Nearly 50 Years after Development of the Polio Vaccine, SV40 Contamination Continues to be a Growing Controversy
- Source : www.anellomedicalwriting.com/SV40-%20HMS%20Beagle.doc
In the year, 1952, the number of Americans stricken with polio exceeded more than 57,000. The disease primarily struck at young children, causing paralysis, muscle atrophy, deformity, and even death. As the leading public health crisis during the first half of this century, fear of contracting polio gripped most of the world.
Consequently, discovery of the polio vaccine in 1953 was universally met with overwhelming anticipation and relief. And in 1955, widespread vaccinations began. Throughout the next 40 years, the scourge of polio was driven back. Remarkably, the World Health Organization declared the Western Hemisphere polio-free in 1994, attesting to the success of this enormous public health initiative.
However, the success of the polio vaccine has always been accompanied by some measure of medical controversy. The source of controversy involves the well-known fact that millions of polio vaccine doses from 1955-1963 were contaminated with simian virus number 40 (SV40). Some 98 million people worldwide were exposed to SV40 through contaminated polio vaccinations. Today, this controversy continues to gain scientific interest and is now garnering public concern, as well.
Members of the scientific, public health, and legal communities are in debate about several questions involving SV40. Does SV40 play some role in certain cancers such as mesothelioma and brain tumors? Was SV40 present in humans before the mass vaccinations? Is SV40 actively spreading in humans through sexual and placental contact? How widespread was the SV40 contamination? There are numerous questions and too few answers.
The following article highlights the controversial history of SV40-contaminated polio vaccine and discusses emerging research findings on the basic virology and oncogenic potential of SV40. After treating this preliminary information, the article addresses a growing debate questioning the extent of polio vaccinations containing SV40 contamination, and the potential ramifications that this new information, if true, may have on past research findings and future studies.
Development of a polio vaccine: problems from the start
In 1953, Jonas Salk formulated the first polio vaccine capable of widespread vaccination. The poliovirus was grown in rhesus monkey kidney cells, and then inactivated or "killed" by the addition of formalin—hence it came to be known as the "killed vaccine." In 1954, the first field trial of the killed vaccine using 400,000 second- graders was undertaken, and in 1955, the vaccine was quickly approved by federal agencies, marking the beginning of the widest mass-vaccination program to date.
Within three months of licensure, problems with the killed vaccine began to surface. In June of 1955, two months after 44 so-called "Polio Pioneers" had contracted polio from the vaccination, the prominent scientist, John Enders, warned that the formulation process was flawed because of its potential failure to kill the poliovirus.
Dr. Enders was the Harvard virologist who won the Nobel Prize for discovering that the poliovirus could be grown in tissue culture. He warned that the production technique could result in contamination of the vaccine by undetected viruses. This is according to an article from The Journal of Legal Medicine, in which the authors, Goldman and Brock, also state that despite this warning, "no official action was taken by any governmental entities or drug companies to halt the production or distribution of the vaccine."
In 1957, after two years of widespread distribution, Dr. Maurice Hilleman, of Merck Laboratories, identified the existence of a virus that concealed itself within the kidney cells of the rhesus monkey—the virus later came to be known as SV40. At the Second International Live Poliomyelitis Vaccine Conference, held in June 1960, Dr. Hilleman presented these findings after isolating the SV40 virus. At this same conference, it was reported that the Sabin live polio virus (discussed below) contained SV40 contamination, and that more than half of all the sera of individuals receiving killed vaccine, tested positive for the SV40 antibody.
Another important development occurred in 1960, when Bernice Eddy, a government researcher, discovered that hamsters developed tumors after receiving injections of kidney cells used in developing the polio vaccine. According to an article in the Atlantic Monthly, "Eddy's superiors tried to keep the discovery quiet, but Eddy presented her data at a cancer conference in New York." According to the article, Eddy was eventually demoted following the conference, and lost her laboratory.
Meanwhile, scientists at Merck, including Dr. Hilleman and Dr. Benjamin Sweet, began conducting experiments with SV40 virus in laboratory animals, eventually finding that the injection of SV40 caused the development of sarcomatous tumors in hamsters. By 1961, scientists concluded that SV40 could infect humans, and in 1962, in vitro experiments confirmed that SV40 could transform human cells. Moreover, scientists found that subcutaneous cysts could be produced from transformed autologous human cells.
As a result of these findings, the United States Food and Drug Administration (FDA) stiffened regulations, requiring that all vaccines submitted to the FDA after June 30th, 1961, be free of SV40 contamination (URL= www.fda.gov). However, the FDA allowed SV40-contaminated polio vaccine, produced prior to this date, to remain on the market until early 1963, when the storage and shelf life of these contaminated doses finally expired.
The extent of exposure to SV40 was enormous. In 1963, the National Cancer Institute (NCI) found that nearly 4 million U.S. children received high levels of SV40 in just three months of inoculation during 1955 (URL= www.nci.nih.gov). In the same period, another 3.7 million children received vaccines containing lower levels of SV40. The Centers for Disease Control (CDC) states that in total, "as many as 10-30 million persons in the U.S. could have received SV40-contaminated injectable polio vaccine." In addition, another 10,000 persons may have received live oral vaccine that was contaminated with SV40 during several clinical trials, according to the CDC (URL= www.cdc.gov).
Sabin develops a live oral polio vaccine
The live oral polio vaccine, developed by Albert Sabin, was based on the theory that certain children found throughout the world had become immune to polio because they had received partial immunity from their mothers, or had been infected by an attenuated or weakened strain of the virus that produced immunity without acute symptoms.
Dr. Sabin eventually identified three weak polio strains from which he developed the live oral vaccine. In 1957, the World Health Organization (WHO) began testing Dr. Sabin's vaccine in some 80 million persons outside the U.S., but it wasn't until April 24th, 1960, that testing began on what came to be known in the U.S. as "Sabin Sunday." The U.S. finally approved the live oral vaccine in 1963. (URL= www.who.int)
The live oral vaccine had several advantages, including ease of administration—especially useful in developing countries. However, the live vaccine was also judged superior because it conveyed both intestinal and bodily immunity—the killed vaccine provided bodily immunity, only. The killed vaccine was also less effective because immunized persons could still harbor or transmit the virus. Finally, the oral live vaccine produced a lifelong immunity without the need for booster shots, unlike the killed vaccine.
The live oral vaccine eventually became the most commonly used polio vaccine, however, not before concerns about manufacturing process and SV40 contamination were addressed. As a result, a meeting was held in August 1960 between potential vaccine manufacturers and members of the Surgeon General's committee, and officials of the Division of Biological Standards.
Discussions at this meeting, together with subsequent recommendations, formed the basis of regulations for the manufacturer of live oral polio vaccine. From these discussions, it was recommended that SV40 would be removed from cultures containing the poliovirus by using successive tissue culture passages.
The Surgeon General's Committee on Poliomyelitis recommended permitting five tissue culture passages based on the committee's judgment that "the removal of adventitious agents particularly the vacuolating and foamy [including SV40], will necessitate more than three virus passages [three passages had been recommended earlier], and that five passages will not have an adverse effect upon the vaccine."
The final federal regulations issued on March 25th, 1961, required that, "each seed virus used in the manufacture shall be demonstrated to be free of extraneous microbial agents." For several decades following the issuance of these regulations, scientists generally assumed that live oral polio vaccine was produced in accordance with the regulations, and therefore, free of SV40 contamination. In the years that followed, concerns about SV40 contamination faded and scientists shifted their interests to investigating the potential effects of SV40 presence in the human population.
SV40 and cancer: scientists choose sides
With the knowledge that the human population had been exposed to SV40 and that the virus could transform human cells, scientists began conducting epidemiological investigations. Two large studies were conducted, one study in the United States in 1963; the other in Germany in 1990.
In the United States, Fraumeni et al. looked at 10 million children representing three cohorts who received killed vaccine in 1955. The three cohorts received vaccine containing either high SV40 titers, low SV40 titers, or no SV40 titers. The study found no difference in death rates due to cancer among the three groups. However, the authors cautioned that the oncogenic effects of SV40 might have been missed, stating that vaccination recipients may have been potentially above the age of susceptibility, or that putative tumors had not lead to death within the study period.
In Germany, Geissler compared 900,000 children who had received contaminated oral polio vaccine as infants to a group of children born later who had presumably received SV40-free vaccines. After 22 years of follow-up, Geissler found no significant difference in cancer rates between the two cohorts.
Although this study would have detected any changes in the incidence rates of ependymomas or osteosarcomas, authors point out that the study would not have been able to detect changes in the incidence rates of mesothelioma, since the onset of this cancer generally occurs later in age.
Other studies, however, detected positive changes in cancer rates associated with individuals receiving contaminated vaccines. In 1967, the Innis study compared 706 children hospitalized with malignancies to a comparable control group matched for age and sex, and found that the frequency of poliovirus vaccination was slightly higher in the children with malignancies.
In another study, Heinonen followed 50,000 pregnant women between 1959 and 1965. The study found that the rate of malignancies was nearly twofold greater in children born to mothers who were immunized with killed vaccines during their pregnancy.
These studies, together with other investigations, had spurred a growing debate among experts as to whether or not an association existed between SV40 and cancer. In the mid-1990s, investigators began using polymerase chain reaction (PCR) methods to demonstrate the presence of SV40-like DNA sequences in brain, osteosarcoma, and mesothelioma tumors. The nineties saw several laboratories independently detecting SV40-like DNA in tumor tissue.
These revelations seemed to fuel the debate, leading to a decision by the U.S. Department of Health and Human Services (URL= www.os.dhhs.gov) to convene a workshop of experts at NIH headquarters in 1997, to discuss the SV40 debate. Although presentations at the workshop reflected a growing consensus that SV40 was somehow associated with certain cancers, the NIH failed to provide any new funding to evaluate the growing evidence of SV40 DNA in tumor tissue, but nevertheless, favored more research.
Throughout the remainder of the decade, evidence supporting an association between SV40 and certain cancers continued to grow. However, it was not until the new millennium dawned that a conference in Chicago brought together a consensus supporting the association of SV40 and certain cancers.
New millennium, same old problem
In April of 2001, the University of Chicago hosted a conference focusing on mesothelioma and the role of SV40. At the conference, it was reported that multiple independent laboratories had verified the presence of SV40 DNA in human pleural mesotheliomas. According to one of the leading experts, Michele Carbone, M.D., as many as 62 papers and 30 different laboratories independently detected the presence of SV40 DNA in mesotheliomas, osteosarcomas, bone tumors, and a variety of brain tumors. The take-home message of the conference was that SV40 definitely plays a role in some patients with mesothelioma cancer.
However, despite a multitude of reports providing this evidence, doubts about SV40 DNA presence in human cancer tissues continues to persist among a minority of investigators, including officials at the CDC and WHO. According to the CDC, "there is limited evidence that SV40 can infect humans, but there is no evidence it causes human health problems." (URL= www.cdc.gov) And according to WHO, "despite almost 40 years of observation, there is still no evidence that SV40 contamination of some early batches of polio vaccine has had any adverse effect on human health." (URL= www.who.int)
Further extent of SV40 contamination: unanswered questions
Perhaps one of the most startling reports at the conference came from the poster presentation made by Counselor Stanley Kops, who represents litigants—paralyzed as a result of taking the vaccine. The poster presented information from Kops’ recent article published in Anticancer Research.
According to Kops, during the course of litigation involving live Orimune polio vaccine, produced by the pharmaceutical company, Lederle, several internal documents suggested that oral vaccine manufactured after 1963 may have been contaminated with SV40.
Kops points to a Lederle document dated November 8th, 1961, in which they disclose that there was possible SV40 contamination in 3 out of the first 15 vaccine pools used to manufacture the newly licensed live vaccine. According to Kops, internal documents show that "all three of these pools were utilized in vaccine commercially sold for several years following licensure in the United States." Moreover, Dr. Roderick Murray, who was the director of the Division of Biologic Standards (the federal agency regulating vaccine manufacture), was aware of the potential contamination, according to this internal documentation.
In 1998, testimony by Dr. Mary Ritchey, then Vice President of Operations for Wyeth-Lederle, indicated that American Cyanamid could not now determine that all the polio vaccine seeds and strains were tested for SV40. According to Kops' article, Dr. Ritchey testified "Lederle did not have protocols in its possession for all of its strain and seed materials." Furthermore, according to Kops, "Dr. Ritchey testified that there were no protocols for any of the three master seeds, type I, type II, and type III."
The paper trail, or lack of paper trail, grows: In 1979, an internal memorandum at American Cyanamid stated that, "it should be made clear that Lederle did not test the original Sabin seeds for extraneous agents or neurovirulence since only 15 ml or less of each seed were provided by Dr. Sabin." The memorandum is startling, since in 1962, Sabin wrote a letter informing American Cyanamid that Dr. Hilleman and his associates, who performed testing for SV40 contamination, "could not be certain that there may not be a trace of SV40 virus in this material." According to the letter, Sabin informed American Cyanamid that, "at the time the tests were made they were not observing the cultures for as long as they are now."
Other litigation also bears out the absence of documentation demonstrating that vaccine seeds were, indeed, free of SV40. Demands for this documentation have been made to the United States in the case of In Re Sabin Litigation, and to American Cyanamid in numerous cases now pending.
Evidence of required testing that demonstrates vaccines to be SV40-free, should exist, according to sworn testimony filed in another litigation case. "Lederle swore that every seed was submitted to the government for the government's review and approved by the government," according to the article by Kops. Yet, documents remain absent to disprove these various claims of SV40 contamination.
If SV40 contamination continued during the production of oral live vaccine, beginning in the early 1960s, there are huge implications for past scientific findings and future research studies. A flawed presumption that certain vaccines were SV40-free, would invalidate hundreds of epidemiological studies.
There is growing scientific evidence, as well, that SV40 may have been a contaminant of polio vaccine manufactured after 1963. Rizzo, Carbone, and others have demonstrated the presence of two SV40 strains—a fast replicating strain and a slow replicating strain they term "archetypal." The new concern this finding raises is whether or not tissue cultures used to produce polio vaccine after 1963, were observed for a period of time, sufficient to detect contamination by the slow replicating archetypal strain.
According to an article by Rizzo, "it may be important to study a larger number of commercial polio vaccines produced after 1963 to rule out occasional contamination with archetypal SV40—contamination of vaccines with archetypal SV40 could help to explain the presence of these SV40 variants in pediatric tumors of children born after 1963."
The current debate
Despite growing legal and scientific evidence that questions the validity of SV40-free claims by vaccine manufacturers, the CDC maintains that contamination is not an issue, saying that "huge amounts of oral polio vaccine have been periodically tested after 1963, using the most sensitive assays available, and SV40 has never been identified." However, the 1999 article by Rizzo states that, "we were surprised to learn that neither molecular or immunohistochemical techniques are used to screen polio vaccines for SV40. . . we suggest that more modern and sensitive techniques be used in place or in addition to the cytopathic test to screen polio vaccines."
So, it appears that the current debate remains at a stalemate. Moreover, uncertainty about the facts sadly pervades the debate. It also remains uncertain, whether or not these questions can be resolved, given the numerous vested interests of the players, including the reputations of federal agencies, vaccine manufacturers, and scientists that have lined up behind the various competing theories, of whom all have much to lose or gain.
And then there are the victims of mesotheliomas, osteosarcomas, and brain tumors—perhaps the interests of these people should carry the most weight in this debate. Unfortunately, public concern in the United States and throughout the world has yet to be vocalized in this debate.
The final word: Scientists are making progress on the treatment of mesothelioma. A vaccine designed to protect against SV40 infection is currently in development for the potential treatment of mesothelioma. It may perhaps, be the saddest medical irony—that a vaccine is currently in development against a virus that was inadvertently introduced into the human population—through mass polio vaccinations, beginning almost 50 years ago.