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Immunization Safety Review: SV40 Contamination of Polio Vaccine and Cancer Immunization to protect children and adults from many infectious diseases is one of the greatest achievements of public health. Immunization is not without risks, however. It is well established, for example, that some influenza vaccines have been associated with a risk of Guillain-Barre syndrome and that vaccines sometimes produce anaphylactic shock. Given the widespread use of vaccines, state mandates requiring vaccination of children for entry into school, college, or day care, and the importance of ensuring that trust in immunization programs is justified, it is essential that safety concerns receive assiduous attention. The Immunization Safety Review Committee was established by the Insti- tute of Medicine (IOM) to evaluate the evidence on possible causal associations between immunizations and certain adverse outcomes, and to then present con- clusions and recommendations. The committee's mandate also includes assess- ing the broader significance for society of these immunization safety issues. In this fifth report in a series, the committee examines the hypothesis that exposure to polio vaccine contaminated with simian virus 40 (SV40) can cause certain types of cancer. THE CHARGE TO THE COMMITTEE Challenges to the safety of immunizations are prominent in public and sci- entific debate. Given these persistent and growing concerns about immunization 19

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20 IMMUNIZATION SAFETY REVIEW safety, the Centers for Disease Control and Prevention (CDC) and the National Institutes of Health (NIH) recognized the need for an independent, expert group to address immunization safety in a timely and objective manner. The IOM has been involved in such issues since the 1 970s. (A brief chronology can be found in Appendix C.) In 1999, as a result of IOM's previous work and its access to independent scientific experts, CDC and NIH began a year of discussions with IOM to develop the Immunization Safety Review project, which addressed both emerging and existing vaccine safety issues. The Immunization Safety Review Committee is responsible for examining a broad variety of immunization safety concerns. Committee members have ex- pertise in pediatrics, neurology, immunology, internal medicine, infectious dis- eases, genetics, epidemiology, biostatistics, risk perception and communication, decision analysis, public health, nursing, and ethics. While all the committee members share the view that immunization is generally beneficial, none of them has a vested interest in the specific immunization safety issues that come before the group. Additional discussion of the committee composition can be found in the Foreword written by Dr. Harvey Fineberg, President of the IOM. The committee is charged with examining three ionization safety hy- potheses each year during the three-year study period (2001-2003~. These hy- potheses are selected by the Interagency Vaccine Group, whose members repre- sent several units of the Department of Health and Human Services (DHHS)- the National Vaccine Program Office, the National Immunization Program, and the National Center for Infectious Diseases at the CDC, the National Institute for Allergy and Infectious Diseases at the NIH, the Food and Drug Administration (FDA), the National Vaccine Injury Compensation Program at the Health Re- sources and Services Administration (HRSA), and the Centers for Medicare and Medicaid Services (CMS, formerly the Health Care Financing Administration), as well as the Department of Defense and the Agency for International Devel- opment. For each topic, the Immunization Safety Review Committee reviews rele- vant literature and submissions by interested parties, holds an open scientific meeting, and directly follows the open meeting with a 1- to 2-day closed meet- ing to formulate its conclusions and recommendations. The committee's find- ings are released to the public in a brief consensus report 60 to 90 days after its meeting. The committee is charged with assessing both the scientific evidence re- garding the hypotheses under review and the significance of the issues for soci- ety. The scientific c assessment has two components: an examination of the epi- demiologic and clinical evidence regarding a possible causal relationship between exposure to the vaccine and the adverse event, and an examination

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S V4 0 CONTAMINA TION OF POLIO VA CCINE AND CA NCER 21 of theory and experimental evidence from human or animal studies regard- ing biological mechanisms that might be relevant to the hypothesis. The significance assessment addresses such considerations as the burden of the health risks associated with the vaccine-preventable disease and with the adverse event. Other considerations may include the perceived intensity of public or professional concern, or the feasibility of additional research to help resolve scientific uncertainty regarding causal associations. The findings of the scientific and significance assessments provide the basis for the co~ttee's recommendations regarding the public health response to the issue. In particular, the committee addresses needs for a review of immuni- zation policy, for current and future research, and for effective communication strategies. See Figure 1 for a schematic representation of the committee's charge. =;~ ~ Clinical ~ Theory| ~ Duaa ~ ~ Data | 41 1~11~ 41 , , Event (3) Preventable \ / \ / Diseases(3) Evidence Base \ / \ / \ ~ \\ _ f _ _ _ _ ~ ~ _ _ _/_ ~ ' ~ , ~ ~ , ~ Causality ~ ~ I Biolo 3ical Mechanisms I 9~t ' / Conclusions I Scientific Assessment / I | The Public | / / Significance ~~3 1 Public I lealih Response: Figure 1: Committee Charge 1 Policy 1 j:3 [I= Recommendations ~ / \ ~ Recommendations tor tYetion 1) in vitro; animal; Herman 2) wild~type disease; estal>lished pati~ophysiological pathways 3) indiv~'al; societal THE STUDY PROCESS The committee held an initial organizational meeting in January 2001. CDC and NIH presented the committee's charge at the meeting, and the committee conducted a general review of immunization safety concerns. At this initial meeting, the committee also determined the basic methodology to be used for

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22 IMMUNIZATION SAFETY REVIEW assessing causality for the hypotheses to be considered at subsequent meetings. A website (www.iom.eduJimsafety) and a listserv were created to provide public access to information about the committee's work and to facilitate communica- tion with the committee. The conclusions and recommendations of the commit- tee's previous reports (see Box 1) are summarized in Appendix A. For its evaluation of the hypothesis on SV40-contaminated polio vac- cine and cancer, the committee held an open scientific meeting in July 2002 (see Appendix B) to hear presentations on issues germane to the topic. The presenta- tions to the committee at the open meeting are available in electronic form (au- dio files and slides) on the project website (www.iom.edu/imsafety). In addition, the committee reviewed an extensive collection of material, primarily from the published, peer-reviewed scientific and medical literature. A list of the materials reviewed by the committee, including many items not cited in this report, can be found on the project's website. THE FRAMEWORK FOR SCIENTIFIC ASSESSMENT Causality The Immunization Safety Review Committee has adopted the framework for assessing causality developed by previous IOM committees (IOM, 1991, 1994), convened under the congressional mandate of P.L. 99-660 to address questions of immunization safety. The categories of causal conclusions used by the committee are as follows: 1. No evidence 2. Evidence is inadequate to accept or reject a causal relationship 3. Evidence favors rejection of a causal relationship 4. Evidence favors acceptance of a causal relationship 5. Evidence establishes a causal relationship.

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SV40 CONTAMINATION OF POLIO VACCINE AND CANCER 23 Assessments begin from a position of neutrality regarding the specific vac- cine safety hypothesis under review. That is, there is no presumption that a spe- cific vaccine (or vaccine component) does or does not cause the adverse event in question. The weight of the available clinical and epidemiologic evidence de- termines whether it is possible to shift from that neutral position to a finding for causality ("the evidence favors acceptance of a causal relationship") or against causality ("the evidence favors rejection of a causal relationship". The commit- tee does not conclude that the vaccine does not cause the adverse event merely if the evidence is inadequate to support causality. Instead, it maintains a neutral position, concluding that the "evidence is inadequate to accept or reject a causal relationship." Although no firm rules establish the amount of evidence or the quality of the evidence required to support a specific category of causality conclusion, the committee uses standard epidemiologic criteria to guide its decisions. The most definitive category is "establishes causality," which is reserved for those rela- tionships where the causal link is unequivocal, as with the oral polio vaccine and vaccine-associated paralytic polio or with anaphylactic reactions to vaccine ad- ministration. The next category, "favors acceptance" of a causal relationship, reflects evidence that is strong and generally convincing, although not firm enough to be described as unequivocal or established. "Favors rejection" is the strongest category in the negative direction. The category of "establishes no causal relationship" is not used because it is virtually impossible to prove the absence of a relationship with the same surety that is possible in establishing its presence. If the evidence is not reasonably convincing either in support of or against causality, the category "inadequate to accept or reject a causal relationship" is used. Evidence that is sparse, conflicting, of weak quality, or merely suggestive either toward or away from causality falls into this category. Some authors of similar assessments use phrases such as "the evidence does not presently support a causal association." The committee believes, however, that such language does not make the important distinction between evidence indicating that a relation- ship does not exist (category 3) and evidence that is indeterminate with regard to causality (category 2~. The category of "no evidence" is reserved for those cases in which there is a complete absence of clinical or epidemiologic evidence. The sources of evidence considered by the committee in its scientific as- sessment of causality include epidemiologic and clinical studies directly ad- dressing the question at hand. That is, the data are specifically related to the ef- fects of the vaccines under review and the adverse health outcomes) under review in the case of this report, the effects of SV40 contamination of the po- lio vaccine and the risk for certain types of cancer. Epidemiologic studies carry the most weight in a causality assessment. These studies measure health-related exposures and outcomes in a defined set of subjects and make inferences about the nature and strength of associations be-

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24 IMMUNIZATION SAFETY REVIEW tween exposures and outcomes in the overall population from which the study sample was drawn. Epidemiologic studies can be categorized as observational or experimental (clinical trial), and as uncontrolled (descriptive) or controlled (ana- lytic). Among these various study designs, experimental studies generally have the advantage of random assignment to exposures and are therefore the most influential in assessing causality. Uncontrolled observational studies are impor- tant but are generally considered less definitive than controlled studies. In un- controlled observational studies, where observations are made over time, con- founding from factors such as changing case definitions or improving case detection may affect the apparent incidence and prevalence of the adverse out- comes studied. By themselves, case reports and case series are generally inadequate to establish causality. Despite the limitations of case reports, the causality argument for at least one vaccine-related adverse event (the relationship between vaccines containing tetanus toxoid and Guillain-Barre syndrome) was strengthened most by a single, well-documented case report on recurrence of the adverse event following re-administration of the vaccine, a situation referred to as a"rechallenge" (IOM, 1994~. Biological Mechanisms Evidence considered in the scientific assessment of biological mechanisms includes human, animal, and in vitro studies related to biological or pathophysi- ological processes by which immunizations could cause an adverse event. When other evidence of causality is available, biological data add supportive evidence, but they cannot prove causality on their own. This committee is often faced with a set of circumstances in which the epi- demiologic evidence is judged inadequate to accept or reject a causal association between a vaccine exposure and an adverse event of concern. It is then left with the task of examining proposed or conceivable biological mechanisms that might be operating if an epidemiologically sound association could be shown between a vaccine exposure and an adverse event. In any case, the committee's causality assessments must be guided by the current understanding of biological processes. In fact, the current thinking on a possible biological explanation for a relationship between immunization and an adverse event will influence the design of a good epidemiologic analysis. The essential consideration of"confounders" in epidemiologic studies depends on an understanding of the biological phenomena that could underlie or explain the observed statistical relationship. A statistical observation can be considered as evidence of causality only when important confounders are considered. How- ~ For a discussion of We evolution of the terminology concerning biological mechanisms, see Me committee's earlier reports (TOM, 2001a,b, 2002a,b).

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SV40 CONTAMINATION OF POLIO VACCINE AND CANCER 25 ever, without evidence of a statistical association or convincing clinical evi- dence, biological mechanisms cannot be invoked as proof of causality. The identification of sound biological mechanisms can also influence the development of an appropriate research agenda and give support for policymak- ers, who frequently must make decisions without having complete information regarding causality. In addition, there is often value in investigating and under- standing possible biological mechanisms even if the available epidemiologic evidence suggests the absence of a causal association. A review of biological data could give support to the negative causality assessment, for example, or it could prompt a reconsideration or further investigation of the epidemiologic findings. If new epidemiologic studies were to question the existing causality assessment, the biological data could gain prominence in the new assessments. The committee has established three general categories of evidence on bio- logical mechanisms: 1. Theory only. A reasonable mechanism can be hypothesized that is commensurate with scientific knowledge and that does not contradict known physical and biological principles, but has not been demonstrated in whole or in part in humans or in animal models. Postulated mechanisms by which a vaccine might cause a specific adverse event but for which no coherent theory exists would not meet the criteria for this category. Thus, "theoretical only" is not a default category, but one that requires thoughtful and biologically meaningful suppositions. 2. Experimental evidence that the mechanism operates in animals, in vitro systems, or humans. Experimental evidence often describes effects on just one or a few of the steps in the pathological process required for expression of dis- ease. Showing that multiple components of the theoretical pathways operate in reasonable experimental models increases confidence that the mechanisms could possibly result in disease in humans. lathe evidence can be derived under highly contrived conditions. For example, achieving the results of interest may require extensive manipulation of the genetics of an animal system, or in vivo or in vitro exposures to vaccine antigen that are extreme in terms of dose, route, or dura- tion. Other experimental evidence is derived under less contrived conditions. For example, a compelling animal or in vitro model exists whereby administration of a vaccine antigen under conditions similar to human use results in a pathologic process analogous to a human disease pathology. Mechanistic evidence also could come from studies in humans, but this is distinct from the evidence (about incidence of adverse events following immunization) that derives from random- ized controlled trials or other population-based epidemiologic studies, which contribute to the causality assessment. 3. Evidence that the mechanism results in known disease in humans. For example, the wild-type infection causes the adverse health outcome, or another vaccine has been demonstrated to cause the same adverse outcome by the same

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26 IMMUNIZATION SAFETY REVIEW or a similar mechanism. Data from population-based studies of the effects of the vaccine administration on the occurrence of the adverse outcomes under review are not considered evidence regarding the biological mechanisms but rather as evidence regarding causality. If the committee identifies evidence of biological mechanisms that could be operational, it will offer a summary judgment of that body of evidence as weak, moderate, or strong. Although the committee tends to judge biological evidence in humans as "stronger" than biological evidence from highly contrived animal models or in vitro systems, the summary judgment of the strength of the evi- dence also depends on both the quantity (e.g., number of studies or number of subjects in a study) and quality (e.g., the nature of the experimental system or study design) of the evidence. Obviously, the conclusions drawn from this re- view depend on both the specific data and on scientific judgment. To ensure that its own summary judgment is defensible, the committee intends to be as explicit as possible regarding the strengths and limitations of the biological data. Published and Unpublished Data Published reports carry the most weight in the committee's assessment be- cause their methods and findings are laid out in enough detail to be assessed. Furthermore, published works, which undergo a rigorous peer review, are sub- ject to comment and criticism by the entire scientific community. In general, the committee cannot rely heavily on unpublished data in making its scientific as- sessments (regarding either causality or biological mechanisms) because they usually lack comment and criticism and must therefore be interpreted with cau- tion. The committee also relies on editorial and peer review procedures to ensure the disclosure of potential conflicts of interest that might be related to the source of funding for the research study. Immunization safety studies and other data reviewed by the committee are funded by a variety of sources, including NIH, CDC, vaccine manufacturers, research advocacy organizations, or foundations. The committee does not investigate the source of funding of the published re- search reports it reviews, nor does the funding source influence the committee's interpretation of the evidence. Unpublished data and other reports that have not undergone peer review do have value, however, and are often considered by the committee. They might be used, for example, in support of a body of published, peer-reviewed literature with similar findings. If the committee concluded that the unpublished data were well described, had been obtained using sound methodology, and presented very clear results, the committee could report, with sufficient caveats in the discus- sion, how the unpublished data fit with the entire body of published literature. Only in extraordinary circumstances, however, could an unpublished study re- fute a body of published literature.

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SV40 CONTAMINATION OF POLIO VACCINE AND CANCER 27 The Immunization Safety Review Committee's scope of work includes con- sideration of clinical topics for which high-quality experimental studies are rarely available. Many other panels making clinical recommendations using evidence-based methods are able to require that randomized trials be available to reach strong conclusions. However, the IOM Committee was convened specifi- cally to assess topics that are of immediate concern and for which data of any kind may just be emerging. Thus, given the unique nature of this project, the committee decided that it was important to review and consider as much infor- mation as possible, including unpublished information. The committee does not perform primary or secondary analyses of unpublished data, however. In review- ing unpublished material, the committee applies generally accepted standards for assessing the quality of scientific evidence, as described above. (All unpublished data reviewed by the committee and cited in this report are available in the form reviewed by the committee through the public access files of the Na- tional Academies. Information about the public access files is available at 202- 334-3543 or www.national-academies.org/publicaccess.) UNDER REVIEW: SV40 CONTAMINATION OF POLIO VACCINE AND CANCER Polio vaccines were developed to prevent poliomyelitis, a highly contagious viral disease that was once common worldwide (See Box 2 for the chronology of polio vaccines used in the United States). Most infections are asymptomatic, but the most widely recognized form of polio is an infection of the central nerv- ous system that results in paralysis of the limbs or respiratory muscles. During the first half of the 20th century, polio was at epidemic levels in the United States, peaking at more than 20,000 reported cases of paralytic disease in 1952 (CDC, 2000~. Following the introduction of a vaccine against polio in 19552, the incidence of the disease rapidly declined. By 1965, only 61 paralytic cases were reported in the United States (CDC, 2002a). In 1994, the entire Western Hemi- sphere was declared free of indigenous wild poliovirus (CDC, 1994~. Despite its great value in controlling a devastating disease, polio vaccine is a source of concern because at least some of the vaccines used between 1955 and 1963, when more than 98 million persons were vaccinated in the United States, are known to have been contaminated with SV40. SV40 is a polyomavi- rus that commonly infects certain species of Asian macaques, especially the rhesus monkey. Other polyomaviruses, which are generally species-specific, include the BK and JC viruses of humans. Polyomaviruses are a genus of the papovavirus family of DNA viruses. This family also includes the papillomavi- 2 IPV was licensed and widely distributed in 1955, however exposure to SV40 may have also occurred in the 1954 field trial of IPV.

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28 IMMUNIZATION SAFETY RE VIE W ruses, of which one human papillomavirus (HP V) is causally associated with cervical cancer. (Source: IOM, 1996; Office of Technology Assessment, 1979) SV40 and other polyomaviruses generally produce inapparent infection in immunocompetent members of their natural host species. SV40 and the closely related human polyomaviruses BK and JC typically reside in renal epithelial cells. These viruses can, however, spread to other tissues and produce pathologi- cal effects in immunocompromised hosts or in non-host species. 1h fact, the presence of SV40 in polio vaccine produced from macaque kidney cell cultures was originally identified because of the cytopathological effects of the contami- nated vaccine in African green monkey kidney cell cultures (Sweet and Hille- man, 1960~. As another example, the JC virus is known to cause progressive multi focal leukoencephalopathy in immunocompromised humans . With continuing controversy about the role of SV40 in human cancers (Brown and Lewis, 1998; Klein et al., 2002), the Interagency Vaccine Group asked the Immunization Safety Review Committee to address the question of whether exposure to the SV40-contaminated polio vaccine causes cancer in hu- mans. The very abundance of new and emerging literature on the oncogenic potential of SV40 and its association with certain cancers suggests that it is not too late to try to resolve the question of whether SV40 contamination of polio vaccines could cause cancers in humans. Four forms of human cancer mesothelioma, osteosarcoma, ependymoma, and non-Hodgkin's lymphoma (NHL) have been linked to SV40 in animal studies. Polio Vaccines and SV40 Efforts to develop a vaccine effective against the three distinct types of the poliovirus began in the 1930s, but progress was hindered by the difficulty of producing an adequate supply of virus in the laboratory. The development in 1949 of a technique for growing the virus in tissue cultures (Enders et al., 1949) was soon followed by successful trials of a trivalent killed-virus vaccine. In 1954, 400,000 of 1.8 million children from the United States, Canada, and Finland actually received the potentially contaminated inactivated poliovirus

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SV40 CONTAMINATION OF POLIO VACCINE AND CANCER 29 vaccine (IPV) developed by Sale and colleagues (Francis et al., 1957~. The vac- cine was licensed for use in the United States in 1955. Vaccines that used a live attenuated virus and were administered orally were also developed, initially in a monovalent form. The trivalent oral poliovirus vaccine (OPV) known as the Sabin vaccine was licensed in the United States in 1963. The tissue cultures used to grow poliovirus for these vaccines came from kidneys of rhesus and cynomolgus macaques.3 In 1960, Sweet and Hilleman (1960) reported that these tissues could be infected with SV40, a previously un- known virus that commonly infects rhesus macaques. Soon after its discovery, SV40 was shown to be able to produce tumors in hamsters and to transform hu- man cells in culture (Eddy et al., 1961, 1962; Girardi et al., 1962; Koprowski et al., 1962; Shein and Enders, 1962a,b). Testing confirmed that some of the tissue cultures used in producing IPV and OPV were contaminated with SV40. In 1961, the U.S. government established requirements for testing to verify that all new lots of polio vaccine are free of SV40 (Eg en, 2002~. Potentially contami- nated vaccine from previously approved lots of IPV was not recalled, however, and might have been used until early 1963. IPV administered between 1955 and 1963 to about 98 million children and adults is assumed to be the primary source of human exposure to SV40 in the United States.4 In addition, experimental lots of OPV contaminated with SV40 was administered to about 10,000 people participating in clinical trials between 1959 and 1961. Recipients of the oral vaccine, in contrast to those receiving contaminated IPV, did not develop an antibody response to SV40 (as reviewed in Shah and Nathanson, 1976~. This suggests that IPV, not OPV, resulted in the infection of humans with SV40. Nonetheless, concerns about the validity, and in particular the specificity for SV40, of the serologic testing create some uncer- tainty about this conclusion. Details of the level and extent of the contamination of IPV are unavailable. Because the process used to inactivate the poliovirus was less effective against SV40, IPV could have included killed or live SV40. Furthermore, manufacturers used different types of cell cultures, and some were less vulnerable to contami- nation (Shah and Nathanson, 1976~. Tests of stored samples of the vaccine that had been administered in the United States from May through July in 1955 found various levels of SV40 contamination, with some vaccine showing no 3 Current formulations of IPV and OPV available in the United States are required by the FDA to be free of SV40. The IPV produced today uses poliovirus grown on Vero cells, a continuous line of green monkey kidney cells. OPV is no longer produced in the United States, but as the recom- mended vaccine to control polio outbreaks, a stockpile of OPV is available for these purposes (CDC, 2000). The OPV was produced in the United States in monkeys raised in colonies free from SV40 or grown in Vero cells and was screened for viruses, including SV40 (Sutter et al., 1999). 4 During the same period, SV40 also contaminated an experimental respiratory syncytial virus vaccine given to about 100 adults and a licensed adenovirus vaccine given to about 100,000 military inductees (Shah and Nathanson, 1976).

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74 IMMUNIZATION SAFETYREVIEW and where they are operating, some immunization providers do not submit data (CDC, 2002b). Even with the benefit of registry data, the challenges of tracing individuals remain. And in their current form, immunization registries do not capture information on vaccine given to adolescents or adults. Research The committee notes that data are accumulating rapidly on many fronts on the potential for viruses to cause cancers in humans, particularly if exposure is early in life. The committee supports continued research in viral oncogenesis broadly, independent of the question of SV40-contamination of polio vaccine. However, the research recommendations are focused specifically on the question of the polio vaccine, in keeping with the charge to the committee. The committee recommends development of sensitive and specific serologic tests for SV40. These would be helpful to resolve the question as to whether or not the SV40 exposure led to infection. The committee recommends the development and use of sensitive and specific standardized techniques for SV40 detection. Included in these efforts should be a documentation that: 1) all test specimens are masked, 2) positive and negative control tissues are both used and are both subjected to the same processing procedures as test specimens, 3) samples are tested in replicate, and 4) an adequate sample of tissue is available. The committee recommends that once there is agreement in the scientific community as to the best detection methods and protocols, prey 1955 samples of human tissues should be assayed for the presence or absence of SV40 in rigorous, multicenter studies. These tests would not address the question of whether or not SV40 can cause cancer, but they could influence the interpretation of some epidemiologic and clinical analyses. They also would be relevant for discussion of the relative contribution of contaminated polio vaccine to the burden of SV40 infection in humans. The committee recommends further study of the transmissibility of SV40 in humans. This will help confirm whether and why SV40 or antibodies specific for SV40 are detected in individuals who have no known exposure to potentially contaminated polio vaccine, animals or laboratory contact. Resolving the issue of transmissibility of SV40 is not directly relevant for a causality assessment, but it would be useful in some of the ancillary debates about the role of the polio vaccine contamination in the cancer burden. In addition to the research recommended above, it is important to resolve the extent of SV40 contamination of past polio vaccine. The uncertainty of exposure makes interpretation of the epidemiologic studies very problematic. In addition, concerns that the oral polio vaccine had been more widely contaminated than assumed require attention. The issue should be resolved

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SV40 CONTAMINATIONOF POLIO VACCINE AND CANCER 75 publicly to the satisfaction of the public as well as the scientific and policy- malcing communities. If researchers can pursue these strategies and obtain a better understanding of SV40 exposure and methods of detection, more meaningful case-control studies can be undertaken to help resolve the question of causality. Und1 some of the technical issues are resolved, the committee does not recommend additional epidemiologic studies of people potentially exposed to the contaminated polio vaccine. SUMMARY Some of the polio vaccine administered from 1955-1963 was contaminated with simian virus 40 (SV40~. The virus came from the monkey kidney cell cultures used to produce the vaccine. Most, but not all, of the contamination was in the inactivated polio vaccine (IPV). Once the contamination was recognized, steps were taken to eliminate it from future vaccines. There have been many questions as to the effects on people who received the contaminated vaccine. SV40 has biological properties consistent with a cancer-causing virus, but researchers have not conclusively established whether or not it could cause cancer in humans. Studies of groups of people who received polio vaccine during 1955-1963 provideevidenceofnoincreasedcancer risk. However, because these epidemiologic studies are sufficiently flawed, the Institute of Medicine's Immunization Safety Review Committee concluded that the evidence was inadequate to conclude whether or not the contaminated polio vaccine caused cancer. In light of the biological evidence supporting the theory that SV40-contamination of polio vaccines could contribute to human cancers, the committee recommends continued public health attention in the form of policy analysis, communication, and targeted biological research. Box 3 summarizes the committee's conclusions and recommendations.

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