Testimony
Statement by
James Goedert, M.D.
Chief, Viral Epidemiology Branch
Division of Cancer Edpidemiology and Genetics
National Cancer Institute
National Institutes of Health
U.S. Department of Health and Human Services
on
"Research on SV 40 Exposure and the Development of Cancer"
before the
The Subcommittee on Wellness and Human Rights
Committee on Government Reform
United States House of Representatives |
September 10, 2003
Introduction
Thank you, Mr. Chairman, for inviting the National Cancer Institute (NCI),
an agency of the National Institutes of Health, Department of Health and
Human Services, to testify before the Subcommittee today. I am James Goedert,
M.D., Captain, US Public Health Service, and Chief of NCI’s Viral
Epidemiology Branch (VEB) in the Division of the Cancer Epidemiology and
Genetics.
Our Branch conducts population-based epidemiology research to clarify
the relationship of infectious agents, especially viruses, to human cancer
and other conditions. Viruses may cause or increase the risk of cancer
through several mechanisms. These include allowing uncontrolled cell division,
blocking DNA repair, and altering the immune system. While some viruses
have been known to be related to cancer for many years, new infectious
carcinogenic agents continue to be found. The Branch utilizes the principles
of both infectious and chronic disease epidemiology, supported by collaborative
statistical modeling and laboratory investigations.
Some cancer-associated viruses appear to rarely cause cancer among exposed
persons. Other viruses substantially increase the risk for cancer and
the burden of this disease in the population. Knowing which cancers are
associated with the different viruses can help promote targeted cancer
screening, early detection, and treatment. If cancer is more common in
people with exposure to the virus, then that suggests that the virus might
cause the cancer. Similarly, if people with cancer are more likely to
have been infected with the virus than healthy people, this also suggests
that the virus could cause cancer.
Like all scientific research, individual epidemiologic studies cannot
provide a definitive answer about the relationship between an exposure
and the development of cancer. Rather, epidemiologic and other scientific
research studies build a body of evidence -- supported over the years
by larger and more rigorous research studies – that ultimately convince
the scientific community, and the policy-makers of state and Federal governments,
of the existence of such a relationship. At this time, our opinion is
that the body of evidence is inconclusive as to the role of SV40 in the
development of cancer.
SV40 in Early Vaccines
Simian virus 40 (SV40) is a virus that infects several species of monkeys
and typically does not cause 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 (1). 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 injecting SV40 into hamsters could
cause tumors (2-5), the United States (U.S.) government instituted a screening
program requiring that all new lots of poliovirus vaccine be free of SV40
because of concerns about possible adverse effects on human health. Already-produced
vaccine may have been used through 1962, but U.S. polio vaccine has been
free of SV40 since 1963 (6). Published results of testing confirm that
no SV40 has been found in U.S. polio vaccine lots tested after 1972 (47).
The polio vaccine currently used in the U.S. is produced under carefully
regulated conditions designed and enforced by the Food and Drug Administration
to ensure that contamination with SV40 does not occur. As a result of
the earlier contamination, however, it is estimated that more than 10
million to 30 million people vaccinated in the United States from 1955
through early 1963 were inadvertently exposed to live SV40 (6).
SV40 in Animals
In laboratory animal studies, the SV40 virus has been found to cause malignancies
(mesothelioma, ependymoma, osteosarcoma, and leukemia and lymphoma) in
newborn rodents, particularly hamsters, exposed to high levels of the
virus (50). However, the question of whether SV40 causes human cancer
is unsettled, as published data are contradictory.
Follow-up of Vaccine Recipients Shows No Excess of Cancer
Over the last four decades, an intense research effort has been made
to determine whether the exposure to SV40 through polio vaccination has
caused cancer in people. Up through the early 1990’s, epidemiologic
studies involving decades of observations and millions of people in the
U.S. 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
(7), a German study with 22 years of follow-up of 886,000 persons who
received the contaminated vaccine as infants (8), a 20-year study of 1,000
people in the United States inoculated during the first days of life with
contaminated vaccines (9), 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) (10), and a 40-year
follow-up study of 1.8 million recipients of a widely contaminated Danish
polio vaccine (38) .
SV40 is Variably Detected in Human Tumors
The issue of SV40 and cancer has surfaced in the last few years when some
laboratories, using an extremely sensitive molecular biology technique,
the polymerase chain reaction (PCR), found traces of SV40 DNA 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 lymphoma (12-29).
Other studies reported that SV40 T-antigen, a viral protein, binds to
human tumor suppressor proteins such as p53 and RB (30-32), suggesting
a possible carcinogenic mechanism. Not all studies, however, have found
that SV40 can be detected in human cancer (33-37, 39-46). When detected,
SV40 has been found at very low levels (40), raising questions about the
biological role that SV40 could play and suggesting that reported detection
could be a laboratory artifact. Finally, some studies have found SV40
in a wide range of other tumors and normal tissues (16), which raises
further questions about the biological interpretation of positive findings.
Laboratory Studies Result in Controversy and Uncertainty
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 NCI. Under a tightly reasoned, thoroughly
vetted, and tightly enforced research protocol (Appendix 1), 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 masked (prepared and labeled so that the
human tumors and controls could not be distinguished). Each laboratory
used one or more assays for detecting SV40, many of which had been used
to detect SV40 previously. The results (36) showed that none of the mesothelioma
specimens was consistently positive for SV40 across all laboratories.
New methods that can be used widely and easily to reliably detect the
presence of SV40 DNA in human tissues are needed.
Recent and Ongoing Research
Since the early 1990’s, the NCI and other investigators continue to
evaluate the possible link between SV40 infection and human cancers. Our
Branch is monitoring populations known to have been exposed to SV40-contaminated
vaccines, and some of our recently completed and ongoing studies are described
below. Additional extramural grant-supported studies funded by NCI to evaluate
the possible relationship of SV40 to cancer are underway (http://researchportfolio.cancer.gov/).
Other institutes at the National Institutes of Health are also funding a
wide range of studies related to SV40 (https://www-commons.cit.nih.gov/crisp).
- Mesothelioma in the U.S. (37) Using data from the Surveillance,
Epidemiology and End Results (SEER) population, which is a 10% sample
of the entire U.S. population, NCI examined the incidence of mesothelioma
of the lining of the lung (the pleura), with a particular focus on individuals’
ages during the 1955-1963 interval when poliovirus vaccines were contaminated
with SV40. The rate of pleural mesothelioma was highest among men over
age 75, who were least likely to have received SV40-contaminated vaccine
and most likely to have been exposed to asbestos, a known cause of mesothelioma.
In middle age individuals, between 25 and 54 years of age, who were
infants or children during 1955-1963 and most likely to have received
SV40-contaminated poliovirus vaccine, mesothelioma rates have been low
and even decreasing. Females, although equally exposed to SV40-contaminated
vaccines during childhood, had much lower mesothelioma rates, probably
because they have been much less exposed to asbestos. We 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.
- Cancer incidence in Denmark. (38) In Denmark, inactivated
poliovirus vaccine was first administered in April 1955, a few weeks
after vaccination campaigns began in the U.S. Because of the urgency
of the epidemic, a concerted effort was mounted to administer poliovirus
vaccine to a large proportion of the population, and Denmark maintained
a high level of vaccination through the early 1960s. NCI and Danish
investigators recently examined cancer incidence in Denmark as a function
of birth year and calendar year, which served to identify exposure to
early poliovirus vaccine. Importantly, review of 1960s Danish records
identified widespread SV40-contamination of previously utilized Danish
poliovirus vaccine, which, unlike in the U.S, was grown in pooled kidney
tissue from dozens of monkeys. A further strength of this study was
the high quality of Denmark’s nation-wide data on cancer incidence,
which go back to 1943. Overall cancer incidence was actually lower in
SV40-exposed individuals (age-adjusted relative risks 0.86, 95%CI 0.81-0.91,
and 0.79, 95%CI 0.75-0.84, for those exposed as infants or children,
respectively, compared with those unexposed). No increased risk was
seen for specific outcomes, including mesothelioma, bone tumors, brain
tumors, and non-Hodgkin’s lymphoma (NHL).
- Brain tumors in northern India.(39) A study involving a population
uniquely exposed to SV40 - people living in northern India - was published
recently. 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.
Non-malignant brain tissues were included as negative controls, and
laboratory workers were masked to the case-control status of specimens.
A further strength of the study was the use of real-time polymerase
chain reaction to quantify SV40 and cellular DNA detected in specimens.
Investigators did not find SV40 in any of the tumors. Given the PCR
assay’s sensitivity, SV40 would have been detected if it was present
in at least one copy per 10 cells.
- Case-control study of non-Hodgkin’s lymphoma in Spain. (45)
In a case/control study in Spain involving 520 lymphoma cases and 587
controls, 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
- Polio vaccination history in brain tumor patients. (46) 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 reported receiving either injected or
oral poliovirus vaccine during the time period (1955-1963) when vaccines
were contaminated with SV40.
- Follow-up of recipients of U.S. Army’s adenovirus vaccine
(48) To eliminate severe outbreaks of respiratory illness in basic
training camps, the U.S. Army administered an inactivated adenovirus
vaccine, grown in monkey kidney tissue, to entering service personnel
in 1960-61. Evidence is compelling that this vaccine was widely contaminated
with live SV40. Adenovirus grows extremely poorly in monkey kidney tissue
without the presence of SV40 as a “helper virus.” This situation
is unlike poliovirus vaccine contamination, which in the U.S. did not
occur uniformly, because SV40 was not a necessary cofactor for poliovirus
replication in vitro. As with poliovirus vaccine, formalin-inactivation
did not completely inactivate contaminating SV40.
NCI investigators are conducting a retrospective cohort study of Army
servicemen from this era. Cases of mesothelioma, brain tumors, and non-Hodgkin’s
lymphoma in military veterans will be linked to military service records
to determine which individuals entered Army service on a date that corresponded
to the Army’s use of this vaccine. An additional advantage of
the study design is the attained age of the men who entered the Army
in 1959-61; by the 1990s, they would have reached an age when mesothelioma
incidence becomes appreciable. Results from this study should be available
soon.
- Case-control study of childhood cancer. NCI investigators
are conducting a case-control study of childhood cancer that should
be informative with respect to the role of SV40 in human cancer. In
the U.S. during the 1950s and 1960s, pregnant women were frequently
given inactivated poliovirus vaccine, potentially leading to infection
of their children with SV40 in utero or soon after birth. Given the
carcinogenic potential of SV40 in newborn laboratory animals, follow-up
of children whose mothers were vaccinated during pregnancy represents
a unique means of determining whether SV40 causes human cancer.
To pursue this line of inquiry, NCI has organized a study of SV40 and
childhood cancer nested in the Collaborative Perinatal Project (CPP)
cohort study. CPP enrolled pregnant women and their subsequently-born
children in 1959-66 at 12 U.S. university medical centers. The cohort
comprises 54,796 children born to 44,621 mothers. Enrolled mothers had
study visits scheduled as part of their prenatal care, and detailed
data on vaccinations during pregnancy reveal that 22.5% of CPP children
were exposed in utero to pre-1963 poliovirus vaccine, 17.0% were exposed
in utero to 1963+ poliovirus vaccine, and 60.5% of children were unexposed.
Through age 8 years, 52 CPP children developed cancer (18 neural tumors,
22 hematologic malignancies, 12 miscellaneous tumors). In a nested case-control
study, paired sera (from early and late in pregnancy) have been selected
from the 50 mothers of these children with available specimens and from
200 CPP control mothers. These sera are being evaluated for SV40 antibodies
using an SV40 plaque neutralization assay and a virus-like particle-based
(VLP) enzyme immunoassay.
- Case-control study of non-Hodgkin’s lymphoma in the U.S.
The possibility that SV40 causes a substantial fraction of non-Hodgkin’s
lymphoma in the U.S. was recently raised by two studies reporting the
molecular detection of SV40 DNA in 40-50% of tissues. However, confirmatory
evidence of SV40 infection (e.g., SV40 antibody) in non-Hodgkin’s
lymphoma cases was lacking, and SV40 was detected in tissues other than
non-Hodgkin’s lymphoma in one of the studies. In addition, these
studies could not provide an estimate of the relative risk associated
with SV40 infection.
NCI and laboratory collaborators at two institutions are pursuing this
question further using samples collected in a case-control study of
non-Hodgkin’s lymphoma in the U.S. This study includes approximately
800 HIV-uninfected non-Hodgkin’s lymphoma cases and 700 age-matched
population controls from the NCI-Surveillance Epidemiology and End Results
(SEER) Case-Control Study of non-Hodgkin’s lymphoma SV40 and BK
serostatus will be assessed using VLP assays. Strengths of the U.S.-based
study include the widespread exposures of the U.S. population to SV40-contaminated
poliovirus vaccine and the representative nature of the non-Hodgkin’s
lymphoma cases (sampled consecutively at four SEER registry sites) and
population-based controls. This study will help answer whether SV40
infection is more common in persons with non-Hodgkin’s lymphoma
than controls and thus provide evidence on whether SV40 might cause
non-Hodgkin’s lymphoma. Importantly, finding low SV40 seroprevalence
in cases (i.e., substantially less than 40%, reported previously) would
argue against SV40 as a cause of non-Hodgkin’s lymphoma.
- AIDS-associated non-Hodgkin’s lymphoma. (49) Recent
reports of the detection of SV40 DNA sequences in 40% of AIDS-associated
non-Hodgkin’s lymphomas prompted NCI investigators to examine
whether, among individuals with AIDS, those exposed to SV40-contaminated
poliovirus as children had an increased risk for non-Hodgkin’s
lymphoma. Non-Hodgkin’s lymphoma incidence was estimated for two
cohorts with AIDS: persons born in 1958-61 (exposed to SV40-contaminated
poliovirus vaccine as infants) or born in 1964-67 (born after the vaccine
was cleared of SV40 and thus unexposed). Non-Hodgkin’s lymphoma
incidence was marginally higher in the exposed cohort (unadjusted relative
risk 1.15, 95%CI 0.99-1.34, vs. unexposed cohort). Notably, however,
the exposed cohort developed AIDS slightly earlier than the unexposed
cohort (mean year of onset 1992 vs. 1993). Due to the temporal evolution
of the U.S. AIDS epidemic, the two cohorts thus differed in composition,
with the exposed cohort having more males and whites, who are known
to be at increased risk of non-Hodgkin’s lymphoma irrespective
of AIDS or vaccination status, than the unexposed cohort. Also, exposed
individuals were, on average, five years older at AIDS onset than unexposed
individuals. With adjustment for these differences, non-Hodgkin’s
lymphoma incidence was identical in exposed and unexposed individuals
(relative risk 0.97, 95%CI 0.79-1.20).
- SV40 infection in primate workers. Evaluation of persons
with occupational exposure to SV40, i.e., exposure to macaques, would
be valuable in documenting whether SV40 infection can occur in humans.
Rhesus macaques are universally infected with SV40 by adulthood, and
cynomolgus macaques are readily infected through rhesus contacts in
captivity. Humans working with monkeys could become infected with SV40
via bites, scratches, or exposure to contaminated urine.
With collaborators at the Centers for Disease Control and Prevention
(CDC) and Johns Hopkins, NCI is undertaking a pilot study to examine
whether workers in primate centers and zoos in North America display
serologic evidence for SV40 infection. Investigators will determine
whether SV40 seroprevalence is higher in workers exposed to primates
than controls. Additionally, SV40-seropositive subjects will be further
characterized, with regards to the specificity of SV40 antibody reactivity
(i.e., evaluation of BK virus reactivity) and SV40 antibody titer. Evidence
for SV40 infections will prompt additional studies that would include
more detailed exposure and health outcome data and other types of biological
specimens.
IOM Report
The Institute of Medicine (IOM) of the National Academy of Sciences issued
a report in October 2002 (50), which concluded that scientific “evidence
is inadequate to accept or reject a causal relationship between SV40-containing
polio vaccines and cancer.” (p. 11, Executive Summary). The committee
stated that the “biological evidence is of moderate strength that
SV40 exposure could lead to cancer in humans under natural conditions”
and that “biological evidence is of moderate strength that SV40
exposure from the polio vaccine is related to SV40 infection in humans.”
(p. 11, Executive Summary)
Based on these conclusions, the Institute of Medicine made the following
research recommendations: (Appendix II)
Research
The committee recommends development of sensitive and specific serologic
tests for SV40.
The committee recommends the development and use of sensitive and specific
standardized techniques for SV40 detection.
The committee recommends that once there is agreement in the scientific
community as to the best detection methods and protocols, pre-1955 samples
of human tissues should be assayed for presence or absence of SV40 in
rigorous, multi-center studies.
The committee recommends further study of the transmissibility of SV40
in humans.
Until some of the technical issues are resolved, the committee does
not recommend additional epidemiological studies of people potentially
exposed to the contaminated polio vaccine.
Our Branch will continue to collaborate with others in multidisciplinary
research fields to settle the uncertainties that remain, and to pursue
new leads to clarify the relationship between SV40 and human cancer, if
any.
Closing
As we move forward to resolve the uncertainties in this field, researchers
will need to understand what the detection -- or lack of detection-- of
SV40 DNA in tumors implies. In recognition of the IOM’s recommendation
that molecular methods for SV40 detection be standardized, future studies
will need to include sufficient numbers and types of positive- and negative-control
specimens and to make the status of the specimens (i.e., controls, tumors,
and others) unknown to the persons performing the laboratory analyses.
Valuable data may come from newly available serologic techniques, but
only with rigorous study designs that mask case-control status and include
sufficient number of subjects. To study whether SV40 is in the human population
and, if so, its modes of transmission, epidemiologic studies could be
conducted if assays, such as the new SV40 antibody techniques, are shown
to be highly sensitive, specific, and reproducible.
Because of the widespread exposure to SV40 through contaminated vaccines,
the question of whether SV40 causes some human cancers has substantial
public health implications. However, the types of claimed to be linked
to SV40 have been and continue to be very rare. In addition, SV40 prevalence
in the general population is unknown, and detection of SV40 in humans
is controversial. We remain committed to helping resolve these questions.
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Last Revised: March 17, 2004 |