Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter.
Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 1
Executive Summary
ABSTRACT
Some of the polio vaccine administeredirom 1955-1963 was contaminated
with a virus, called simian virus 40 (SV409. The virus came from the monkey
kidney cell cultures used to produce the vaccine. Most, but not all, of the con-
tamination was in the inactivated polio vaccine (IPV7. Once the contamination
was recognized, steps were taken to eliminate it from future vaccines. Research-
ers have long wondered about the effects of the contaminated vaccine on people
who received it. Although SV40 has biological properties consistent with a can-
cer-causing virus, it has not been conclusively established whether it might have
caused cancer in humans. Studies of groups of people who received polio vac-
cine during 1955-1963 provide evidence of no increased cancer risk.
However, because these epidemiologic studies are suff ciently flawed, the
Institute of Medicine's Immunization Safety Review Committee concluded that
the evidence was inadequate to conclude whether or not the contaminated polio
vaccine caused cancer. In light of the biological evidence supporting the theory
that SV40-contamination of polio vaccines could contribute to human cancers'
the committee recommends continued public health attention in the form of pol-
icy analysis, communication' and targeted biological research. See Box ES-l for
a summary of all conclusions and recommendations.
1
OCR for page 2
2
IMMUNIZATION SAFETY REVIEW
Immunization to protect children and adults from many infectious diseases
is one of the greatest achievements of public health. Immunization is not without
risks, however. Given the widespread use of vaccines, state mandates requiring
vaccination of children for entry into school, college, or day care, and the impor-
tance of ensuring that trust in immunization programs is justified, it is essential
that safety concerns receive assiduous attention.
The Immunization Safety Review Committee was established by the Insti-
tute of Medicine (IOM) to evaluate the evidence on possible causal associations
between immunizations and certain adverse outcomes, and to then present con-
clusions and recommendations. The committee's mandate also includes assess-
ing the broader societal significance of these immunization safety issues. While
all the committee members share the view that immunization is generally bene-
ficial, none of them has a vested interest in the specific immunization safety
issues that come before the group.
The committee reviews three immunization safety review topics each year,
addressing each one at a time. In this fifth report in a series, the committee ex-
amines the hypothesis that exposure to polio vaccine contaminated with simian
virus 40 (SV40), a virus that causes inapparent infection in some monkeys, can
cause certain types of cancer.
The committee is charged with assessing both the scientific evidence re-
garding the hypotheses under review and the significance of the issues for soci-
ety.
. The scientific c assessment has two components: an examination of the epi-
demiological and clinical evidence regarding a possible causal relationship
between exposure to the vaccine and the adverse event, and an examination of
theory and experimental evidence from human or animal studies regarding bio-
logical mechanisms that might be relevant to the hypothesis.
. The sigr~if cance assessment addresses such considerations as the burden
of the health risks associated with the vaccine-preventable disease and with the
adverse event. Other considerations may include the perceived intensity of pub-
lic or professional concern or the feasibility of additional research to help re-
solve scientific uncertainty regarding causal associations.
The findings of the scientific and significance assessments provide the basis
for the committee's recommendations regarding the public health response on
the issue. In particular, the committee addresses needs for a review of immuni-
zation policy, for current and future research, and for effective communication
strategies.
For its evaluation of the hypothesis relative to SV40-contaminated polio
vaccine and cancer, the committee held an open scientific meeting in July to
hear presentations on issues germane to the topic. The presentations to the
committee at the open meeting are available in electronic form (audio files and
OCR for page 3
EXECUTIVE SUMMARY
slides) on the project website (www.iom.edu/imsafety). In addition, the commit-
tee reviewed an extensive collection of material, primarily from the published,
peer-reviewed scientific and medical literature. A list of the materials reviewed
by the committee, including many items not cited in this report, can be found on
the project's website.
THE FRAMEWORK FOR SCIENTIFIC ASSESSMENT
Causality
The Immunization Safety Review Committee has adopted the framework
for assessing causality developed by previous IOM committees (IOM, 1991,
1994), convened under the congressional mandate of P.L. 99-660 to address
questions of immunization safety. The categories of causal conclusions used by
the committee are as follows:
1. No evidence
2. Evidence is inadequate to accept or reject a causal relationship
3. Evidence favors rejection of a causal relationship
4. Evidence favors acceptance of a causal relationship
5. Evidence establishes a causal relationship.
Assessments begin from a position of neutrality regarding the specific vac-
cine safety hypothesis under review. That is, there is no presumption that a spe-
cific vaccine (or vaccine component) does or does not cause the adverse event in
question. The committee does not conclude that the vaccine does not cause the
adverse event merely if the evidence is inadequate to support causality. Instead,
it concludes that the "evidence is inadequate to accept or reject a causal relation-
ship."
Biological Mechanisms
Evidence considered in the scientific assessment of biological mechanisms)
includes human, animal, and in vitro studies related to biological or pathophysi-
ological processes by which immunizations could cause an adverse event. When
other evidence of causality is available, biological data add supportive evidence
but cannot prove causality on their own.
The committee has established three general categories of evidence on bio-
logical mechanisms:
' For a discussion of We evolution of the terminology conceiving biological mechanisms, see
the committee's earlier reports (TOM, 2001a,b, 2002a,b).
OCR for page 4
4
IMMUNIZATION SAFETY REVIEW
1. Theory only. A reasonable mechanism can be hypothesized that is
commensurate with scientific knowledge and that does not contradict
known physical and biological principles, but it has not been demon-
strated in whole or in part in humans or in animal models.
Experimental evidence that the mechanism operates in animals, in vi-
tro systems, or humans. Experimental evidence often describes ef-
fects on just one or a few of the steps in the pathological process re-
quired for expression of disease. Showing that multiple components
of the theoretical pathways operate in reasonable experimental mod-
els increases confidence that the mechanisms could possibly result in
disease in humans.
Evidence that the mechanism results in Mown disease in humans.
For example, the wild-type infection causes the adverse health out-
come, or another vaccine has been demonstrated to cause the same
adverse outcome by the same or a similar mechanism
If the committee identifies evidence of biological mechanisms that could be
operational, it will offer a summary judgment of that body of evidence as weak,
moderate, or strong. The summary judgment of the strength of the evidence also
depends on both the quantity (e.g., number of studies or number of subjects in a
study) and quality (e.g., the nature of the experimental system or study design)
of the evidence.
SV40 Contamination of Polio Vaccine
The tissue cultures used to grow poliovirus for the vaccines in question
came from kidneys of rhesus and cynomolgus macaques.2 In 1960, Sweet and
Hilleman (1960) reported that these tissues could be infected with SV40, a pre-
viously unknown virus that commonly infects rhesus macaques. SV40 is a
member of the polyomav~rus family3. Soon after its discovery, SV40 was shown
to be able to produce tumors in hamsters and to transform human cells in culture
(Eddy et al., 1961, 1962; Girardi et al., 1962; Koprowski et al., 1962; Shein and
Enders, 1962a,b). Testing confirmed that some of the tissue cultures used in
producing inactivated polio vaccine (IPV) and oral polio vaccine (OPV) were
contaminated with SV40. In 1961, the U.S. government established require-
2 Current formulations of IPV and OPV available in the United States are required by the FDA
to be free of SV40. The IPV produced today uses poliovirus grown on Vero cells, a continuous line
of green monkey kidney cells. OPV is no longer produced in the United States, but as the recom-
mended vaccine to control polio outbreaks, a stockpile of OPV is available for these purposes (CDC,
2000). The OPV was produced in the United States in monkeys raised in colonies free from SV40 or
grown in Vero cells and was screened for viruses, including SV40 (Sutter et al., 1999).
3 Polyomaviruses generally cause inapparent infection in the natural host but can cause disease
in non-host species or in immune-compromised hosts. Two over human polyomaviruses are known
as JC and BK.
OCR for page 5
EXECU17VE SUMMARY
s
meets for testing to verify that all new lots of polio vaccine are free of SV40
(Egan, 2002~. Potentially contaminated vaccine from previously approved lots
of IPV was not recalled, however, and might have been used until early 1963.
IPV administered between 19554 and 1963 to about 98 million children and
adults is assumed to be the primary source of human exposure to SV40 in the
United States.s In addition, experimental lots of OPV contaminated with SV40
are known to have been administered to about 10,000 people participating in
clinical trials between 1959 and 1961. Tests of stored samples of the IPV that
had been administered in the United States from May through July in 1955
found varied levels of SV40 contamination, with some vaccine showing no con-
tamination (Fraumeni et al., 1963~. From these data, Shah and Nathanson (1976)
estimated that 10% to 30% of IPV contained live SV40 and that similar percent-
ages of the approximately 98 million Americans who had been vaccinated by
1961 were exposed to SV40.
While it is certain that many people were directly exposed to SV40 through
injections of IPV, two related matters remain unresolved. First, it is possible that
some portion of the population might have been exposed to SV40 before IPV
was introduced (Geissler et al., 1985; Shah et al., 19723. Second, it is unclear
whether the SV40 received through the vaccine could be transmitted within the
population once the contaminated vaccine was no longer in use.
SCIENTIFIC ASSESSMENT
Causality
For its review of the epidemiologic evidence on the association between ex-
posure to polio vaccines containing SV40 and the subsequent development of
cancer, the committee found studies examining cancer incidence or mortality.
Also included in the committee's review are studies of cancers occurring in
children who may have had a prenatal exposure to SV40 through vaccination of
their mothers.
The available studies are reviewed in the following three categories: cancer
incidence, cancer mortality, and cancers following prenatal exposure to SV40-
containing vaccine. For cancer incidence, the committee reviewed five ecologic
studies (Fisher et al., 1999; Geissler, 1990; Olin and Giesecke, 1998; Stickler et
al., 1998; Stickler et al., 1999) and two controlled observational studies (Innis
1968; Stewart and Hewitt, 1965~. For cancer mortality, the committee reviewed
two ecologic studies (Fraumeni et al., 1963; Strickler et al., 1998) and one un-
4 IPV was licensed and widely distributed in 1955, however exposure to SV40 may have also
occurred in the 1954 field trial of IPV.
s During the same period, SV40 also contaminated an experimental respiratory syncytial virus
vaccine given to about 100 adults and a licensed adenovirus vaccine given to about 100,000 military
inductees (Shah and Nathanson, 1976).
OCR for page 6
6
IMMUNIZATION SAFETY REVIEW
controlled observational study, including two follow-ups to the study (Carroll-
Pankhurst et al., 2001; Fraumeni et al., 1970; Mortimer et al., 1981~. For cancers
following prenatal exposure to SV40-containing vaccine, the committee re-
viewed two controlled studies (Farwell et al., 1979; Heinonen et al., 1973~. The
majority of the studies showed no increase in cancers.
All of the studies that the committee reviewed concerning cancer incidence
or cancer mortality and exposure to polio vaccine containing SV40 have sub-
stantial limitations. Many of these studies were ecologic in design. In an ecolo-
gic study, the unit of analysis is a group. Because data on exposure and disease
are available only on a group level, it is difficult to make causal inferences re-
garding the association between an exposure and disease at the individual level
(Kleinbaum et al., 1982~.
Most of the epidemiologic studies on polio vaccine containing SV40 and
cancer are subject to misclassification bias because they rely on year of birth to
designate exposure status. Even though polio vaccine known to contain SV40
was in use from 1955 to 1963, it is difficult to accurately determine which indi-
viduals received the vaccine without having access to individual vaccination
records. The studies may also be subject to misclassification bias because of a
lack of detailed and specific information about the presence of SV40 contamina-
tion in individual vaccine doses. In addition, the assumption that persons who
received polio vaccine after 1963 were unexposed to SV40 may not be accurate
if sources of exposure other than contaminated IPV exist.
The studies were also limited by the rarity of the tumors thought to be asso-
ciated with exposure to SV40. The effect estimates calculated from a small
number of tumors are more sensitive to distortion from confounders, bias, and
chance. The cohort exposed to contaminated vaccine has not yet reached the age
when the cancers of interest are of high incidence, so these associations in par-
ticular cannot be ruled out by the evidence to date. Studies of cancer mortality
are also subject to confounding due to improvements over time in the e~ective-
ness of treatments, which may produce a decline in mortality rates that is unre-
lated to the incidence of the cancer. Even if the associations suggested by some
studies in this body of weak epidemiological evidence are true, the absolute
risks for additional cancer cases or deaths are small and cannot necessarily be
attributed solely to exposure to SV40-contaminated polio vaccine.
Based on these limitations, the committee concludes that the evidence is
inadequate to accept or reject a causal relationship between SV40-
containing polio vaccines and cancer.
Biological Mechanisms
Given that the epidemiologic evidence regarding a causal relationship was
inconclusive, the committee reviewed the biological evidence with an eye to-
OCR for page 7
EXECUTIVE SUMMARY
ward additional research that might be needed to better understand the putative
role that exposure to SV40 from polio vaccines might have in cancer. The com-
mittee reviewed the evidence on biological mechanisms related to this hypothe-
sis through three key questions:
1. Is SV40 a transforming virus?
Can SV40 cause cancer in humans under conditions of natural ex-
posure?
Is contamination of the polio vaccine with SV40 responsible for
SV40 infection in humans?
A wealth of literature exists on topics such as the presence of SV40 in tu-
mors and the effects of the virus or its gene products (particularly Tag, the large
tumor antigen) in cell cultures. Several large scientific conferences have also
been held to review progress in understanding the role of SV40 in human can-
cers. Because the Immunization Safety Review Committee was not charged with
resolving the full range of uncertainties about the biology of SV40 and the role
of this virus in human cancers, the review that follows provides only highlights
of the key arguments on these issues. More detailed discussion is available in
several excellent and comprehensive reviews (Brown and Lewis, 1998; Butel
and Lednicky, 1999, Carbone et al., 1997; Klein et al., 2002; Strickler, 2001b).
Is SV40 a Transforming Virus?
Evidence suggesting that SV40 can produce oncogenic transformation of
cells comes from four sources: rodents, nonhuman primates, cell culture studies,
and humans.
The earliest studies of SV40 were conducted with rodents and showed that
administration to neonatal and weanling hamsters causes cancers. A seminal
study (Eddy et al., 1961) demonstrated that injection of extracts of rhesus mon-
key kidney-cell cultures into newborn hamsters was followed by the occurrence
of neoplasms in approximately 70°/O of the animals. Despite the limitations in
their applicability to humans, these animal systems are notable in that the tumors
seen mesothelioma, ependymoma, osteosarcoma, and lymphoma- are the
same as the human cancers that have been associated with the presence of SV40
or its Tag or viral fragments in rodents.
Macaques that were immunocompromised as a result of SIV-infection have
developed central demyelinating disease (Holmberg et al., 1977; Horvath et al.,
1992) suggesting central nervous system (CNS) migration of SV40. At least one
SIV-immunocompromised macaque developed an astrocytoma that was positive
for SV40 DNA (Hurley et al., 19979.
It was established shortly after the identification of SV40 that the virus can
transform cultured human cells (Koprowki et al., 19629. It now appears that the
OCR for page 8
8
IMMUNIZATION SAFETY REVIEW
transforming properties of SV40 are due to the effects of specific gene product,
Tag, on key proteins involved in controlling cell growth (Butel and Lednicky,
1999; Kim et al., 1998; Rundell et al., 1998~. In particular, Tag inactivates the
tumor-suppressor proteins p53 and Rb. These gene products nonnally suppress
tumor growth by preventing cell cycling and by promoting the death of cells
with genetic damage. By inactivating these proteins, SV40 Tag promotes both
transformation and immortalization of cells. There are an abundance of data
from cell culture systems demonstrating effects of SV40 or Tag on many steps
related to cell transformation. In addition, evidence from cell cultures of human
mesothelial cells suggests that SV40 might preferentially infect these cells with-
out lysis (Bocchetta et al., 2000~. This could explain effects of SV40 leading to
tumors in some tissues and not others.
Cells transformed by SV40 have been shown to grow in humans and be-
come tumors. In a study by Jensen and colleagues (1964), persons terminally ill
with cancer received implants of either homologous or autologous tissue via
subcutaneous injection. When cells transformed by SV40 were implanted, nod-
ules of undifferentiated tumor cells developed. This study provides evidence
from contrived clinical conditions that cells transformed by SV40 can develop
into undifferentiated tumors in a human host.
The committee concludes that the biological evidence is strong that
SV40 is a transforming virus.
Can SV40 Cause Cancer in Humans under Conditions of Natural
Exposure?
There is a theoretical basis for the existence of mechanisms by which SV40
could cause cancer in humans. The principal lines of evidence for the operation
of specific mechanisms are that SV40 acts in ways consistent with tumorigene-
sis and that DNA sequences consistent with SV40 have been detected in several
types of human tumors.
Evidence that SV40 could be tumorigenic comes from in vitro studies and
studies in animals. These studies, some of which were reviewed above, point to
the critical role of SV40 Tag, which is found in the nuclei of transformed cells.
As noted, substantial evidence suggests that Tag binds and inactivates the prod-
ucts of tumor-suppressor genes, especially the p53 and Rb proteins. The inacti-
vation of these proteins allows for unregulated cell division (Butel and Led-
nicky, 1999; Klein et al., 2002~.
Data on the association between SV40 and human tumors are inconsistent.
A growing body of clinical studies reports the detection of SV40 DNA in sev-
eral types of tumors. The most notable and well-studied of these is meso-
thelioma (Carbone et al., 1999~. In addition, SV40 DNA has been detected in
bone cancers (Carbone et al., 1996), ependymomas (Bergsagel et al., 1992; Led-
nicky et al., 1995), and in non-Hodgkin's lymphoma (Shivapurkar et al., 2002;
OCR for page 9
EXECUTIVE SUMMARY
9
Vilchez et al., 2002~. Other studies, however, report an inconsistency or absence
of SV40 in mesotheliomas, osteosarcomas, and brain tumors (Engels et al.,
2002; Heinsohn et al., 2000; Strickler et al., 1996; Strickler, 2001a).
The conflicting results in the detection of SV40 have also led to questions
about technical aspects of the detection of the virus. There are questions as to
whether positive findings are the result of overly sensitive but nonspecific tests
that are detecting other viruses (i.e., human polyomaviruses BK or JC) or SV40
from laboratory contamination, or whether negative findings arise from a lack of
sensitivity in the detection methods used. Two multicenter studies (Strickler,
2001a; Testa et al., 1998) have attempted to resolve some of the uncertainty re-
garding the detection of SV40 in human mesothelioma samples, but were not
successful in resolving the controversy for varying reasons.
The detection of SV40 in tumors does not, by itself, demonstrate a causal
relationship. SV40 could be a passenger virus, infecting the cells but causing no
pathology. Findings Tom studies examining SV40 in mesothelioma demonstrate
a great deal of variability which precludes the ability at present to draw conclu-
sions regarding the frequency with which SV40 can be detected in specific neo-
plasms and/or normal tissues in humans. Some studies have detected SV40 in
normal tissue from healthy subjects (Martini et al., 1996; Woloschak et al.,
1995~. Its detection in multiple types of tumors (i.e. its lack of specificity for a
single type of cancer) also leads to doubts about a causal link (Strickler, 2001b).
The committee concludes that the biological evidence is moderate that SV40
exposure could lead to cancer in humans under natural conditions.
Is Contamination of the Polio Vaccine with SV40 Responsible for SV40
Infection in Humans?
Although it is incontrovertible that some polio vaccine was contaminated
with SV40, the nature and extent of human exposure to SV40 through this or
other sources are less clear. In the United States, potentially contaminated IPV
was administered between 1955 and 1963. Because the process for inactivating
the live polio virus could be expected to kill some of the SV40, some vaccinees
were likely exposed to a mixture of the live and killed virus while others were
exposed only to killed SV40. Thus, exposure to IPV between 1955 and 1963
cannot be equated with exposure to live SV40 or, by extension, to infection with
SV40.
OPV also was contaminated with SV40. Although the level of contamina-
tion was high, exposure was more limited, with approximately 10,000 people
who might have received vaccine from contaminated lots (Shah and Nathanson,
1976~. Studies showed, however, that the recipients of contaminated OPV pro-
duced no antibody response to SV40 Previewed by Shah and Nathanson, 1976),
indicating less likelihood of infection through oral exposure. This suggests that
OCR for page 10
10
IMMUNIZATION SAFETY REVIEW
IPV, not OPV, resulted in the exposure of humans to SV40. Nonetheless, con-
cerns about the validity—and in particular the specificity for SV40—of the sero-
logic testing create some uncertainty about this conclusion.
There is additional uncertainty about the possible contribution of vaccine-
based SV40 exposure to SV40 infection and carcinogenesis because of the age
at which vaccinees were exposed. Because the incidence of ependymomas is
highest in children under age 5 and osteosarcoma is most common in adoles-
cents, contemporary evidence of SV40 in such tumors does not provide a direct
link to exposure to contaminated IPV between 1955 and 1963. But with the long
latency period for mesothelioma, exposure to contaminated IPV remains a pos-
sibility.
Other sources of exposure to SV40 may also exist. A limited number of
people are known to have been exposed to SV40 through other vaccines, includ-
ing an experimental live-virus vaccine against respiratory syncytial virus and a
licensed inactivated adenovirus vaccine that was administered to military re-
cruits. Evidence of SV40 exposure has also been detected in serologic samples
obtained before 1955 and from studies of persons too young to have received
contaminated polio vaccine.
Detection of SV40 in persons too young to have received contaminated po-
lio vaccine suggests the possibility of continuing transmission of SV40 through
means other than the polio vaccine. Possible sources of exposure to SV40 are
person-to-person transmission, animal-to-person transmission, and laboratory
exposure to SV40.
Finally and perhaps most importantly, measures of infection remain prob-
lematic. The serology data are unclear, in part because of concerns about cross-
reactivity with the JC and BK viruses. The tension between sensitivity and
specificity is especially important for this assay because BK and JC are ubiqui-
tous in the human population and SV40 is apparently present only at low levels.
The committee concludes that the biological evidence is moderate that SV40
exposure from the polio vaccine is related to SV40 infection in humans.
In summary, the committee's scientific assessment concludes that moderate
to strong lines of biological evidence support the theory that SV40-
contamination of polio vaccine could contribute to human cancers.
Specifically, the evidence is strong that:
SV40 contaminated some polio vaccine used from 1955-1963, and
SV40 has transforming properties in several experimental systems.
In addition, evidence has accumulated suggesting that SV406 is likely pre-
sent in some human tumors. The data regarding detection of SV40 in many but
6 In Me form of virus, viral fragments, DNA, or SV40 gene products
OCR for page 11
EXECUTIVE SUMMARY
11
not all mesothelioma samples, coupled with the evidence for the oncogenic po-
tential of SV40, suggest that SV40 could contribute to cancers in humans7.
However, it is not clear
what proportion (if any) of the people exposed to the SV40-
contaminated vaccine were infected,
what proportion (if any) of the human cancers in which SV40 is
detected are caused by the SV40,
that the sole source of SV40 is due to the contaminated polio vac-
cine, or
that SV40-contaminated polio vaccine did or did not cause cancer
in the vaccine recipients.
SIGNIFICANCE ASSESSMENT
Most of the issues reviewed by this committee concern vaccines presently
in use. In the present case, however, current use of IPV is not in question. The
issue instead is the possibility that the occurrence of certain cancers might be
related to past use of SV40-contaminated polio vaccine between 1955 and 1963.
Even today, this issue carries a major societal significance because exposure to
the contaminated vaccine was so extensive and because cancer is such a serious
and widely feared disease.
The committee's review of the epidemiologic and biological evidence has
shown that the effects of exposure to the contaminated polio vaccine remain
uncertain, with important questions regarding the role of SV40 in human cancers
unresolved. Even if future epidemiologic studies were to provide more compel-
ling evidence for a causal link, the current evidence is sufficiently robust to sug-
gest that the relative contribution of SV40 to overall risk would have to be
small. Nevertheless, the possibility that millions of healthy individuals were
exposed to a disease-causing agent could easily damage public confidence in the
nation's immunization program and the oversight groups responsible for assur-
ing that it is safe.
The United States has a responsibility to thoroughly address health concerns
stemming Tom the SV40 contamination of polio vaccine to ensure Cat any ad-
verse health effects are identified and to help produce Me scientific evidence
necessary for assurance that exposure to the contaminated vaccine has not had
adverse effects.
The committee concludes that concerns about exposure to SV40
through inadvertent contamination of polio vaccines are significant because
of the seriousness of cancers as the possible adverse health outcomes and
7 The data regarding mesothelioma are more stubstantial and more abundant than for other can-
cers, such as non-Hodgkin's lymphoma (NHL), osteosarcoma, or ependymomas.
OCR for page 12
12
IMMUNIZATION SAFETY REVIEW
because of the continuing need to ensure and protect public trust in the na-
tion's immunization program.
RECOMMENDATIONS FOR PUBLIC HEALTH
RESPONSE
The scientific and policy issues considered by the committee lead to rec-
ommendations for targeted public health attention in the form of policy analysis,
communication, and targeted research. The committee does not recommend a
policy review of polio vaccine by any of the national or federal vaccine advi-
sory bodies on the basis of concerns about cancer risks that might be asso-
ciated with exposure to SV40, because the vaccine in current use is free of
SV40.
Policy Analysis and Communication
The committee hopes that contamination of a vaccine never occurs again,
but also considers it prudent to have a comprehensive plan in place for preven-
tion of contamination, as well as for response and communication should such
an event occur. Pieces of such a plan already exist within the various agencies
with responsibility for assuring the safety of vaccines. For example, FDA has
regulatory authority over the production of vaccines. Currently, all vaccines
licensed by the FDA are required to fulfill general safety, sterility, and purity
requirements (Code of Federal Regulations, 2001~. However, the committee is
not aware of a comprehensive and transparent system. The most recent compre-
hensive plan by the federal government on vaccine safety does not address con-
tamination issues (NIH, 1998~. The committee recommends that the appro-
pmate federal agencies develop a Vaccine Contamination Prevention and
Response Plan. The appropriate agencies should be given the authority and
resources to implement the plan once it is in place. This plan should identify the
steps already in place, or those that need to be developed, to prevent contamina-
tion of vaccine and to respond to concerns about possible contamination. The
plan should include strategies for routine assessment of vaccine for possible
contamination; notification of public health officials, health care providers, and
the public if contamination occurs; identification of recipients of contaminated
vaccine; and surveillance and research to assess health outcomes associated with
the contamination. Clearly the plan will need to allow for the scientific and
technical uncertainties surrounding an assertion that contamination has occurred
or is possible. Implementation of the plan will require considerable judgment as
to the level of response required to deal with a specific contamination concern.
Because the plan will involve multiple agencies and offices, the National Vac-
cine Program Office is probably the best positioned to organize and coordinate
the development of the plan. Once a plan is developed, a communication cam-
OCR for page 13
EXECUTIVE SUMMARY
13
paign should be undertaken to inform the public and medical practitioners. This
is important to assure that the trust in the vaccine supply is deserved and is
widespread.
Research
The committee recommends development of sensitive and specific sero-
log~c tests for SV40. These would be helpful to resolve the question as to
whether or not the SV40 exposure led to infection.
The committee recommends the development and use of sensitive and
specific standardized techniques for SV40 detection. These efforts should
include documentation that: 1) all test specimens are masked, 2) positive and
negative control tissues are not only used but subjected to the same processing
procedures as test specimens, 3) samples are tested in replicate, and 4) there is
an adequate sample of tissue.
The committee recommends that once there is agreement in the scien-
tific community as to the best detection methods and protocols, pre-1955
samples of human tissues should be assayed for the presence or absence of
SV40 in rigorous, multicenter studies. This would not address the question of
whether or not SV40 can cause cancer, but could influence the interpretation of
some epidemiologic and clinical analyses. It would also be relevant for discus-
sion of the relative contribution of contaminated polio vaccine to the SV40 bur-
den of infection in humans.
The committee recommends further study of the transmissibility of
SV40 in humans. This will help confirm whether and why SV40 or antibodies
specific for SV40 are detected in individuals who have no known exposure to
potentially contaminated polio vaccine, animals or laboratory contact. ~ addi-
tion to the research recommended above, it is important to resolve the extent of
past SV40 contamination of polio vaccine. The uncertainty of exposure makes
interpretation of the epidemiologic studies very problematic. If researchers can
pursue these strategies and obtain a better understanding of exposure and meth-
ods of detection, more meaningful case-control studies can be undertaken to
help resolve the question of causality. 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.
OCR for page 14
14
IMMUNIZATION SAFETY REVIEW
OCR for page 15
EXECUTIVE SUMMARY
15
REFE"NCES
Bergsagel DJ, Finegold As, Butel JS, Kup sky WJ, Garcea RL. 1992. DNA sequences similar to
those of simian virus 40 in ependymomas and choroid plexus tumors of childhood. N Engl J
Med 326(15):988-93.
Bocchetta M, Di Resta I, Powers A, Fresco R. Tosolini A, Testa JR, Pass HI, Rizzo P. Carbone M.
2000. Human mesothelial cells are unusually susceptible to simian virus 40-mediated trans-
formation and asbestos cocarcinogenicity. Proc NatlA cad Sci USA 97(18):10214-9.
Brown F. Lewis AM. 1998. Simian Virus 40 (SV40): A Possible Human Polyomavirus. New York:
Karger.
Butel JS, Lednicky JA. 1999. Cell and molecular biology of simian virus 40: implications for human
infections and disease. JNatl CancerInst 91(2):119-34.
Carbone M, Fisher S. Powers A, Pass HI, Rizo P. 1999. New molecular and epidemiological issues
in mesothelioma: role of SV40. J Cell Physiol 180(2):167-72.
Carbone M, Rizo P. Pass HI. 1997. Simian virus 40, poliovaccines and human tumors: a review of
recent developments. Oncogene 15(16):1877-88.
Carbone M, Rizo P. Procopio A, Giuliano M, Pass HI, Gebhardt MC, Mantham C, Hansen M,
Malkin DF, Bushart G. Pompetti F. Picci P. Levine AS, Bergsagel JD, Garcea RL. 1996.
SV40-like sequences in human bone tumors. Oncogene 13(3):527-35.
Carroll-Pankhurst C, Engels BA, Strickler HD, Goedert JJ, Wagner J. Mortimer EA Jr. 2001. Thirty-
five year mortality following receipt of SV40- contaminated polio vaccine during the neonatal
period. Br J Cancer 85(9):1295-7.
CDC (Centers for Disease Control and Prevention). 2000. Poliomyelitis prevention in the United
States: Updated recommendations of the Advisory Committee on Immunization Practices
(ACIP). MM~2 49(RR-5):1-22.
Code of Federal Regulations, Title 21, Sec. 610. Release Requirements. April 1, 2001. Release Re-
quirements.
Eddy BE, Borman GS, Berkeley WH, Young RD. 1961. Tumors induced in hamsters by injection of
rhesus monkey kidney cell extracts. Proc Soc E~p Biol Med.;107:191-197.
OCR for page 16
16
IMMUNIZA17ON SAFETY REVIEW
Eddy BE, Borman GS, Grubbs GE, Young, RD. 1962. Identification of oncogenic substance in
rhesus monkey kidney cell cultures as simian virus 40. Virolo`gy;17:65-75.
Egan W. 2002. Brief History and Important Questions. Presentation to Immunization Safety Review
Committee. Citing Murray, R., 1961. Citing Roderick Murray memorandum of 6/30/61 to
manufacturers of IPV. Washington DC.
Engels EA, Sarkar C, Daniel RW, Gravitt PE, Verma K, Quezado M, Shah KV. 2002. Absence of
simian virus 40 in human brain tumors from northern India. Int J Cancer 101: 348-352.
Farwell JR, Dohrmann GJ, Marrett LD, Meigs JW. 1979. Effect of SV40 virus-contaminated polio
vaccine on the incidence and type of CNS neoplasms in children: a population-based study.
Trans Am Neurol Assoc 104:261-4.
Fisher SG, Weber L, Carbone M. 1999. Cancer risk associated with simian virus 40 contaminated
polio vaccine. Anticancer Res 19(3B):2173-80.
Fraumeni JF Jr, Stark CR, Gold E, Lepow ML. 1970. Simian virus 40 in polio vaccine: follow-up of
newbornrecipients.Sciencel67(914~:59-60.
Fraumeni JF Jr, Ederer F. Miller RW. 1963. An evaluation of the carcinogenicity of simian virus 40
inman.JAAt4; 185(9):85-90.
Geissler E. 1990. SV40 and human brain tumors. Prog Med Virol 37:211-22.
Geissler E, Konzer P. Scherneck S. Zimmermann W. 1985. Sera collected before introduction of
contaminated polio vaccine contain antibodies against SV40. Acta Virol 29(5):420-3.
Girardi AJ, Sweet BH, Slotnick VB, Hilleman MR. 1962. Development oftumors in hamsters inocu-
lated in neonatal period with vacuolating virus, SV40. Proc SocExp Biol Med.;109:649-660.
Heinonen OP, Shapiro S. Monson RR, Hartz SC, Rosenberg L, Slone D. 1973. humunizabon during
pregnancy against poliomyelitis and influer~za in relation to childhood malignancy. Int J Epi-
demiol 2(3):229-35.
Heinsohn S. Scholz RB, Weber B. Wittenstein B. Werner M, Delling G. Kempf-Bielack B. Setlak P.
Bielack S. Kabisch H. 2000. SV40 sequences in human osteosarcoma of German origin. Anti-
cancer Research. ;20(6B):4539-4545.
Holmberg CA, Gribble DH, Takemoto KK, Howley PM, Espana C, Osburn BI. 1977. Isolation of
simian virus 40 from rhesus monkeys (Macaca mulatta) with spontaneous progressive multifo-
cal leukoencephalopathy. JInfect Dzs 136~4~:593-6.
Horvath CJ, Simon MA, Bergsagel DJ, Pauley DR, King NW, Garcea RL, Ringler DJ. 1992. Simian
virus 40-induced disease in rhesus monkeys with simian acquired immunodeficiency syn-
drome.Am JPathol 140(6):1431-40.
Hurley JP, Ilyinskii PO, Horvath CJ, Simon MA. 1997. A malignant astrocytoma containing simian
virus 40 DNA in a macaque infected with simian immunodeficiency virus. J Med Primatol
26(3):172~0.
~nis MD. 1968. Oncogenesis and poliomyelitis vaccine. Nature 219(157):972-3.
IOM (Institute of Medicine). 1991. Adverse Events Following Pertussis and Rubella Vaccines.
Washington DC: National Academy Press.
IOM. 1994. Adverse Events Associated With Childhood Vaccines: Evidence Bearing on Causality.
Washington DC: National Academy Press.
IOM. 2001a. Immunization Safety Review: Measles-Mumps-Rubella Yaccine and Autism. Washing-
ton, DC: National Academy Press.
IOM. 2001b. Immunization Safety Review: Thimerosal-Containing Vaccines andNeurodevelopmen-
tal Disorders. Washington DC: National Academy Press.
IOM. 2002a. Immunization Safety Review: Hepatitis B Vaccine and emyelinating Neurological Dis-
orders. Washington DC: National Academy Press.
IOM. 2002b. Immunization Safety Review: Multiple Immunizations and Immune Dysfunction. Wash-
ington DC: National Academy Press.
Jensen F. Koprowski H. Pagano JS, Ponten J. Ravdin JG. 1964. Autologous and Homologous hn-
plantation of Human Cells Transformed in Vitro by Simian Virus 40. JNCI; 32:917-937.
OCR for page 17
EXECUTIVE SUMALARY
17
Kim SH, Banga S. Jha KK, Ozer HL. 1998. SV40-mediated transformation and immortalization of
human cells. Dev Biol Stand 94:297-302.
Klein G. Powers A, Croce C. 2002. Association of SV40 with human tumors. Oncogene
21(8):1141-9.
Kleinbaum DO, Kupper LL, Morgenstern H. 1982. Epidemiologic Research: Principles and Quanti-
tafive Methods. Belmont, California: Lifetime Learning Publications, Wadsworth, Inc.
Koprowski H. Ponten JA, Jensen F. Rabdin RG, Moorhead P. Saksela E. 1962.Transforrnation of
cultures of human tissue infected with SV40. J Cell Comp Physiol.,59(281-292).
Lednicky JA, Garcea RL, Bergsagel DJ, Butel JS. 1995. Natural simian virus 40 strains are present
in human choroid plexus and ependymoma tumors. Virology 212(2):710-7.
Martini F. Iaccheri L, Lazzarin L, Carinci P. Corallini A, Gerosa M, I~olino P. Barbanti-Brodano
G. Tognon M. 1996. SV40 early region and large T antigen in human brain tumors, peripheral
blood cells, and sperm fluids from healthy individuals. Cancer Res 56(20):4820-5.
Mortimer EA Jr, Lepow ML, Gold E, Robbins FC, Burton GJ, Fraumeni JF Jr. 1981. Long-term
follow-up of persons inadvertently inoculated with SV40 as neonates. N Engl J Med
305(25):1517-8.
NIH (National Institutes of Health). 1998. Task Force on Safer Childhood Vaccines Final Report
and Recommendations. National Institute of Allergy and Infectious Diseases.
Olin P. Giesecke J. 1998. Potential exposure to SV40 in polio vaccines used in Sweden during 1957:
no impact on cancer incidence rates 1960 to 1993. Dev Biol Stand 94:227-33.
Rundell K Gaillard S. Porras A. 1998. Small-t and large-T antigens cooperate to drive cell prolifera-
tion. DevBiol Stand 94:289-95.
Shah K, Nathanson N. 1976. Human exposure to SV40: review and comment. Am J Epidemiol
103(1): 1-12.
Shah KV, McCrumb FR Jr, Daniel RW, Ozer HL. 1972. Serologic evidence for a simian-virus-40-
like infection of man. JNatl Cancer Inst 48(2):557-61.
Shein HM, Enders JF. 1962a. Multiplication and cytopathogenicity of simian vacuolating virus 40 in
cultures of human tissues. Proc SocExpBiol Med.;109:495-500.
Shein HM, Enders JF.1962b. Transformation induced by simian virus 40 in human renal cell cul-
tures. I. Morphology and growth characteristics. Proc Nat Acad Sci.;48:1164-1172.
Shivapurkar N. Harada K, Reddy J. Scheuermann RH, Xu Y. McKenna RW, Milchgrub S. Kroft
SH, Feng Z. Gazdar AF. 2002. Presence of simian virus 40 DNA sequences in human lym-
phomas. Lancet 359(9309):851-2.
Stewart AM, Hewitt D. 1965. Aetiology of childhood leukemia. Lancet;2(7416):789-90.
Strickler HD. 2001a. A multicenter evaluation of assays for detection of SV40 DNA and results in
masked mesothelioma specimens. Cancer Epidemiol Biomarkers Prev 10(5):523-32.
Strickler HD. 2001b. Simian v~rus 40 (SV40) and human cancers. Einstein Quarterly Journal of
Biology and Medicine;18: 14-20.
Strickler HD, Goedert JJ, Fleming M, Travis WD, Williams AK, Rabkin CS, Daniel RW, Shah KV.
1996. Simian v~rus 40 and pleural mesothelioma in humans. Cancer Epidemiol Biomarkers
Prev 5(6):473-5.
Strickler HD, Rosenberg PS, Devesa SS, Fraumeni JF Jr, Goedert JJ. 1999. Contamination of polio-
virus vaccine with SV40 and the incidence of medulloblastoma. Med. Pediatr Oncol 32~1~:77-
8.
Strickler HD, Rosenberg PS, Devesa SS, Hertel J. Fraumeni JF Jr, Goedert JJ. 1998. Contamination
of poliovirus vaccines with simian virus 40 (1955-1963) and subsequent cancer rates. JAM4
279(4):292-5.
Sutter RW, Cochi SL, Melnick JL. 1999. Live attenuated poliovirus vaccines. Plotkin S. Orenstein
W. Vaccines. 3rd ed. New York: W.B. Saunders Company. Pp. 364-408.
Sweet BH, Hilleman MER. 1960. The vacuolating virus, SV40. Proceedings for the Society for Ex-
perimental Biology and Medicine; 105:42~427.
OCR for page 18
18
I M M U N I Z A T I O N S A F E T Y R E V I E W
Testa JR, Carbone M, Hirvonen A, Khalili K, Krynska B. Linnainmea K, Pooley FD, Rizzo P. Rusch
V, Xiao GH. 1998. A multi-institutional study confirms the presence and expression of simian
virus 40 in human malignant mesotheliomas. Cancer Res 58(20):4505-9.
Vilchez RA, Madden CR, Kozinetz CA, Halvorson SJ, White ZS, Jorgensen JL, Finch CJ, Butel JS.
2002. Association between simian virus 40 and non-Hodgkin lymphoma. Lancet
359(9309):817-23.
Woloschak M, Yu A, Post KD. 1995. Detection of polyomaviral DNA sequences in normal and ade-
nomatous human pituitary tissues using the polymerase chain reaction. Cancer 76(3):490-6.
Representative terms from entire chapter:
simian virus
