New documents show the monkey virus is present in more recent polio vaccine
William Carlsen / SF Chronicle 22jul01
mindfully.org note: it is strongly suggested that you browse the genetic engineering index on this site.
Students at St. Vibiana's school in Los Angeles were among the first to receive the Salk vaccine. Associated Press File Photo
A monkey virus linked to human cancers may have contaminated the oral polio vaccine for years after the U.S. government ordered manufacturers to remove it, according to drug company documents obtained by The Chronicle.
The Chronicle reported last week that the simian virus SV40 had contaminated early polio vaccine given to millions of Americans. When health officials discovered in 1961 that SV40 caused malignant tumors in lab animals, they ordered the virus eliminated from all future vaccine.
But internal memos from Lederle Laboratories, the chief producer of polio vaccine in the United States, indicate SV40 may not have been completely removed.
According to one memo, SV40 was found in three of 15 lots of the oral vaccine seven months after the federal directive was issued in March 1961. Lederle released the contaminated vaccine to the public anyway, the memo shows.
The documents also suggest that the company failed to test the monkey- kidney seed strains used to make the bulk polio vaccine for contamination, despite a written warning from Dr. Albert Sabin, who developed the oral vaccine.
Lederle and the U.S. government insist there is no evidence that any contaminated vaccine was distributed after the directive went into effect.
Scientists discovered SV40 in the Salk polio vaccine in 1960. By then as many as 30 million Americans had been given injections of the SV40-tainted polio vaccine, which was first licensed in 1955.
In recent years more than 60 scientific studies have found SV40 in rare human brain, bone and lung-related cancers, the same kinds of tumors the virus caused in laboratory animals. Some scientists believe SV40 may play a role in causing those cancers.
One of the biggest mysteries, however, is why SV40 has been found in tumors removed from people who never received the contaminated Salk vaccine.
Researchers have several theories for how the virus could have spread from those infected through the Salk vaccine: in transmission from mother to fetus or through breast milk; through sexual activity or a flu-like virus.
But the Lederle documents, which were obtained by Philadelphia attorney Stanley Kops in litigation not related to SV40, raise the possibility the virus might have been transmitted by contaminated oral vaccine, licensed for production in 1962.
The documents include:
-- A November 1961 memo saying the virus was found in three of 15 lots of vaccine. According to the memo, Dr. Roderick Murray, head of the government's program to ensure vaccine purity, allowed the lots to be released.
To comply with the removal order, Lederle had switched from rhesus monkeys, which are natural hosts for SV40, to African green monkeys, supposedly free from SV40. However, the memo notes that SV40 was found in 10 percent of the green monkeys.
-- A letter from Sabin to Lederle in October 1962, warning that sufficient testing for SV40 contamination had not been done on one of his strains of weakened polio virus that formed the seed for bulk vaccine production.
-- A confidential memo in 1979 from a Lederle official stating: "It should be noted that Lederle did not test the original Sabin seeds for extraneous agents or neurovirulence since Dr. Sabin assured us that this had been done."
-- Another memo stating that Lederle did not test the seed "since only 50 (milliliters) or less of each seed were provided by Dr. Sabin."
The two memos added that testing was unnecessary because later vaccine samples submitted for license were free of SV40.
Kops also said that he had taken testimony in 1998 from a top Lederle official who said the company did not have the test results from many of the vaccine lots.
"The vaccine manufacturers and the government need to disclose what really happened," said Kops. "Without the facts, (scientists) will continue to look in the wrong places to explain how people were infected with SV40 after 1961."
Lederle did not respond to requests for comment.
At a 1997 conference, however, a company representative outlined the series of tests the company uses to detect SV40 contamination. The company also says that it uses antiserum to neutralize any SV40 in the "master seeds."
But it is not clear whether these procedures were in place in the years after the U.S. government issued its directive.
Last year, a lawsuit was filed in Los Angeles against Lederle by the parents of 2 1/2-year-old Alexander Horwin who died of a brain tumor that later tested positive for SV40. The suit claims that the tumor was caused by SV40 and that he became infected through a 1997 oral polio vaccine.
Kops and attorney Donald MacLachlin represent a New Jersey family that is considering a suit against vaccine manufacturers.
In 1970, surgeons removed a large brain tumor from 2-year-old Mark Moreno. He since has undergone five more surgeries and now wears a protective helmet over the large opening in his cranium where bone grafts never took. Moreno, now 33, lives with his mother and requires daily assistance.
Recent tests show Moreno's tumor was riddled with SV40, according to the lawyers.
Eileen Moreno, Mark's mother, believes her son's brain tumor was caused by SV40 and that he was infected through the oral polio vaccine in 1968.
Last year, two investigators from the U.S. Food and Drug Administration used genetic testing to examine 30 samples of bulk oral polio vaccine used in the United States going back to 1972. They reported finding no SV40.
But the government has not used the genetic tests to determine whether vaccine made prior to 1972 was contaminated.
Dr. William Egan, deputy director of the FDA's vaccine research branch, said testing went back only to 1972 because those samples were the only ones available to them. "There was nothing sinister," he said.
MacLachlin said he finds it "incredible" that the government hasn't comprehensively investigated the possibility of SV40 contamination of the oral vaccine.
Simian virus Q&A Q: How widespread is the SV40 infection?
A: Scientists and government health officials don't know, because no comprehensive studies have addressed the question. What is known is that during the 1950s and '60s, at least 10 million to 30 million Americans -- and more than 100 million people worldwide -- were given SV40-contaminated polio vaccine. The virus also has been found in people who did not receive contaminated vaccine.
Q: Can I be tested for SV40?
A: An accurate blood test does not exist. Current antibody blood tests can be inaccurate, scientists say, because they also may detect the presence of closely related viruses, and SV40 may be present at such a low level that no antibodies are produced. Researchers are working to create an effective test.
Q: In which kinds of cancers has SV40 been found?
A: The virus has been detected in rare cancers, including:
- Mesothelioma, a fatal tumor of the membrane surrounding the lungs. Few cases were reported prior to 1950, but the incidence has grown in the United States to 2,000 to 4,000 cases a year, with greater incidence in Europe.
- Brain cancers: Primarily ependymomas and choroid plexus tumors, but also astrocytomas, glioblastomas, medulloblastoma, and meningiomas. Fewer than 1, 000 cases of these cancers are reported in the United States each year.
- Bone cancers: Primarily osteosarcomas, but also chondrosarcoma and giant cell tumors. These also make up fewer than 1,000 cases annually.
For more information on SV40 and the polio virus www.sfgate.com/chronicle/sv40/
Early polio vaccine harbored virus now feared to cause cancer in humans
William Carlsen / SF Chronicle 15jul01
A growing number of medical researchers fear that a monkey virus that contaminated polio vaccine given to tens of millions of Americans in the 1950s and '60s may be causing rare human cancers.
For four decades, government officials have insisted that there is no evidence the simian virus called SV40 is harmful to humans. But in recent years, dozens of scientific studies have found the virus in a steadily increasing number of rare brain, bone and lung-related tumors - the same malignant cancer SV40 causes in lab animals.
Even more troubling, the virus has been detected in tumors removed from people never inoculated with the contaminated vaccine, leading some to worry that those infected by the vaccine might be spreading SV40.
The discovery of SV40 in human tumors has generated intense debate within the scientific community, pitting a handful of government health officials, who believe that the virus is harmless, against researchers from Boston to China who now suspect SV40 may be a human carcinogen. At stake are millions of research dollars and potential medical treatments for those afflicted with the cancers SV40 may be causing.
In April, more than 60 scientists met in Chicago to discuss the controversial virus and how it works to defeat certain cells' natural defenses against cancer.
"I believe that SV40 is carcinogenic (in humans)," said Dr. Michele Carbone of Loyola University Medical Center in Maywood, Ill. "We need to be creating therapies for people who have these cancers, and now we may be able to because we have a target - SV40."
But scientists at the National Cancer Institute say their studies show almost no SV40 in human tumors and no cancer increase in people who received the contaminated vaccine.
"No one would dispute there's been a widespread, very scary exposure to the population of potentially cancer-causing virus," said Dr. Howard Strickler, NCI's chief investigator. "But none of our studies and other major analyses have shown an inkling of an effect on the population."
Critics charge, however, that the few studies done by the government are scientifically flawed and that health officials have downplayed the potential risks posed by SV40 ever since they learned in 1961 that the virus contaminated the polio vaccine and caused tumors in rodents.
"How long can the government ignore this?" asked Dr. Adi Gazdar, a University of Texas Southwestern Medical Center cancer researcher. "The government has not sponsored any real research. Here's something possibly affecting millions of Americans, and they're indifferent.
"Maybe they don't want to find out."
The recent SV40 discoveries come at a time of growing concern over the dangers posed by a range of animal viruses that have crossed the species barrier to humans, including HIV, which scientists now believe came from chimpanzees and ultimately caused the AIDS epidemic.
Based on dozens of interviews and a review of the medical research, this is the story of how the campaign to eradicate polio may have inadvertently permitted another potentially deadly monkey virus to infect millions of people - and why the government for years discounted the accumulating evidence suggesting that SV40 may be a health risk for humans.
Polio epidemic, 1955
During the first half of the 20th century, polio struck down hundreds of thousands of people, leaving many paralyzed - some in iron lung machines - and killing others. The worst year was 1952, when more than 57,000 polio cases were reported in the United States. Three thousand died.
Then on April 12, 1955, Dr. Jonas Salk, a slightly built, soft-spoken researcher from Pittsburgh, mounted the podium at the University of Michigan and announced that he had developed a vaccine. That afternoon, the government licensed the vaccine for distribution.
Salk's vaccine was made by growing live polio virus on kidney tissue from Asian rhesus monkeys. The virus was then killed with formaldehyde. When the vaccine was injected in humans, the dead virus generated antibodies capable of fending off live polio.
Dr. Dwight Murray, then chairman of the American Medical Association, called Salk's announcement "one of the greatest events in the history of medicine."
Within weeks, the stockpiled vaccine was being injected into the arms of millions of people worldwide.
Virus and the tumors, 1959
Four years later, Bernice Eddy, a researcher at the National Institutes of Health, noticed something strange while looking through her microscope. Monkey kidney cells - the same kind used to make the vaccine - were dying without apparent cause.
So she tried an experiment. She prepared kidney extracts from eight to 10 rhesus monkeys and injected tiny amounts under the skin of 23 newborn hamsters. Within nine months, "large, malignant, subcutaneous tumors" appeared on 20 of the animals.
On July 6, 1960, concerned that a monkey virus might be contaminating the polio vaccine, Eddy took her findings to Dr. Joseph Smadel, chief of the NIH's biologics division. Smadel dismissed the tumors as harmless "lumps."
The same year, however, at a Merck laboratory in Pennsylvania, Dr. Maurice Hilleman and Dr. Ben Sweet isolated the virus. They called it simian virus 40, or SV40, because it was the 40th virus found in rhesus kidney tissue.
Immunization campaign, 1961
By then, the nation was winning the war against polio. Nearly 98 million Americans - more than 60 percent of the population - had received at least one injection of the Salk vaccine, and the number of cases was plummeting.
At the same time, an oral polio vaccine developed by virologist Albert Sabin was in final trials in Russia and Eastern Europe, where tens of millions had been inoculated, and it was about to be licensed in the United States. Unlike the Salk vaccine, the oral version contained a live but weakened form of polio virus and promised lifelong immunity.
But U.S. Public Health Service officials were worried. Tests had found SV40 in both the Sabin and Salk vaccines - it was later estimated that as much as a third of the Salk vaccine was tainted - and that SV40 was causing cancer in lab animals.
In early 1961, they quietly met with the agency's top vaccine advisers. The agency found no evidence that the virus had been harmful to humans, but in March, the officials ordered manufacturers to eliminate SV40 from all future vaccine.
New procedures were adopted to neutralize the tainted polio virus seed stock and SV40-free African green monkeys were used to produce the bulk vaccine instead of rhesus monkeys.
But officials did not recall contaminated Salk vaccine - more than a year's supply - still in the hands of the nation's doctors.
And they did not notify the public of the contamination and SV40's carcinogenic effect on newborn hamsters.
Hilleman would later explain that government officials were worried that any potentially negative information could ignite a panic and jeopardize the vaccination campaign.
The first public disclosure that the Salk vaccine was contaminated came in the New York Times on July 26, 1961. A story on Page 33 reported that Merck and other manufacturers had halted production until they could get a "monkey virus" out of the vaccine.
When asked to comment, the U.S. Public Health Service stressed there was no evidence the virus was dangerous.
No cause for alarm, 1962
The next year, a young Harvard-trained epidemiologist named Dr. Joseph Fraumeni joined the National Cancer Institute and was assigned one of the agency's most important projects: to determine if there was any cancer increase among those injected with the Salk vaccine.
His research would form the basis of the government's position for decades.
Working with two colleagues, Fraumeni tested stored vaccine samples from May and June of 1955, the first months of the national immunization campaign, then ranked the samples according to how much SV40 they contained - no, low or high amounts.
It would be the only time U.S. health officials measured the level of SV40 in the 1955-1962 vaccine. Stored samples from that period were later discarded.
Fraumeni identified the states where the SV40-contaminated vaccines had been distributed during those two months. California, for example, received vaccine with a low level of the virus.
The study looked at cancer mortality rates for 6- to 8-year-old children vaccinated during that narrow time frame, tracking the group for four years.
The findings, which were published in the Journal of the American Medical Association, showed no significant difference in cancer deaths in states with high or low levels of SV40 in the vaccine when compared with cancer deaths in states with no SV40 in the vaccine.
Cleveland children, 1976
Fourteen years later, after isolated reports linking the virus and human cancers, Fraumeni decided to look at another group that had received contaminated vaccine.
The group had been the subject of experiments conducted in the early 1960s at Cleveland Metropolitan General Hospital. To determine the effect of different amounts of the vaccines, researchers at the hospital inoculated newborns from mostly lower-income black families with doses ranging up to more than 100 times the dose recommended for adults.
The experiments took place over three years and involved 1,073 infants. Most were given Sabin oral vaccine later determined to contain SV40.
From 1976 to 1979, Fraumeni and his associates sent letters to the children - now age 17 to 19 - but fewer than half responded. The researchers found no SV40-related health problems from exposure to contaminated vaccine.
However, their 1982 report published in the New England Journal of Medicine acknowledged the study's limitations: A majority of the children had not responded; SV40-related cancers might take longer than 17 to 19 years to develop, and SV40 appears less likely to infect humans through the oral vaccine.
Nevertheless, they called their findings "reassuring and consistent with the prevailing view that SV40 is not carcinogenic in human beings."
Then they decided to end the study, citing "the mounting complexities and obstacles in tracing this particular group and the negative results to date."
The study's closure appeared to end the government's research into the virus. But a few years later there would be a tectonic shift in SV40 research.
First discovery, 1988
In Boston, two researchers stumbled onto something disturbing.
Dr. Robert Garcea and his assistant, Dr. John Bergsagel, were using a powerful new tool called polymerase chain reaction, or PCR, to look for a pair of common human viruses in children's brain tumors.
But a different DNA footprint kept popping up in more than half the tumors. They finally realized they were seeing SV40.
For more than a decade, scientists had reported sporadic findings of SV40- like proteins in human tumors. But the earlier tests were primitive and the results suspect. PCR, however, is capable of amplifying infinitesimal fragments of DNA, which makes detections far more credible.
The findings were troubling. The researchers noted in their published report that the children were too young to have received the contaminated vaccine. But somehow the virus had infected them and embedded itself in their tumors.
That same year, Dr. Michele Carbone was surprised to find a milky, rindlike tumor in a laboratory hamster at the National Institutes of Health in Bethesda, Md.
The animal was one of a group given an SV40 injection directly into their hearts. Sixty percent of those hamsters developed the fatal cancer called mesothelioma.
Carbone, a postdoctoral fellow at the institute, knew that SV40 caused tumors in hamsters but only in specific locations where large doses of virus were injected. Here the mesothelial membrane lining the lungs apparently became cancerous from minuscule amounts of SV40 shed by the tip of the needle on the way to the hamsters' hearts.
So he tried another experiment, this time injecting SV40 directly into the thin mesothelial walls of another group of hamsters. Within six months, every animal developed mesothelioma.
Carbone was puzzled. Mesothelioma is a rare cancer. Few human cases were reported before the 1950s, but its incidence had been increasing steadily, reaching several thousand cases a year in the United States by 1988.
Studies had linked mesothelioma to asbestos exposure - with tumors usually appearing many decades later. Yet 20 percent of victims had no asbestos exposure.
Carbone decided to use PCR to test 48 human mesotheliomas stored at the NIH.
He was stunned: 28 of them contained SV40.
More cancers, 1996
PCR unleashed a wave of SV40 discoveries.
By the end of 1996, dozens of scientists reported finding SV40 in a variety of bone cancers and a wide range of brain cancers, which had risen 30 percent over the previous 20 years.
Then, Italian researchers reported finding SV40 in 45 percent of the seminal fluid samples and 23 percent of the blood samples they had taken from healthy donors.
That meant SV40 could have been spreading through sexual activity, from mother to child, or by other means, which could explain how those never inoculated with the contaminated vaccine, such as the Boston children, were being infected.
Government assurances, 1996
At the National Cancer Institute in Bethesda, officials were growing increasingly concerned about the SV40 discoveries.
The findings were of particular interest to Fraumeni, who had been promoted to director of NCI's Division on Cancer Epidemiology and Genetics. His earlier studies concluding that SV40 posed little or no health risk were now under challenge.
But the scientific community was skeptical of the recent SV40 discoveries. As a potent carcinogen in lab animals, SV40 had been used for years as a tool to study cancer. Therefore, the powerful PCR test was suspected of finding stray SV40 fragments that might have contaminated laboratories.
So Dr. Howard Strickler, one of Fraumeni's epidemiologists, led a study using PCR on 50 mesotheliomas from Armed Forces hospitals across the country. And he found no SV40.
Although the findings bolstered the government's long-standing position that SV40 did not appear to be a health risk, federal officials decided to convene a conference on the virus.
In January 1997, 30 scientists gathered at the National Institutes of Health in Maryland. Garcea, Carbone and others presented their evidence showing SV40 in tumors and pleaded for research funding.
Strickler presented his mesothelioma study, as well as new research he had just completed, this time working with Fraumeni.
Their new study compared 20 years of cancer rates of people born between 1947 and 1963, and therefore likely to have been exposed to the contaminated polio vaccine, with people born after 1963, who they believed weren't exposed.
Their study found no significant difference between the two groups.
Letter of protest, 1998
But when Susan Fisher read Strickler and Fraumeni's study in the Journal of the American Medical Association, she fired off a letter of protest to the publication.
An epidemiologist at Loyola University Medical Center in Maywood, Ill., Fisher challenged the study's methodology, calling it "an error in judgment" and misleading.
Using the same 20-year national cancer database for the two groups, Fisher compared people of the same age - "because these cancers are highly correlated with age" - and she came up with very different results.
Studying 18- to 26-year-olds who probably had been exposed to the contaminated vaccine, Fisher found a 19.6 percent greater incidence of the two major brain cancers linked to SV40 when compared with the incidence in people the same age who were not exposed. She also found 16.6 percent more bone cancers and 178 percent more mesotheliomas among those exposed to the vaccine.
But Fisher cautioned against comparing the two groups. She argued that if SV40 is being transmitted and circulating in the population, then many people in the "unexposed" group would also be carrying the virus and that would undermine the comparison.
Two types of SV40, 1999
For years, researchers had believed that all SV40-contaminated Salk vaccine made between 1955 and 1963 had been used or discarded.
Then in 1999, Carbone was contacted by a former public health director in Oak Park, Ill., who said he had seven sealed vials of vaccine dated October 1955 in a refrigerator in his basement.
Carbone, who had left the NIH and joined the faculty at Loyola University Medical Center, ran tests on the vaccine and made a startling discovery: Not only was the vaccine contaminated, it contained a second form of the virus - an "archetypal" SV40 strain.
Although manufacturers switched from rhesus monkeys to SV40-free green African monkeys to grow the bulk vaccine in 1961, they have continued to use potentially contaminated polio seed strains originally grown on the rhesus monkey tissue to start the bulk vaccine process.
Manufacturers check the purity of their vaccine with a series of 14-day tests to detect whether any SV40 slipped through.
But when Carbone replicated the tests, he found that the second, slower- growing "archetypal" strain took 19 days to emerge.
It was possible, Carbone noted in a published report, that this second strain of SV40 had been evading manufacturers' screening procedures for years - and infecting vaccine recipients after 1962.
Controversial study, 2000
Meanwhile, a new study led by Strickler had bogged down in bitter internal conflict.
After the NIH's 1997 conference, nine laboratories were recruited to participate in a government-sponsored study to determine if tests were really finding SV40 in tumors or whether earlier detections were the result of laboratory contamination.
Carbone and other researchers considered the study unnecessary. A similar multilab study led by Dr. Joseph Testa of Philadelphia had just been completed, and it virtually eliminated the contamination theory. The prestigious journal Cancer Research published Testa's findings in 1998.
But Strickler pressed on.
An independent laboratory in Maryland prepared mesothelioma samples for the nine labs.
When tests revealed almost no SV40 in the tumor samples, some participants questioned the preparation methods used by the Maryland lab. They also challenged Strickler's written conclusion implying that contamination had caused the earlier findings of SV40 in tumors.
If Strickler was right, the earlier SV40 detections were probably the result of stray SV40 in the labs. But critics argued that the study was scientifically flawed and should be scrapped.
The dispute became so contentious that FDA officials were forced to intervene and a neutral arbitrator assigned to mediate.
Finally, in early 2000, more than two years after the study was initiated, a carefully rewritten report emerged for publication.
It concluded that contamination was an unlikely explanation for earlier SV40 findings. Then it struggled to explain the discrepancy between earlier detections of SV40 in about half of all mesotheliomas tested and the fact that the nine labs found the virus in only slightly more than 1 percent of the study's tumor specimens.
The report noted that discrepancy might be because of the inefficiency of the method used by the Maryland lab to recover DNA - like the genetic sequences of SV40 - from the mesothelial tissue to create the test samples.
The Maryland lab also had inadvertently contaminated some of the laboratory controls and "theoretically" could have contaminated others.
The report concluded by calling for further research.
Despite the study's ambivalent conclusions and technical problems, the NCI submitted it to Cancer Research, the journal that had published Testa's study.
It was rejected.
Further discoveries, 2000
In laboratories around the world, researchers continued to find SV40 in a widening range of tumors that now included pituitary and thyroid cancers and some lymphomas.
Meanwhile, an NCI investigator named Dr. David Schrump was able to gut a common respiratory virus and use it to deliver genetic material called "antisense" into SV40-infected mesothelial cells and stop the cells' malignant growth.
His discovery, which was patented by the government, strongly suggested that SV40 contributed to mesothelioma and that a treatment might be possible.
Then in August, Carbone and several colleagues published a major study providing a "mechanistic" explanation of how SV40 contributes to the uncontrolled growth of mesothelial cells. The key, they found, was the large number of "tumor suppressor" proteins found in the mesothelial cells that makes them unusually susceptible to SV40.
In most human cells, they said, the virus reproduces itself and kills the infected cell in the process. But in mesothelial cells, SV40 is especially attracted to the "tumor suppressor" proteins and binds to them, knocking them out of action. The virus then lives on in the cell.
The result, they said, is a rate of malignant cell transformation in tissue cultures 1,000 times higher than has ever been observed.
In a paper published in the Proceedings of the National Academy of Science, Carbone further explained that asbestos fibers appear to act as a co- carcinogen in mesothelioma by somehow suppressing the immune system's response, which is designed to kill the infected cells.
Chicago conference, 2001
Carbone and others believed that the time had come for another conference on the virus he calls "a perfect little war machine."
In April, more than 60 scientists gathered on a warm weekend at the University of Chicago's downtown conference center. Despite numerous faxes and certified letters inviting him, Strickler declined to attend.
Carbone opened the conference by confronting the question of whether SV40 is present in humans.
"Sixty-two papers from 30 laboratories from around the world have reported SV40 in human tissues and tumors," he said. "It is very difficult to believe that all of these papers, all of the techniques used and all of the people around the world are wrong."
For two days, scientists from as far away as China and New Zealand presented the results of their studies, with almost every speaker concluding that SV40 was present in the tissues they examined.
One of the newest discoveries came from Dr. Jeffrey Kopp, an NIH scientist who reported finding SV40 in a high percentage of patients with kidney disease. The virus was also present, he said, in 60 percent of a new "collapsing" type of renal disease that was unknown before 1980 but has since increased rapidly in incidence.
There were also reports on efforts to develop a vaccine, recently funded by the NCI, that would allow the immune system to target and eliminate SV40.
At times, the meeting took on almost revivalist overtones as scientist after scientist said he or she was initially very skeptical of SV40's presence in human tumors but was now a believer.
"I was a hard sell," said Testa, the Philadelphia geneticist who conducted the first multilaboratory tests, noting that the study had convinced him.
Gazdar, the cancer researcher from Texas, showed a slide describing his transformation: "Nonbeliever -- Believer - Zealot."
The conference concluded with a consensus among the leading scientists that SV40's presence in human tumors was no longer in question. They were more circumspect about the virus' possible role in causing cancer.
If SV40 is a human carcinogen, they said, the virus probably requires interaction with other cancer-causing substances like asbestos.
Dr. Janet Butel from Baylor Medical College in Houston said that it simply might be too soon to make a determination, citing the many years it has taken to establish that other viruses cause cancer.
But even renowned tumor biologist George Klein from Sweden said he was impressed by Carbone and Schrump's work.
"This strongly suggests that the virus plays a role (in causing tumors)," said Klein, a former chairman of the Nobel Assembly.
Low priority, 2001
In May, shortly after the conference, Strickler's multilab study was published in a small journal called Cancer Epidemiology, Biomarkers & Prevention.
Carbone and other SV40 experts dismissed the study.
"A garbage paper in a garbage journal," said Garcea, now on the faculty at the University of Colorado School of Medicine.
But Strickler strongly defends the study. He said it was the first to use strict controls not used in other studies. He acknowledged, however, that the study "doesn't prove that SV40 is not out there."
Strickler, who now teaches at Albert Einstein School of Medicine in New York, said he remains skeptical about whether SV40 has infected humans, a suspicion he says is shared by the broader scientific community.
But the NCI recently acknowledged that there is evidence to suggest that SV40 "may be associated with human cancer." The NCI statement, released last month, also said that SV40's interaction with "tumor suppressor proteins" indicates "possible mechanisms that could contribute to the development of cancer."
Top NCI officials declined to be interviewed on the record for this report. Fraumeni also declined several requests for an interview.
Dr. James Goedert, the chief of the NCI's Viral Epidemiology Branch who supervised Strickler's work, said that if SV40 is in human tumors, it must be at extremely low levels. To critics who claim the government has downplayed SV40's potential health risks, Goedert responded: "Absolutely not."
He acknowledged that research is needed to resolve the question of whether SV40 is prevalent in the human population and, if so, how it might be spreading. But Goedert said he has no plans for such studies.
"It's not our highest priority," he said.
Key figures in developing vaccines and tracing SV40
Dr. Jonas Salk Developed the first polio vaccine using killed virus in 1955.
Virologist Albert Sabin Developed an oral vaccine using weakened live virus.
Dr. Robert Garcea Used new technology to trace SV40 in children's brain
Q&A on polio vaccine contaminated with SV40 Q: How widespread is the SV40 infection?
A: Scientists and government health officials don't know because no comprehensive studies have addressed the question.
What is known: During the 1950s and '60s, more than 100 million people worldwide were given SV40-contaminated polio vaccine. The virus also has been found in people who did not receive contaminated vaccine, as well as laboratory workers and monkey handlers. No studies, however, have examined how SV40 might be transmitted between people, or if somehow humans might have become infected with SV40 before the introduction of the tainted vaccines.
Q: Can I be tested for SV40?
A: An accurate blood test does not exist. Current antibody blood tests can be inaccurate, scientists say, because they may also detect the presence of other closely related viruses, and SV40 may be present at such a low level that no antibodies are produced. Researchers are working to create an effective test.
Q: Is the current
polio vaccine safe?
A: Vaccine producers, health officials and most scientists believe that it is safe. Manufacturers say they take elaborate steps to test their vaccine for SV40, and the government says it recently tested vaccine samples back to 1972 and found no trace of SV40.
Some scientists, including Dr. Michele Carbone, have raised questions about whether manufacturers' testing techniques have been adequate. Carbone, however, tested vaccine from 1996 and found no SV40. He has had his children inoculated.
Q: In which kinds of cancers has SV40 been found?
A: The virus has been detected in rare cancers:
-- Mesothelioma, a fatal tumor of the membrane surrounding the lungs. Few cases were reported prior to 1950, but the incidence has grown in the United States to 2,000 to 4,000 cases a year, with greater incidence in Europe.
-- Brain cancers: Primarily ependymoma and choroid plexus tumors, but also astrocytoma, glioblastoma, medulloblastoma and meningioma. These make up a total of less than 1,000 U.S. cases each year.
-- Bone cancers: Primarily osteosarcoma but also chondrosarcoma and giant cell tumors. These also make up less than 1,000 cases annually.
-- Other cancers: A few detections in pituitary and thyroid tumors and
The sources for this report include the books "The Saga of Jonas Salk" by Richard Carter and "The Health Century" by Edward Shorter; articles in Atlantic Monthly and New York magazine; newspaper archives at The Chronicle and the New York Times; transcript of the 1997 National Institutes of Health Conference in Bethesda; a review of dozens of scientific journal articles and scores of interviews.
Related series: Quest for the Origin of AIDS.
How SV40 contaminated polio vaccine
When Dr. Jonas Salk introduced the first polio vaccine in 1955, it was hailed as "one of the greatest events in medicine." Within 10 years, U.S. polio cases plummeted from 30,000 to less than 1,000. But in 1960, a monkey virus called SV40 was found in the Salk vaccine. As much as one-third of the vaccine was contaminated. SV40 was also found in earlier versions of an oral vaccine developed by Dr. Albert Sabin that replaced the Salk vaccine in the 1960s. When it was discovered that SV40 caused cancer in lab animals, U.S. health officials ordered vaccine manufacturers in 1961 to eliminate the virus from all future vaccine, although questions remain about whether they succeeded with the Sabin vaccine. .
Making the Sabin vaccine: 1955-1961 Starting in the mid-1950s, both Sabin and Salk vaccines are made by growing polio virus on kidney tissue from Asian rhesus monkeys, which are natural hosts for the simian virus known as SV40. Special weakened seed strain of polio virus developed by Sabin is grown on rhesus kidney tissue to make large bulk amounts of vaccine. SV40 from the kidney tissue contaminates the vaccine. .
Making the vaccine safe: 1961 In 1961, after SV40 is discovered in the vaccines, U.S. health officials order manufacturers to eliminate SV40. Antiserum is used to neutralize SV40 in seed stock, and SV40-free African green monkeys are used to grow bulk vaccine. But some researchers believe small amounts of SV40 may have survived. .
Testing Manufacturers check the safety of the vaccine pools by using a series of 14- day growth tests to see if SV40 is present.
Making the Salk vaccine: 1955-1961 Full strength polio virus is grown on rhesus kidney to make bulk Salk vaccine. SV40 from the kidney tissue contaminates the vaccine. The polio virus is then killed with formaldehyde, but some SV40 survives. .
Making the vaccine safe: 1961 In the original vaccine, the SV40 survives, contaminating up to 30 million Americans. But after 1961, African green monkeys are used to grow bulk vaccine and SV40 is eliminated.
Sources: Children's Hospital of Philadelphia; SEER; virus images by Jean Yves Sgro, University of Wisconsin; Chronicle research
For more information about the simian virus SV40, the following studies or scientific reviews were published during that past year:
A multicenter evaluation of assays of detection of SV40 DNA and results in masked mesothelioma specimens. Strickler H, Goedert J., Cancer Epidemiology, Biomarkers & Prevention. Vol. 10, 523-532, May 2001.
Simian virus 40 and human cancers, Strickler H., Einstein Quarterly J. Biol. and Med. (2001) 18:14-21. This includes a detailed bibliography that will lead readers to earlier scientific articles.
Oral polio vaccine and human cancer: a reassessment of SV40 as a contaminant based upon legal documents. Kops S., Anticancer Research (2000) 20: 4745-4750.
Human mesothelial cells are unusually susceptible to SV40-mediated transformation and asbestos cocarcinogenicity. Bocchetta M, Di Resta I, Powers A, Fresco R, Tosolini A, Testa J, Pass H, Rizzo P, Carbone M., Proc. Natl. Acad. Sci. USA, Vol. 97, Issue 18, 10214-10219, Aug. 29, 2000.
In addition, a bibliography of journal articles by leading SV40 researcher Dr. Michele Carbone can be viewed by clicking on the following link: www.chestsurg.org/carbone7.htm
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