Medical Intelligence

Long-Term Follow-up of Persons Inadvertently Inoculated with SV40 as Neonates

Edward A. Mortimer, Jr., M.D., Martha Lipson Lepow, M.D., Eli Gold, M.D., Frederick C. Robbins, M.D., George J. Burton, Ph.D., and Joseph F. Fraumeni, Jr., M.D.

N Engl J Med 1981; 305:1517-1518December 17, 1981DOI: 10.1056/NEJM198112173052507

Article

SIMIAN virus 40 (SV40) is a papovavirus that is latent in rhesus-monkey kidneys used for tissue culture of poliovirus. SV40 was present in vaccines administered to millions of people and was later found to be oncogenic in laboratory animals, notably newborn hamsters, and capable of transforming human cells in vitro. However, studies of large groups of people inoculated with SV40-contaminated vaccines have yielded no evidence of oncogenicity in human beings, despite continued concern.1 ^, 2

We studied mortality from cancer in 1073 children who were born between 1960 and 1962 and who, as newborn infants, received monovalent oral poliovirus vaccine or inactivated poliovirus vaccine that inadvertently contained SV40. A follow-up study of these children over six to eight years has been reported elsewhere.3 A follow-up study over 17 to 19 years has revealed no deaths from cancer, as compared with the expected rate of one on the basis of rates in the general population. Contact was established with 95 per cent of the subjects in 1977 and 87 per cent in 1979, but only one child was found to have cancer, a mixed salivary-gland tumor of low malignancy. Since studies in animals have shown that tumor susceptibility is greatest after neonatal exposure, the findings are reassuring and consistent with the prevailing view that SV40 is not carcinogenic in human beings.

Methods

In Cleveland, Ohio, during the period 1960–1962, 1073 infants less than three days of age received live, attenuated, monovalent (Sabin) poliomyelitis vaccine orally, or inactivated (Salk) polio-myelitis vaccine intramuscularly, in an effort to determine whether newborn infants would respond satisfactorily to such immunization.4 Once it was recognized that SV40 was present in the preparations administered, annual follow-up was initiated from 1964 to 1979 to determine the status of each child (i.e., alive or dead and, if dead, the cause of death). From 1976 to 1979 an attempt was made to assess each living subject's health by means of a personal note.

Numerous approaches were used to trace the study subjects. With cooperation from local school boards in the Cleveland area, school registration records were examined to identify the study subjects who were attending school. Other sources of information included hospital records for the mother and child, Ohio death certificates, drivers' licenses, the regional cancer registry, telephone books (from local areas or elsewhere if the family was believed to have moved), letters to last known addresses, employment records, and visits to former neighbors. In the last few years, follow-up became increasingly difficult as subjects left school, as women married and changed names, and as substantial numbers of subjects moved from the area.

Expected mortality from cancer was calculated by applying United States age-specific rates for all malignant neoplasms (International Classification of Diseases Adapted [ICDA] 140 to 205 for the years 1960 to 1967 and ICDA 140 to 209 for 1968 to 1979) to the population at risk, using the following age groups: less than one year, 1 to 4 years, 5 to 9, 10 to 14, and 15 to 19. The 1976 rates, the most recent available, were used for the period 1977 to 1979. Rates for non-whites were used because most of the study subjects were black.

Results

Table 1Table 1Features of 1073 Subjects Receiving Polio Vaccine in the Neonatal Period. describes the six study groups, including the numbers of children in each group, the ages at which vaccine was given, and the titers of SV40 in the vaccines. Table 2Table 2Status of Study Subjects in 1977 and 1979. shows the numbers of children whose status was determined in 1977 (the year in which the status of the largest number of study subjects was identified) and in 1979, the final year of the study.

A total of 15 study subjects died, all of identified causes, chiefly birth defects or trauma. No child died of cancer, as compared with the figure of one expected. A 15-year-old girl in Group 3 had a mixed tumor of the salivary gland with histopathological features of a "low degree of malignancy." There was no recurrence six years after surgery. Responses from letters to study subjects and their parents regarding health status were received from less than half the subjects, but no unusual patterns of disease were reported. As of 1979, 45 female subjects had borne children, none of whom was noted to have a congenital anomaly at birth.

Discussion

No excess risk of cancer was observed in persons who were exposed as newborns to SV40-contaminated polio vaccine and followed for 17 to 19 years. This finding is reassuring since SV40 is carcinogenic in laboratory animals and produces subclinical infections indicated by serum antibody and viral isolation in human beings.5 6 7 There have been reports that SV40-like antigens are present in tumors of patients,8 ^, 9 and that inactivated poliomyelitis vaccine given during pregnancy may be associated with tumors in offspring.10 However, there has been no evidence to date that cancer trends in the population have been affected by the widespread administration of polio vaccines containing SV40.1 ^, 3 ^, 11 SV40-related antigens have also been detected in certain degenerative neurologic disorders,1 but no cases were reported in this cohort of children.

This study group of newborn infants is of special interest since the risk of SV40-induced cancer in animals is greatest after neonatal exposure. These findings are consistent with previous studies suggesting that SV40 is not carcinogenic in human beings. Several caveats remain, however. First of all, it is conceivable that one or more children with tumors escaped notice in the group lost to follow-up, or that the latency period for cancer exceeds the 17 to 19 years of observation in this study. In addition, it is possible that the amount of SV40 inoculated parenterally was insufficient to cause infection. The titers of SV40 in the parenterally administered killed polio vaccine were determined to be 10 TCID₅₀ per milliliter (Table 1) — far less than the dose of more than 10^3.5 TCID₅₀ per milliliter required for oncogenesis in hamsters.12 However, viral-isolation techniques employed in 1960 may have underestimated actual titers. Finally, SV40 administered orally does not appear to be infective in human beings according to serum antibody studies, although intestinal colonization may occur.2 However, nasopharyngeal inoculation of SV40 has resulted in subclinical infections with antibody responses,5 and some infants with immature swallowing mechanisms may have been infected by this route.

Because of the mounting complexities and obstacles in tracing this particular group of subjects and the negative results to date, surveillance has been terminated.

Supported by the National Cancer Institute under a contract (N01–CP4–3201) and its predecessors.

We are indebted to Susie Malone, René DeWitt, Scott Spence, Christine Robbins, Stephen Malone, and many record librarians who helped locate the study subjects, and to Abba Schwartz of the Cleveland Board of Education for his help.

Source Information

From the departments of Epidemiology and Community Health and Pediatrics, Case Western Reserve University School of Medicine, and the Environmental Epidemiology Branch, National Cancer Institute, Bethesda, Md. Address reprint requests to Dr. Mortimer at the Department of Epidemiology and Community Health, Case Western Reserve University School of Medicine, Cleveland, OH 44106.

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