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Immunization Safety Review: SV40 Contamination of Polio Vaccine and Cancer
Pages 19-84

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From page 19...
... The committee's mandate also includes assessing 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)
From page 20...
... (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.
From page 21...
... 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
From page 22...
... 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)
From page 23...
... does or does not cause the adverse event in question. The weight of the available clinical and epidemiologic evidence determines whether it is possible to shift from that neutral position to a finding for causality ("the evidence favors acceptance of a causal relationship")
From page 24...
... 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 pathophysiological processes by which immunizations could cause an adverse event.
From page 25...
... 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 biological mechanisms: 1.
From page 26...
... 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.
From page 27...
... 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)
From page 28...
... 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 humans.
From page 29...
... Potentially contaminated 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.
From page 30...
... The latency period for mesotheliomas linked to asbestos exposure can range from 30 to 50 years, but the disease can occur at any age (NIH, 2002~. s Incidence rates are age-adjusted to Me 2000 U.S.
From page 31...
... A small portion of brain cancers in children have 6 Incidence rates are age-adjusted to the 1970 U.S. standard population.
From page 32...
... t° NHL incidence rates are age-adjusted to the 2000 U.S. standard population.
From page 33...
... Cancer Incidence Ecologic Studies United States. Three published studies relied on data from the SEER Program of the National Cancer Institute to examine trends in cancer incidence rates in relation to exposure to SV40 in polio vaccines between 1955 and 1963.
From page 37...
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From page 44...
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From page 46...
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From page 47...
... They found a 13% difference, which was used to adjust downward the incidence rates for the unexposed cohort. The authors note that the study is limited by the assumptions regarding exposure and potential biases from diagnostic and coding errors.
From page 48...
... used SEER data to examine trends in ependymoma, osteosarcoma, and mesothelioma in relation to presumed exposure to SV40 in polio vaccines. Age-specific cancer incidence rates for three birth cohorts were compared.
From page 49...
... Although relative risks for the exposed versus the unexposed cohorts were reported, no confidence intervals were provided. In addition, the relative risks were not consistent across age groups and no statistical tests for trends were performed.
From page 50...
... Controlled Observational Studies The committee also reviewed two early case-control studies that examined the oncogenic potential of the polio vaccine. These studies have critical limitations, however.
From page 51...
... examined cancer mortality rates from 1950 through 1959 to assess the effect of exposure to SV40 containing polio vaccines. Use of polio vaccine began in 1955 and was initially targeted to children in first and second grades (approximately 6 to 8 years old)
From page 52...
... In general, the mortality rates peaked in 1951-1952 and then decreased through 1959, when the study ended. Mortality rates were higher both before and after vaccination began in states that had contaminated vaccine than in states with SV40-free vaccine.
From page 53...
... Heinonen and colleagues (1973) compared cancer incidence rates in children born to mothers who, between 1959 and 1965, received the killed polio vaccine (n = 18,342)
From page 54...
... Each case was matched to two controls on the basis of sex, birth date, and birth place. Questionnaires were sent to the obstetricians who delivered the children for information on the mothers' history of polio vaccination during pregnancy.
From page 55...
... For this report, however, because of the few controlled observational studies available and the public health importance of the issue at hand, the committee has included all of the studies it reviewed in the relevant evidence tables (Tables 1, 2, Andy. Most of the epidemiologic studies on polio vaccine containing SV40 and cancer are subject to misclassification bias because they rely on year of birth to designate exposure status.
From page 57...
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From page 59...
... Because the Immunization Safety Review Committee was not charged with resolving the full range of uncertainties about the biology of SV40 and the role of this virus in human cancers, the review that follows provides only highlights of the key arguments on these issues. More detailed discussion is available in several excellent and comprehensive reviews (Brown and Lewis,
From page 60...
... demonstrated that injection of extracts of rhesus monkey kidney-cell cultures into newborn hamsters was followed by the occurrence of neoplasms in approximately 70°/0 of the animals. The presence of SV40 in these extracts was confirmed in a subsequent study Giddy et al., 1962~.
From page 61...
... The principal lines of evidence for the operation of specific mechanisms are that SV40 acts in ways consistent with tumorigenesis and that DNA sequences consistent with SV40 have been detected in several types of human tumors. Evidence that SV40 could be tumorigenic comes from in vitro studies and studies in animals.
From page 62...
... In some cases, the presence or absence of SV40 in tumors was attributed to geographic differences in exposure to SV40 (e.g., in Finland and Turkey, SV40 containing polio vaccines were never used) or to the multifactorial nature of some cases (DeRienzo et al., 2002; Hirvonen et al., 1999; Reuther et al., 2001~.
From page 63...
... Prevalence (%) in normal tissue Tissue Method of in tumor tissue adjacent to tumor Handling detection Reference 29/48 (60)
From page 64...
... * Samples from Turkey where SV40-contaminated poliovaccine was not used methods used.
From page 65...
... Because these collaborative efforts failed to resolve why some laboratories detect SV40 and others do not, the presence, specificity and strength of the association between SV40 and certain types of human tumors remain uncertain. The detection of SV40 in tumors does not, by itself, demonstrate a causal relationship.
From page 66...
... In healthy rhesus monkeys, SV40's natural host, the virus infects primarily kidney cells. HPV, a related papovavirus, has been linked only with a single type of tumor—cervical cancer.
From page 67...
... Human exposure to SV40 occurred through contaminated IPV and OPV, but other sources of exposure to SV40 may also exist. A limited number of people are known to have been exposed to SV40 through other vaccines.
From page 68...
... In a study of sera collected prior to polio vaccination from medical students in Wisconsin in 1952, IgG against the capsid antigen of SV40 was detected by ELISA in 6 of 51 samples tested (Geissler et al., 1985~. Other studies of people not exposed to the contaminated polio vaccine also showed evidence of antibodies to SV40 that were not obviously due to cross-reactivity to BK or JC viruses (Shah et al., 1972~.
From page 69...
... of the human cancers in which SV40 is detected are caused by the SV40, that the sole source of SV40 is due to the contaminated polio vaccine, or that SV40-contaminated polio vaccine did or did not cause cancer in the vaccine recipients. SIGNIFICANCE ASSESSMENT The Immunization Safety Review Committee's charge for the present series of studies includes consideration of the significance of the immunization safety issues for society the context in which policy decisions must be made.
From page 70...
... In contrast, the incidence of mesothelioma is highest at older ages, and survival following diagnosis averages less than 2 years (Ho et al., 2001~. The committee's review of the epidemiologic and biological evidence has shown that the effects of exposure to the contaminated polio vaccine remain uncertain, with important questions regarding the role of SV40 in human cancers unresolved.
From page 71...
... Therefore, the committee does not recommend a policy review of polio vaccine by any of the national or federal vaccine advisory bodies on the basis of concerns about cancer risks that might be associated with exposure to SV40, because the vaccine in current use is free of SV40. Claims have been made that some oral polio vaccines might have been contaminated after 1963 (Kops, 2000~.
From page 72...
... In addition, the plan should include strategies for routine assessment of vaccine for possible contamination; notification of public health officials, health care providers, and the public if contamination occurs; identification of recipients of contaminated vaccine; and surveillance and research to assess health outcomes associated with the
From page 73...
... The large cohorts that were included in the some of the epidemiologic studies reviewed here (e.g., Heinonen et al., 1973; Fraumeni et al., 1970, finis, 1968; Stewart and Hewitt, 1965) would be almost impossible to establish without laying the appropriate groundwork (e.g., consent for contact for future research studies)
From page 74...
... 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.
From page 75...
... 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.
From page 78...
... 1994. Simian virus 40-like DNA sequences in human pleural mesothelioma.
From page 79...
... Simian virus 40 is not a cofactor in the pathogenesis of environmentally induced malignant pleural mesothelioma in Turkey. Anticancer Res 20(2A)
From page 80...
... -like DNA sequences not detectable in finnish mesothelioma patients not exposed to SV40-contaminated polio vaccines. Mol Carcinog 26(2)
From page 81...
... 2002a. Immunization Safety Review: Hepatitis B Vaccine and Demyelinating Neurological Disorders.
From page 82...
... 1998. Human mesotheliomas contain the simian virus-40 regulatory region and large tumor antigen DNA sequences.
From page 83...
... 1996. Simian virus 40 and pleural mesothelioma in humans.
From page 84...
... 1998. Simian virus 40 DNA sequences in human brain and bone tumours.


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