Aug. 25, 2004 Two upcoming studies by scientists at the National Cancer Institute (NCI), one of the National Institutes of Health, provide further evidence that exposure to simian virus 40 (SV40) is not associated with cancer in humans. Some U.S. polio vaccines administered from 1955-1962 were accidentally contaminated with SV40 because the vaccines were grown in monkey kidney tissue. Before the discovery of the virus led to changes in vaccine manufacture, millions of Americans received SV40-contaminated polio vaccines. This has been a significant public health concern, as SV40 has been shown to cause cancer in experimental animals. However, studies in humans have not proved conclusive.
Because some laboratory studies report that SV40 DNA can be detected in various childhood tumors, scientists led by Eric Engels, M.D., M.P.H., an investigator in NCI's Division of Cancer Epidemiology and Genetics, evaluated cancer risk of 54,796 U.S. children whose mothers received polio vaccine during pregnancy that may have been contaminated with SV40. Engels and colleagues hypothesized that mothers who were vaccinated against polio before 1963 might have become infected with SV40 by this route and transmitted the virus to their children. In animals, SV40 is most likely to cause cancer when infection occurs during infancy. The scientists wondered whether transmission of infection from a mother to her child during pregnancy or soon after birth might be related to the later development of childhood cancer.
The researchers compared cancer risk in children whose mothers received pre-1963 polio vaccine with cancer risk in children whose mothers did not receive pre-1963 polio vaccine. They also measured SV40 antibodies in the mothers of 50 of these children who developed cancer and the mothers of 200 children without cancer. One of this study's strengths is the researchers' use of two different means of detecting SV40 antibodies, which are produced by exposure to or infection with the virus. The first method, called a plaque neutralization assay, has long been considered the gold standard. They also used a virus-like particle assay, a newer test with high sensitivity and specificity, allowing researchers to distinguish between SV40 antibodies and those against other related viruses.
Interestingly, the investigators found that the incidence of neural tumors and hematologic malignancies was roughly 2.5 times higher in children whose mothers received pre-1963 vaccine than in children whose mothers did not. However, the pattern of cancers in children whose mothers received the vaccine was not what would be predicted if SV40 caused cancer: the types of cancers varied and did not correspond to the types in which SV40 DNA has reportedly been detected. "It was notable that only one brain tumor of the types in which SV40 DNA has reportedly been detected--an ependymoma--was observed, and that was in a child whose mother had not received pre-1963 polio vaccine," explained Engels. "More cases of the types of cancer hypothesized to be linked to SV40--for example ependyomas, choroid plexus tumors, and osteosarcomas--would be expected if SV40 were the cause of the tumors in these children." Additionally, few women had antibodies to SV40 by either of the antibody tests, and there was no consistent relationship between the development of SV40 antibodies during pregnancy and cancer in children.
The scientists acknowledge that the small number of children and the number of individual cancer types seen were limitations. Nonetheless, as Engels summarized, "Overall, these results argue against an important role for SV40 in childhood cancers."
In the second study, Engels and scientists at other institutions evaluated cancer risk in veterans who were exposed to SV40 in an early U.S. Army adenovirus vaccine given between 1959 and 1961. This is the first follow-up study of recipients of SV40-contaminated adenovirus vaccine. The adenovirus vaccine was administered to new military recruits, who experienced epidemics of respiratory disease caused by adenovirus arising from crowded living conditions during basic training. Like the polio vaccine, adenovirus vaccine was grown in monkey kidney tissue. However, because adenovirus cannot grow in such tissue without SV40 acting as a helper virus, almost all batches of this vaccine probably contained SV40. The adenovirus vaccine was given to Army recruits during two well-defined time periods, alternating with three periods of non-use, during the period 1959-1961. This pattern of exposure to SV40-contaminated adenovirus vaccine allowed for a rigorous comparison of cancer risk in vaccine-exposed and unexposed servicemen.
The researchers used Veterans Administration and military records to identify individuals with cancer and to classify them with respect to receipt of the Army's adenovirus vaccine. The study included cases of mesothelioma, brain tumors, and non-Hodgkin lymphoma, which are tumor types previously hypothesized to be linked to SV40. Importantly, the investigators did not find evidence that SV40-contaminated adenovirus vaccine was associated with an increased risk for these cancers.
The authors noted some limitations of the study. There were only 10 mesothelioma cases and the numbers of cases for individual types of brain tumors were small. These small numbers limit the study's statistical power. Nonetheless, the numbers for all types of brain tumors combined, and for non-Hodgkin lymphoma, were substantial. Additionally, most subjects would also have received polio vaccine possibly contaminated with SV40. However, not every dose of polio vaccine contained SV40, and exposure to polio vaccine was not dependent on whether individuals received adenovirus vaccine. Thus, while the widespread use of polio vaccine could have diluted an association between adenovirus vaccine and cancer, this effect was likely minor.
Engels concluded, "Our results should be reassuring to military veterans of the 1950s and 1960s, some of whom received adenovirus vaccines. This study did not find that their exposure to this vaccine was related to an increased risk of cancer."
Although SV40 causes cancer in laboratory animals, substantial epidemiological evidence has accumulated to indicate that SV40 likely does not cause cancer in humans. However, additional laboratory research is needed to better define methods for SV40 detection, as laboratory studies looking for SV40 DNA in human tumors have offered conflicting results. There is also a need to conduct additional studies evaluating cancer patients and controls for antibodies to SV40, which would be present in cancer patients if SV40 causes cancer.
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For further information, please see the NCI's fact sheet about SV40, available at http://www.cancer.gov/newscenter/sv40.
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