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INCONSISTENT REPORTS

ENTER THE SEWAGE SAMPLERS

INCONSISTENT REPORTS

ENTER THE SEWAGE SAMPLERS

INCONSISTENT REPORTS

ENTER THE SEWAGE SAMPLERS

WashingtonIt was a dirty job and nobody had to do it. But an international team of scientists did it anyway, testing dozens of sewage samples for simian virus 40 (SV40), which in the 1950s and 1960s contaminated millions of doses of polio vaccine. The unsavory task yielded compelling evidence of person-to-person transmission of SV40, evidence that complicates the contentious search for links between the monkey virus and human cancers.

During the past decade, an increasingly acrimonious debate over the issue has split researchers. One camp, mainly pathologists, reports finding the virus in human brain, bone, and lung tumors. The other, mainly epidemiologists, counters that cancer trends discount any link.

Colored transmission electron micrograph of polyoma viruses, simian viruses (SV40) that are a type of papovavirus. Under laboratory conditions, they can cause the development of tumors in mice. (Photo credit: CDC / Photo Researchers, Inc.)

The sewage study is a wild card. In their figuring, epidemiologists assume that only certain recipients of the vaccines were exposed to SV40. This assumption allows them to isolate SV40 as a variable and gauge whether cancer rates increased after 1961, when the last known contaminated vaccines were given. But what if SV40 circulates in people like it does in monkeys?

"If SV40 is transmitted from person to personand I'm not saying that it isthat would throw the epidemiology off," said Susan Fisher, PhD, chief of the epidemiology department at the University of Rochester School of Medicine, during a July presentation to the vaccine safety review committee assembled by the Institute of Medicine (IOM). "Any cohort called 'unexposed' after 1961 may not truly be unexposed." If no group is truly unexposed, the effect of SV40 on cancer rates would be difficult to discern.

INCONSISTENT REPORTS

For decades, scientists have known that SV40 causes malignancy in hamster cells. Beginning in 1992, an increasing number of studies has documented the presence of the virus inside various human tumors. (Other similar laboratory studies do not support these findings, sparking a debate over laboratory methods.) A group of researchers led by Michael Carbone, MD, PhD, a University of Chicago pathologist, are convinced that combined exposure to SV40 and asbestos leads to mesothelioma, a rare lung cancer (Semin Oncol. 2002;29:2-17). Most recently, two pathology articles hint at a link to non-Hodgkin lymphoma (NHL), the incidence of which has increased 82% during the last 25 years, an increase more dramatic than in any cancer except melanoma (Lancet. 2002;359:817-823 and 2002;359:851-852).

"It's not such a stretch to see non-Hodgkin lymphoma as being caused by SV40," Fisher said in her IOM presentation. "There's a long history of lymphoma and viruses," she said, listing HIV, Epstein-Barr, hepatitis C, and human herpesvirus 8. All are known to cause various types of lymphoma.

But many epidemiologists are skeptical that SV40 causes any type of cancer. The incidence trends clearly do not support the link, they say. "In the end, it is just unclear whether it plays a role in human cancers," said Howard Strickler, PhD, who has led several SV40 epidemiology projects at the National Cancer Institute and, more recently, at Albert Einstein College of Medicine at Yeshiva University. During his presentation to the IOM, Strickler said that compared with the weighty evidence supporting human papillomavirus as a cause of cervical cancer, the SV40 hypothesis is weak. "With HPV, causality has been checked and triple checked by various groups in various labs and so on," he said.

ENTER THE SEWAGE SAMPLERS

To help break the deadlock, University of Barcelona microbiologist Rosina Girones, PhD, pursued research based on the hypothesis that if the virus circulates among people, it would appear in sewage. With funding from the US Food and Drug Administration (FDA), she collected samples from Washington, DC, and sites in Spain, Sweden, England, Greece, and South Africa. All turned up negative for SV40, down to a detection level of five viral particles/mL. So far so good.

Next, she teamed with researchers in Northern India, where troops of rhesus macaques, a natural SV40 reservoir, commingle with humans. They team searched for SV40 in three areas: back country monkey habitats, cities with roaming monkeys, and Calcutta, which is well outside the monkeys' range.

Rhesus macaques (Macaca mulatta) (Photo credit: Photo Researchers, Inc./S. Nagendra)

As expected, shallow pools of water in the monkey habitats tested positive for the virus. So did sewage from monkey-colonized cities. (As India's population burgeoned and cities swelled during the past 50 years, the monkeys moved in; one census counted 75% of all Indian rhesus macaques as urban.) The twist came from Calcutta's waste. It too tested positive for SV40, in high concentrations.

"We're quite sure it's not from monkeys," Girones told a score of National Institutes of Health scientists who gathered in a small conference room in mid-July. "The high prevalence of SV40 in raw sewage [from Calcutta] suggests that SV40 is being transmitted among humans. We're pretty sure it is." She said that the data also make it clear that the virus can jump from monkeys to people, further complicating the picture. If the virus has been circulating in India and perhaps elsewhere, researchers will have an even thornier time parceling populations into SV40-exposed and SV40-naive groups, a distinction crucial for their studies.

The finding injects new possibilities into the debate. Perhaps SV40 has deep roots as an undetected human parasite. A precedent for such a stealthy infection exists. Epstein-Barr virus and human herpesvirus 6, for example, only recently came to light as common, long-surviving, and occasionally harmful. Or perhaps human infection with SV40 did begin with polio vaccines and started spreading via person-to-person contact. In any case, widespread SV40 exposure creates a lot of epidemiological noise that will be difficult to filter out.

That means scientists will need to turn to other tools. Screening for SV40 antibodies in various groups would help match exposure patterns to cancer trends, said Keerti Shah, PhD, a Johns Hopkins Medical Institutions epidemiologist. But current antibody assays yield crude data, as polyomaviruses similar to SV40 can also trigger positive results. "We definitely need some better serology," said Girones.

Although she appears to be convinced that SV40 is transmissible, a host of associated questions remain unanswered. Why did sewage tests from the United States and Sweden, where tainted vaccines were once common, return negative results? What vectors transmit the virus from person to person? And most important, said Girones, "We don't know what kind of infection it causes, self-limiting and transient, or disease-causing." In monkeys, SV40 infection is chronic and harmless.

If the same is true of humans, and "it turns out SV40 is not harmful, we will have dodged a bullet," said William Egan, PhD, who directs vaccine safety research at the FDA. Addressing the IOM panel, which is charged with the task of sorting out the SV40 conundrum, Egan finished by saying, "And it won't be because we were smart, it will be because we were lucky."