

Substantially reducing the transmission of HIV worldwide requires two approaches: behavioral modification and vaccination. Given the urgency to develop a vaccine effective against all known subtypes of HIV, which now number nine, the continued use of chimpanzees will be required. Most studies with the HIV-chimpanzee model have used subtype B strains. Although HIV-1 subtype A and E strains have also been shown to infect chimpanzees, the latter by both intravenous and mucosal routes (Barre-Sinoussi and others 1997), HIV-naive chimpanzees also will be required to determine whether HIV strains representing the other subtypes are infectious in this species. Furthermore, transmission occurs by both parenteral and mucosal (vaginal-cervical and rectal) routes, and it will be necessary to use additional animals to demonstrate infection by each route. If controlled vaccine-efficacy trials are conducted in chimpanzees, challenge stocks of each HIV subtype first must be titrated in vivo to identify minimal chimpanzee infectious doses by the various routes; and chimpanzees will be required as naive control animals in vaccine-efficacy trials. It is projected that two groups of chimpanzees will be important for future HIV research sponsored by NIH: about six to nine HIV-naive chimpanzees per year will be required for vaccine studies, and at least five HIV-infected chimpanzees per year will be used as surrogates for chimpanzees immunized with attenuated vaccines. Given the uses foreseen here—testing the infectivity of non-subtype-B HIV, establishing mucosal-challenge models, and serving as naive controls—as well as evaluating the pathogenesis of the HIV-1 isolated from the chimpanzee that succumbed to AIDS, the requirement could be 11-14 chimpanzees per year. If alternative models, such as transgenic mice that express both the primary and secondary receptors for HIV or infection of macaques with chimeric simian immunodeficiency virus SIV/HIV (SHIV), are validated, the numbers required will decrease. However, transgenic mice are unlikely to replace chimpanzees in HIV vaccine studies, and although the SHIV-macaque model might provide preliminary data for novel vaccine strategies, the macaque models have inherent limitations in that the infecting virus expresses only a subset of HIV antigens. Moreover, new targets for therapeutic intervention, such as coreceptors for HIV, might trigger new avenues of research with chimpanzees.

MALARIA

Malaria presents a major threat to world health. Recent publications indicate that the chimpanzee is uniquely susceptible to infection with the Plasmodium ovale strain of the parasite (Morris and others 1996; Thomas and others 1994). From 1983 to 1995, 28 chimpanzees were used to study various aspects of infection with P. ovale (Morris and others 1996). Although chimpanzees might not be used for evaluation of antimalarial vaccines, there will be a continuing need for them in malaria research, primarily for the production of antigens for immunization purposes.

EMERGING INFECTIOUS AGENTS

Scientists, physicians, and public-health officials knowledgeable about infectious diseases accept the validity of the assumption that sometime in the future, new or old microbial pathogens will present major threats to the population. That idea was examined by a panel of experts convened by the Institute of Medicine (Lederberg and others 1992). In 1995, the Centers for Disease Control and Prevention began publishing a new journal, Emerging Infectious Diseases, dedicated solely to identifying and analyzing new and re-emerging infectious diseases around the world. The emerging or re-emerging infections have the potential not only to reach epidemic proportions in their country of origin, but also to become global pandemics, as was demonstrated recently by HIV infection (Quinn 1994). In an increasingly open and extensively traveled globe, the extent to which infectious agents can be transported rapidly around the world is almost unlimited.

The list of emergent microorganisms that have caused substantial morbidity and mortality in the last few decades is long; the best known is HIV. AIDS was first recognized in the early 1980s in the United States, and HIV, a retrovirus, was later identified as its etiologic agent. However, by the time HIV was identified, it had already been disseminated from the African continent, its place of origin, into defined populations, such as homosexuals, injecting drug-abusers, and hemophiliacs (Anderson and others 1991; Curran and others 1985; Quinn 1994). Multiple factors, most of which resulted from human activities, contributed to both the emergence and the spread of HIV. Those factors included urbanization and movement of segments of the population from rural African villages to expanding cities; changes in lifestyle and sexual behavior, including increased prostitution in African cities and high-risk sexual behavior in the homosexual population; increased illicit drug use; increased international travel between all continents; and medical technology, for example, blood transfusions and immunosuppressive regimens associated with tissue transplantation.

We cannot predict what infectious disease will emerge next or when, but because the factors that contributed to the HIV pandemic will continue, new ones are inevitable. During the last 20 years, new etiologic agents of major emergent infectious diseases have been identified at the rate of one per year (Satcher 1995). Furthermore, it is highly probable that most factors associated with the emergence or re-emergence of infectious diseases—whether their origin is viral, bacterial, protozoan, or fungal—will persist or new ones will arise (Morse 1995). Likewise, just as the chimpanzee is the only nonhuman animal that HIV and some hepatitis viruses infect, other unknown pathogens might also exhibit this property. Thus, it is critical that the captive chimpanzee population be maintained in sufficient numbers to meet a potential public-health emergency. Because experimental infection with one pathogen does not necessarily preclude use of an animal in infectious disease studies with an unrelated pathogen, many of the chimpanzees now being used in hepatitis, RSV, and HIV research could meet a future need. However, because we cannot predict when a new infectious agent will emerge or the nature of that agent, naive chimpanzees also must be held in reserve. Chapter 4 discusses possible strategies by which to address recurring national emergencies and continuing need for small numbers of chimpanzees.

OTHER RESEARCH

In addition to their use and value in biomedical research on infectious diseases, chimpanzees have provided and will continue to provide important information in existing fields—such as behavior, language, reproduction, and development of therapeutic agents—and in new fields, such as correction of inherited diseases in utero. Furthermore, as the average age of the US population rises, this will also occur in the captive chimpanzee population because of reduced breeding, making them obvious subjects for research related to medical problems of the elderly.

Behavioral research is usually performed with chimpanzees in social groups or of defined ages, such as nursery-reared infants. Thus, depending on specific requirements, future needs for these projects can be met by existing chimpanzee populations, such as the breeding colonies. Potential groups of animals for behavioral studies include those designated for uses specified above, those in breeding pools, and those housed in sanctuaries. In this context, it will be important for the Chimpanzee Management Program (ChiMP) office proposed in chapter 5 to publicize the availability of a pool of chimpanzees for new fields of research, such as those discussed above.

There will probably be a requirement for a substantial number of chimpanzees in pivotal studies of novel xenobiotics that have potential therapeutic benefit to humans. Of particular importance are studies to define mechanisms of action or efficacy when sensitivity of the molecular target of a novel agent is similar in chimpanzees and humans but different in other species. Pharmacokinetics of drugs are known to vary greatly across species, but in this respect chimpanzees and humans are similar most of the time. In the past, critical decisions on the choice of specific agents from among groups of novel therapeutic agents were made on that basis. In general, studies of novel xenobiotics are of short duration, and any compromise of the well-being of the animals is minimized by prior extensive toxicologic evaluation in other species.

MAXIMIZING THE AVAILABILITY OF CHIMPANZEES

Chimpanzees are often used in research protocols that do not preclude their later use in unrelated research protocols. To illustrate, most chimpanzees in HIV studies were used previously in hepatitis research; in fact, their prior exposure to hepatitis virus was generally considered a prerequisite for entry into an HIV study. As indicated above, young chimpanzees in RSV studies can be used later in studies with other infectious agents or for breeding. All animals, irrespective of prior research use, would be candidates for aging studies. Moreover, it would be appropriate to draw chimpanzees from a long-term care facility into short-term research protocols that have no zoonotic potential. Currently, because of the costs of using them, chimpanzees are used primarily for studies of diseases of major human-health importance. The committee encourages ethically justifiable, IACUC-approved research with a broader perspective, such as benefits to chimpanzee well-being, basic scientific knowledge, and aging. For-profit organizations, particularly pharmaceutical companies, use chimpanzees in research and product development. In general, although the chimpanzees are housed at private facilities, including those which are part of the NIH Chimpanzee Breeding and Research Program, they are generally not the animals that are supported by NIH funds. For-profit organizations maintain, but do not own, chimpanzees housed at the existing research facilities. The preference for using privately owned, rather than government-owned, animals is the combined result of delays encountered in complying with administrative requirements and the expectation that proprietary information would have to be disclosed. To secure the use of government-owned chimpanzees by for-profit organizations, procedures should be streamlined to eliminate redundant aspects of the process, such as review and approval of protocols by more than one committee. Furthermore, the protection of proprietary aspects of a study should be guaranteed. Encouraging and soliciting the use of government-owned chimpanzees by for-profit organizations to generate supplemental income for their support should be a responsibility of the ChiMP office (see chapter 5).

Animals determined to be no longer needed for research and transferred to a long-term care facility might be used in some kinds of research. See “Research” discussion under “Special Considerations in Chapter 3.

TERMINAL STUDIES

Although acute terminal studies with chimpanzees have been rare, they are justified in some circumstances. If such studies are proposed, they should be carefully reviewed for scientific qualification. If they are approved, they should be designed so that the maximal amount of information will be obtained, ideally benefiting more than one field of research. No obvious paradigms for such use are known. In the context of infectious diseases, it is possible that inoculation of chimpanzees with an agent could elicit disease that culminates in death. That was the original expectation when chimpanzees were infected with HIV; such experiments are justified when society is faced with new epidemics. However, care should be taken that terminal studies do not become a de facto form of euthanasia for population control.

CONCLUSIONS AND RECOMMENDATIONS

The use of chimpanzees in biomedical research has resulted in major advances in maintenance of human health and in development of vaccines and new therapeutic approaches to disease. In several instances, success was based on the sustained availability of large populations of chimpanzees suitable for research for 10 years or more. Specific examples discussed in this chapter include the successful development of an HBV vaccine and similar efforts related to HIV and HCV. Obvious future threats to human health will be infectious agents that potentially could emerge or re-emerge anywhere and spread around the world with the help of social and behavioral patterns and routine international travel. Chimpanzees are used in diverse fields of biomedical research, primarily because of physiological characteristics resulting from their phylogenetic proximity to humans. The uses listed in this “snapshot in time” do not provide a complete picture of the needs for a captive population of chimpanzees ready for emerging global challenges to the health and well-being of mankind. In planning for future requirements for chimpanzees in biomedical research, the predictions cannot be restricted to a single year, but rather must anticipate demands for at least 5-yr in advance, as illustrated by the paradigms for HBV and HIV in which several hundred animals were used over 10-year periods. In planning for the future, one must take into account that both previously used animals and research-naive animals might meet requirements for specific studies and that the duration of studies can vary from days to years. It is therefore impossible to predict the long-term demands for chimpanzees from current usage. Hence, there is a need for a well-informed group to assess the demographics of the captive chimpanzee population continuously.

On the basis of those considerations, a review of past use of chimpanzees, and the status of the current captive population, the committee offers the following conclusions and recommendations.

  • The present chimpanzee population is sufficient in overall number, and a moratorium on breeding, effective until the year 2001, should be formalized in writing. Future needs and policies on breeding should be continuously assessed, preferably by an appropriately constituted advisory council working in concert with the ChiMP office proposed in chapter 5. In this continuing assessment of needs, projections should be for periods of a decade or more (the time required for full implementation of research programs on hepatitis and HIV).
  • Chimpanzees suitable for biomedical research but held in facilities intended to provide long-term care and housing should be made available for research protocols, if needed, to maximize their utility and to contribute to the financial base required for their long-term support. In addition to emergency situations associated with new infectious disease epidemics, the older chimpanzees should be valuable for aging research.
  • To promote the use of government-owned chimpanzees by for-profit organizations, procedures to obtain access to the animals should be streamlined to minimize delays in initiating studies and to eliminate requirements for full disclosure of proprietary information.
  • Acute terminal studies involving chimpanzees are justified under some circumstances and, when possible, should be designed as collaborative efforts to yield the maximal amount of information with the potential to benefit more than one field of research. The ChiMP office, in consultation with colony directors and investigators, should identify candidate animals for such protocols.
Copyright © 1997, National Academy of Sciences.
Bookshelf ID: NBK109752

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