SV-40 Contamination of Poliovirus Vaccine
Dr. W. John Martin, Center for Complex Infectious Diseases
SV-40 is a small double stranded, circular DNA virus of rhesus monkey origin. It is closely related to JC and BK viruses of human origin. While BK virus may not cause human disease, JC virus can cause a very severe brain illness in HIV infected patients, that is called progressive multifocal leukoencephalopathy or PML. SV-40 is also distanly related to human papillomaviruses, some of which cause cervical cancers.
SV-40 infection is now widespread within the human population almost certainly as a result of poliovaccine produced in rhesus monkey kidney cells during the 1950s. A recent study showed infection in 23% of blood samples from normal individuals. The virus can also be detected in sperm fluid and is likely to be passed congenitally to future generations (Martini et al. SV40 Early Region and Large T Antigen in Human Brain Tumors, Peripheral Blood Cells, and Sperm Fluids from Healthy Individuals. Cancer Research 56: 4820-4825, 1996). As the title indicates this paper also confirms previous reports that SV-40 is present in a significant proportion of human brain tumors. Other reports have shown SV-40 in human brain tumors, e.g. Bergsagel et al. New England Journal of Medicine 326: 988-993, 1992. SV-40 has also been detected in a high proportion of human mesotheliomas (Carbone et al. Oncogene 9: 1781-1790, 1994); and in bone tumors called osteogenic sarcomas (Carbone et al. Oncogene 1996). FDA has been reluctant to act on reports of SV-40 but will have to respond to forthcoming publications in the "New Yorker" and "Money" magazines.
SV-40 contamination was detected in the rhesus monkey kidney cells used to make poliovaccine as early as 1960. A Federal employee, Dr. Bernice Eddy, decided on her own inititive, to test extracts from the monkey kidney cells used to make poliovaccine for possible cancer causing agents. She chose to use newborn hamsters since these animals developed tumors with a type of virus she and Sarah Stewart had discovered in mice and named polyoma virus. The inoculated hamsters developed tumors similar to those induced with polyoma virus. The results of Dr. Eddy's unauthorized testing was meet with the same scorn and indifference as her earlier warings that some of the initial lots of Salk vaccine retained live poliovirus.
Again, frustrated by the unwillingness of her supervisors to act on her tumor findings, Dr. Eddy went around channels and disclosed her results in a 1990 scientific meeting. Her punishment was to be taken off poliovaccine safety testing and prohibited for over a year from submitting her work for publication. Dr. Eddy's findings did however leak out and were replicated by Drs. Sweet and Hilleman at Merck. Initially, Hilleman thought the SV-40 problem would apply mainly to the live polio vaccines developed by Dr. Sabin and used extensively in the Soviet Union. He even suggested that the Russians would be no threat at the upcoming 1962 Olympics because they would be dragging with tumors (The Health Century, by Edward Shorter). Unfortunately, it was soon realized that the polio vaccine developed by Dr. Salk was the more dangerous because the 1:4,000 dilution of formaldehyde, which barely inactivated the poliovirus, did not fully inactivate SV-40. Because the Salk vaccine was injected through the skin, it allowed the SV-40 a better chance to infect.
To his credit, Dr. Hilleman repeatedly sounded warnings about the risks inherent in the use of monkey tissue for vaccine production. For example, he has made the following comments " ...use of tissues of wild-caught animals is just asking for trouble because of the lack of control and the known high proability for viral contamination. Monkeys are too expensive to be grown in specific pathogen-free colonies and, hence, the simple solution to the monkey problem is to eliminate the monkey" and also "The tissues of wild-caught animals, and certainly monkeys, are commonly infected with wild viruses. The simplest way to solve the monkey problem is to eliminate the monkeys and this is being done using diploid cells. Monkey tissues came into use by historic decisions to use monkey kidney to make poliovaccine. There is no need to continue using monkeys when acceptible alternatives are available." This advice was never taken especially in the face of pressure from Lederle/American Cyanamid to continue to use monkeys.
The main result of finding SV-40 virus in rhesus monkeys was simply to switch poliovaccine production to African green monkeys. Existing stocks of SV-40 poliovaccines were not withdrawn from the market, nor was any effort made to suspend the military's use of adenoviral vaccines, also known to contain SV-40. Short termed follow studies on some of the children exposed to SV-40, to see if brain tumors had developed, satisfied those in charge of Public Safety, that no harm had been done.
Since the hamster tumor model required virus exposure to newborn animals, Public Health officials should have predicted the need to maintain surveillance for the subsequent human generation. Now that evidence is accumulating that a problem exists, the continued reluctance of FDA to respond is, to say the least, disappointing.
The overall story with SV-40 is being replicated with the resistance of FDA and of Industry to meaningfully address the question of other monkey viruses having been transmitted to humans through poliovaccines. While the African green monkey is generally free of SV-40 virus, it does carry a number of viruses, including simian cytomegalovitrus (SCMV). As an aside, rhesus and not African green monkeys are used for testing the virulence of live polio vaccines, because even the control African green monkeys often show evidence of neural infection.
In an effort to underscore, the need for a more responsive FDA, samples of a 1954 polio vaccine, held by Dr. Ratner, a Public Health official whose concerns about poliovaccine safety had been largely ignored, have been sent to investigators studying SV-40 to show how easy it is to detect contaminants using the PCR assay. This assays was not available in the 1950s, but now that it is, there is no excuse for not using it on polio and other vaccines to exclude contaminants including SCMV and related stealth viruses.
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