Simian virus 40 (SV40) is a virus that infects several species of monkeys and typically does not cause symptoms or disease in them. The virus was discovered in 1960 in rhesus macaque monkey kidney cells that were used in the production of the original Salk and Sabin polio vaccines. Since the mass immunization program for polio began in 1955 before the discovery of the virus, contaminated vaccine lots were inadvertently used for the first few years of the program.
When reports appeared in 1961 that injection of SV40 into hamsters could induce tumors, the United States government instituted a screening program requiring all new lots of polio virus vaccine be free of SV40 because of concerns about possible adverse effects on human health. (Earlier lots were not withdrawn from the mass immunization program.) No SV40 has been found in the polio vaccine lots tested after 1963. The polio vaccine currently used in the United States is produced under carefully regulated conditions designed to ensure that contamination with SV40 does not occur. As a result of the earlier contamination, however, it is estimated that 10 million to 30 million people vaccinated in the United States from 1955 through early 1963 were inadvertently exposed to live SV40.
When reports appeared in 1961 that injection of SV40 into hamsters could induce tumors, the United States government instituted a screening program requiring all new lots of polio virus vaccine be free of SV40 because of concerns about possible adverse effects on human health. (Earlier lots were not withdrawn from the mass immunization program.) No SV40 has been found in the polio vaccine lots tested after 1963. The polio vaccine currently used in the United States is produced under carefully regulated conditions designed to ensure that contamination with SV40 does not occur. As a result of the earlier contamination, however, it is estimated that 10 million to 30 million people vaccinated in the United States from 1955 through early 1963 were inadvertently exposed to live SV40.
Epidemiology Studies
Over the last four decades, an intense research effort has been made to determine whether this route of exposure to SV40 has caused health problems in people, including cancer. Epidemiology studies involving decades of observations in the United States and Europe have failed to detect an increased cancer risk in those likely to have been exposed to the virus. These include a long-term Swedish study, which followed 700,000 people who received SV40-contaminated vaccine, a German study with 22 years of follow-up of 886,000 persons who received the contaminated vaccine as infants, a 20-year study of 1,000 people in the United States inoculated during the first week of life with contaminated vaccines, and a 30-year follow-up of approximately 10 percent of the entire U.S. population (using data from the National Cancer Institute's Surveillance, Epidemiology, and End Results registry). The Centers for Disease Control and Prevention finds no evidence that SV40-contaminated vaccine lots cause cancer.
Laboratory Studies and Additional Epidemiology Reports
The issue of SV40 resurfaced in the last few years when an increasing number of laboratories, using an extremely sensitive molecular biology technique, the polymerase chain reaction (PCR), found traces of the virus in some rare human tumors including pleural mesothelioma (a cancer of the lining of the lung), osteosarcoma (a type of bone cancer), ependymoma and choroid plexus tumors of the brain, and recently non-Hodgkin's lymphoma. Other studies reported that SV40 T-antigen, a viral protein, binds to human tumor suppressor proteins such as p53 and RB, suggesting a possible carcinogenic mechanism. Not all studies, however, find that SV40 plays a significant role in human cancer.
In order to resolve why some laboratories detect traces of SV40 in mesothelioma while others do not, an International SV40 Working Group, which included the majority of laboratories studying SV40 in human tissues, was formed in 1997. Nine laboratories from the working group agreed to participate in a study, funded and organized by the National Cancer Institute (NCI). Each group was given 25 paired-duplicate samples of human mesotheliomas, a single set of 25 normal lung tissue samples, and positive and negative control samples. All the samples were blinded (labeled so that the human tumors and controls could not be distinguished) and each laboratory used its particular assay for detecting SV40, many of which had been used to detect SV40 previously. The results, published in the May 2001 issue of Cancer Epidemiology, Biomarkers and Prevention, showed that none of the mesothelioma specimens was consistently positive for SV40. Although methods in the study appeared to perform well on the control samples, additional methods that can be used widely and easily to detect the presence of SV40 DNA in human tissues are needed.
In order to resolve why some laboratories detect traces of SV40 in mesothelioma while others do not, an International SV40 Working Group, which included the majority of laboratories studying SV40 in human tissues, was formed in 1997. Nine laboratories from the working group agreed to participate in a study, funded and organized by the National Cancer Institute (NCI). Each group was given 25 paired-duplicate samples of human mesotheliomas, a single set of 25 normal lung tissue samples, and positive and negative control samples. All the samples were blinded (labeled so that the human tumors and controls could not be distinguished) and each laboratory used its particular assay for detecting SV40, many of which had been used to detect SV40 previously. The results, published in the May 2001 issue of Cancer Epidemiology, Biomarkers and Prevention, showed that none of the mesothelioma specimens was consistently positive for SV40. Although methods in the study appeared to perform well on the control samples, additional methods that can be used widely and easily to detect the presence of SV40 DNA in human tissues are needed.
Recent Research
To further explore the relationship between poliovirus vaccine exposure and the incidence of pleural mesotheliomas, a recent study compared vaccine exposure and subsequent rates of these tumors in the United States. The authors found that incidence rates for pleural mesotheliomas increased the most among males who were age 75 or older, the age group least likely to have been exposed to the contaminated poliovirus vaccine. Incidence rates among males in the age groups most heavily exposed to SV40-contaminated poliovirus vaccine (between ages 25 and 54) remained stable or decreased from 1975 through 1997. Similar trends were seen among women whose over-all rates of pleural mesothelioma are six times lower than the rates for men. In fact, even though women had similar or greater exposure to SV40-contaminated vaccine as men, pleural mesotheliomas were persistently rare (an average of less than 38 cases each year among the more than 13 million women in SEER), and the few female cases that did occur were mainly in age groups unlikely to have ever received any poliovirus vaccine. Sophisticated “age-period-cohort models” were used to obtain a comprehensive statistical assessment of trends in pleural mesothelioma incidence, and failed to detect any increases in rates that could be attributed to SV40-contaminated poliovirus vaccine in males or females.
The authors concluded that after almost 40 years of follow-up, U.S. cancer incidence data have not shown an increased incidence of pleural mesothelioma among the age groups that were exposed to SV40-contaminated poliovirus vaccine. However, they noted that continued surveillance of people who received the vaccine is needed, in view of conflicting reports on the detection of SV40 genomic DNA sequences in mesothelioma tumor samples.
Another epidemiology study involved analyzing cancer incidence data from Denmark following exposure to SV40-contaminated poliovirus vaccine. A vigorous vaccination campaign in Denmark, beginning in the spring of 1955 and extending through the early 1960s, resulted in nearly 100 percent vaccination rate in targeted groups, particularly children and young adults. In addition, there is good evidence that most, if not all, of the poliovirus vaccine lots used during this time contained live SV40. From 1963 on, new production techniques eliminated SV40 from lots of Danish poliovirus vaccine.
Using data from the Danish Cancer Registry covering the period from 1943 through 1997, the researchers compared the cancer incidence in people vaccinated with SV40-contaminated poliovirus vaccine as infants (i.e., those born from 1955–1961) or children (i.e., those born from 1946–1952), to those not exposed to SV40 (i.e., those born from 1964–1970). Those exposed to SV40 had a lower overall cancer risk than those not exposed. Furthermore, they did not have an increased incidence of mesothelioma, brain tumors (including ependymoma and choroid plexus tumors), osteosarcoma and other bone tumors, non-Hodgkin's lymphoma, or testicular cancer, compared to those not exposed to the virus.
To look at the short-term effects of SV40 exposure on cancer risk, the authors also compared cancer incidence among children ages 0 to 4 years who were exposed or unexposed to SV40-contaminated poliovirus vaccine. They found that the incidence of cancers combined, intracranial tumors, or leukemia was not elevated in years when these children had received SV40-contaminated poliovirus vaccine. Although the incidence of one type of brain tumor, ependymoma, was significantly higher in the exposed vs. the unexposed group, the authors noted that because the peak incidence of ependymoma occurred in 1969, well after SV40 was removed from the Danish vaccine, the effect probably was not due to SV40 exposure.
A study involving a population uniquely exposed to SV40—people living in northern India—was also published recently (39). It is unclear whether humans can be infected with SV40 but, if this occurs, human infection might be especially common in northern India, where contacts between humans and SV40-infected monkeys frequently occur. NCI researchers and collaborators tested for the presence of SV40 in 47 archived samples of choroid plexus tumors and ependymomas, which are rare human brain tumors reportedly linked with SV40 (15, 17), from the All India Institute of Medical Sciences in northern India. They did not find SV40 in any of the tumors.
In a case/control study in Spain involving 520 lymphoma cases and 587 controls (45), researchers tested blood samples from cases and controls for the presence of antibodies to SV40. If SV40 circulates in human populations and is implicated in lymphomas, SV40 serum antibodies might be detected at high levels in lymphoma cases. However, the researchers found no increased antibody levels to SV40 detected in lymphoma cases vs. the controls.
Overall, SV40 antibody levels were low in both cases and controls. Additional testing suggested that a large part of these antibodies may be antibodies to the human virus BK, and not to SV40. Because the DNA of the SV40 virus is nearly 70 percent identical to the BK virus, it is difficult to distinguish between antibodies to the two viruses. Most humans carry antibodies to BK in their blood, since the virus commonly infects humans as children. BK, however, is not associated with any disease in healthy people.
In another case/control study involving 782 brain tumor cases and 799 controls (46), the risk of developing glioma, meningioma, or acoustic neuroma was not associated with having received either injected or oral poliovirus vaccine during the time period (1955–1963) when vaccines were contaminated with SV40. Exposure to the potentially contaminated poliovirus vaccine was based on self-reporting. Although some participants may not have been able to recall vaccinations they received as young children, the high percentage (85 percent) of reported vaccinations among controls less than 20 years of age in 1961 was similar to the values reported during the same period for the general population.
The authors concluded that after almost 40 years of follow-up, U.S. cancer incidence data have not shown an increased incidence of pleural mesothelioma among the age groups that were exposed to SV40-contaminated poliovirus vaccine. However, they noted that continued surveillance of people who received the vaccine is needed, in view of conflicting reports on the detection of SV40 genomic DNA sequences in mesothelioma tumor samples.
Another epidemiology study involved analyzing cancer incidence data from Denmark following exposure to SV40-contaminated poliovirus vaccine. A vigorous vaccination campaign in Denmark, beginning in the spring of 1955 and extending through the early 1960s, resulted in nearly 100 percent vaccination rate in targeted groups, particularly children and young adults. In addition, there is good evidence that most, if not all, of the poliovirus vaccine lots used during this time contained live SV40. From 1963 on, new production techniques eliminated SV40 from lots of Danish poliovirus vaccine.
Using data from the Danish Cancer Registry covering the period from 1943 through 1997, the researchers compared the cancer incidence in people vaccinated with SV40-contaminated poliovirus vaccine as infants (i.e., those born from 1955–1961) or children (i.e., those born from 1946–1952), to those not exposed to SV40 (i.e., those born from 1964–1970). Those exposed to SV40 had a lower overall cancer risk than those not exposed. Furthermore, they did not have an increased incidence of mesothelioma, brain tumors (including ependymoma and choroid plexus tumors), osteosarcoma and other bone tumors, non-Hodgkin's lymphoma, or testicular cancer, compared to those not exposed to the virus.
To look at the short-term effects of SV40 exposure on cancer risk, the authors also compared cancer incidence among children ages 0 to 4 years who were exposed or unexposed to SV40-contaminated poliovirus vaccine. They found that the incidence of cancers combined, intracranial tumors, or leukemia was not elevated in years when these children had received SV40-contaminated poliovirus vaccine. Although the incidence of one type of brain tumor, ependymoma, was significantly higher in the exposed vs. the unexposed group, the authors noted that because the peak incidence of ependymoma occurred in 1969, well after SV40 was removed from the Danish vaccine, the effect probably was not due to SV40 exposure.
A study involving a population uniquely exposed to SV40—people living in northern India—was also published recently (39). It is unclear whether humans can be infected with SV40 but, if this occurs, human infection might be especially common in northern India, where contacts between humans and SV40-infected monkeys frequently occur. NCI researchers and collaborators tested for the presence of SV40 in 47 archived samples of choroid plexus tumors and ependymomas, which are rare human brain tumors reportedly linked with SV40 (15, 17), from the All India Institute of Medical Sciences in northern India. They did not find SV40 in any of the tumors.
In a case/control study in Spain involving 520 lymphoma cases and 587 controls (45), researchers tested blood samples from cases and controls for the presence of antibodies to SV40. If SV40 circulates in human populations and is implicated in lymphomas, SV40 serum antibodies might be detected at high levels in lymphoma cases. However, the researchers found no increased antibody levels to SV40 detected in lymphoma cases vs. the controls.
Overall, SV40 antibody levels were low in both cases and controls. Additional testing suggested that a large part of these antibodies may be antibodies to the human virus BK, and not to SV40. Because the DNA of the SV40 virus is nearly 70 percent identical to the BK virus, it is difficult to distinguish between antibodies to the two viruses. Most humans carry antibodies to BK in their blood, since the virus commonly infects humans as children. BK, however, is not associated with any disease in healthy people.
In another case/control study involving 782 brain tumor cases and 799 controls (46), the risk of developing glioma, meningioma, or acoustic neuroma was not associated with having received either injected or oral poliovirus vaccine during the time period (1955–1963) when vaccines were contaminated with SV40. Exposure to the potentially contaminated poliovirus vaccine was based on self-reporting. Although some participants may not have been able to recall vaccinations they received as young children, the high percentage (85 percent) of reported vaccinations among controls less than 20 years of age in 1961 was similar to the values reported during the same period for the general population.
On-Going Research
The NCI is continuing to evaluate the possible link between SV40 infection and human cancers through intramural research conducted by the Division of Cancer Epidemiology and Genetics (DCEG), which is still monitoring populations known to have been exposed to SV40-contaminated vaccines. A number of additional extramural grant-supported studies funded by NCI to evaluate the possible relationship of SV40 to cancer are underway (http://fundedresearch.cancer.gov/). Other institutes at the National Institutes of Health are also funding a wide range of studies related to SV40 (http://crisp.cit.nih.gov/).
IOM Report
The Institute of Medicine (IOM) issued a report in October 2002, which concluded that the scientific evidence was insufficient to prove or disprove the theory that exposure to poliovirus vaccine contaminated with SV40 resulted in cancer in humans (http://www.iom.edu/?id=6014). The IOM is one of the National Academies to which the nation’s leaders often turn for conducting independent scientific studies.
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