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Executive Summary
ABSTRACT
Infection with the influenza virus can have a serious effect on the health of
people of all ages, although it is particularly worrisome for infants, the elderly,
and people with underlying heart or lung problems. At least 35,000 people die
in the United States every year from influenza infection. A vaccine exists (the
"flu" shotJ that can greatly decrease the impact of influenza. Because the
strains of virus that are expected to cause serious illness and death are slightly
different every year, the vaccine is also slightly different every year and it must
be given every year, unlike other vaccines. The influenza vaccine that was used
in 1976 for the expected "Swine Flu " epidemic (which never materialized was
associated with cases of a nervous system condition called Guillain-Barre'
syndrome (GBSJ. Ever since that time, public health leaders, doctors and nurses,
and the public have wondered whether every year's influenza vaccine can cause
GBS or other similar conditions.
The Immunization Safety Review committee reviewed the data on influenza
vaccine and neurological conditions and concluded that the evidence favored
acceptance of a causal relationship between the 1976 swine influenza vaccine
and GBS in adults. The evidence about GBS for other years' influenza vaccines
is not clear one way or the other (that is, the evidence is inadequate to accept or
reject a causal relationships.
The committee concluded that the evidence favored rejection of a causal
relationship between influenza vaccines and exacerbation of multiple sclerosis.
For the other neurological conditions studied, the committee concluded the
evidence about the effects of influenza vaccine is inadequate to accept or reject
a causal relationship. The committee also reviewed theories on how the inJ?u-
1
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2
IMMUNIZATION SAFFI Y REVIEW
enza vaccine could damage the nervous system. The evidence was at most weak
that the vaccine could act in humans in ways that could lead to these neurological
problems. See Box ES-1 for a summary of all recommendations and conclusions.
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 day care, school, or college, 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
the committee members all share the view that immunization is generally benefi-
cial, 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 one at a time. In this seventh report in the series, the committee
examines the hypothesis that influenza vaccines are associated with an increased
risk of neurological complications, particularly Guillain-Barre syndrome (GBS)
and multiple sclerosis (MS).
The committee is charged with assessing both the scientific evidence regard-
ing the hypotheses under review and the significance of the issues for society:
· The scientific assessment has two components: an examination of the
epidemiologic 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 significance 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 public
or professional concern, or the feasibility of additional research to help resolve
scientific uncertainty regarding causality.
The findings of the scientific and significance assessments provide the basis
for the committee's recommendations regarding the public health response to the
issues. In particular, the committee addresses needs for a review of immunization
policy, for current and future research, and for effective communication strategies.
For its evaluation of the question concerning influenza vaccines and neuro-
logical complications, the committee held an open scientific meeting in March
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EXECUTIVE SUMMARY
3
2003 (see Appendix B) to hear presentations on issues germane to the topic.
These presentations are available in electronic form (audio files and slides) on the
project website (www.iom.edu/imsafety). In addition, the committee reviewed an
extensive collection of material, primarily from the published, peer-reviewed
scientific and medical literature. A list of the materials reviewed by the com-
mittee, 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; 1994a,b),
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
specific 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 rela-
tionship."
Biological Mechanisms
Evidence considered in the scientific assessment of biological mechanisms)
includes human, animal, and in vitro studies related to biological or patho-
physiological processes by which immunizations could cause an adverse event.
When other evidence of causality is available, biological data add supportive
evidence but they cannot prove causality on their own.
{For a discussion of the evolution of the terminology concerning biological mechanisms, see the
committee's earlier reports (IOM, 2001 a,b; 2002a,b).
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IMMUNIZATION SAFFI Y REVIEW
The committee has established three general categories of evidence on bio-
logical mechanisms:
1. Theoretical. A reasonable mechanism can be hypothesized that is com-
mensurate with scientific knowledge and does not contradict known physical and
biological principles, but it has not been demonstrated in whole or in part in
humans or in animal models.
2. Experimental. A mechanism can be shown to operate in in vitro systems,
animals, or humans. But, experimental evidence often describes mechanisms that
represent only a portion of the pathological process required for expression of
disease. Showing that multiple portions of a process operate in reasonable experi-
mental models strengthens the case that the mechanisms could possibly result in
disease in humans.
3. Evidence that the mechanism results in known disease in humans. For
example, the wild-type infection causes the adverse health outcome, 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 both on 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.
Influenza Vaccines and Neurological Complications
The committee's review of the evidence concerning risks that might be
associated with influenza vaccines had to take into account a distinctive feature
of the vaccine: its formulation changes from year to year to reflect changes in the
strains of influenza virus circulating in the population. As a result, the question
before the committee actually concerns many different influenza vaccines rather
than a single, consistent product used over many years. In terms of the neuro-
logical outcomes of concern, GBS is the most widely cited. Other outcomes
considered by the committee are multiple sclerosis (MS) and optic neuritis.
Influenza and Influenza Vaccines
Influenza is an acute and highly contagious viral respiratory disease that
occurs worldwide. Although some infections are subclinical, influenza is respon-
sible for substantial morbidity and mortality. The elderly, young children, and
persons with chronic cardiac or pulmonary diseases are generally at greatest risk
for fatal complications (Dolin, 2001~. In the United States alone, the disease is
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EXECUTIVE SUMMARY
s
now estimated to contribute to an average of 36,000 deaths each year, a toll that
has risen as the population has aged (Thompson et al., 2003~. The extent and
severity of influenza infections can vary widely from year to year.
The influenza viruses infects the respiratory epithelium. Onset of illness is
often abrupt, with systemic symptoms that include fever, chills, headache,
myalgias and respiratory signs such as cough and sore throat. In uncomplicated
cases, acute illness typically resolves over 2 to 5 days. Recovery may be complete
within a week, but some patients experience persistent weakness or lassitude
(Dolin, 2001~. Many of the influenza-related deaths result from complications,
the most common being secondary bacterial pneumonia. Influenza can also
exacerbate chronic pulmonary conditions or contribute to a general deterioration
in cardiac or pulmonary function, especially in the elderly or persons with chronic
illness.
Influenza viruses are members of the family Orthomyxoviridae. Three forms
of the virus referred to as types A, B. and C are known to infect humans. The
B and C viruses circulate only in humans, with type C producing little illness.
Type A viruses, however, circulate not exclusively in humans but also in wild
aquatic birds, their natural reservoir. In addition, the type A viruses infect other
birds and several species of mammals. Influenza A viruses are subtyped based on
antigenic characteristics of their spike-like surface glycoproteins hemagglutinin
(HA) and neuraminidase (NA) (Dolin, 2001~. Influenza B and C viruses also
carry HA and NA surface antigens, but they are not given subtype designations.
Immunity to influenza depends on the formation of antibodies to the glyco-
protein surface antigens HA and NA (Dolin, 2001; Hilleman, 2002~. However,
influenza viruses of types A and B are successful in evading pre-existing immu-
nity from prior infections or vaccination because HA and NA continuously evolve
(Dolin, 2001; CDC, 2002a). Replication of the genetic material in the influenza A
and B virus genomes is error-prone and there is no proofreading mechanism,
allowing for the accumulation of point mutations (Dolin, 2001; Hilleman, 2002;
Steinhauer and Skehel, 2002; Ziegler and Cox, 1999~. Such mutations in the
genes encoding the surface antigens lead to what is called antigenic drift. The
influenza A virus is also subject to antigenic shift a major change in the HA or
NA antigens (e.g., from HI to H2 or N1 to Net. Antigenic drift occurs often,
leading the need for annual influenza vaccination. Antigenic shift occurs less
frequently and is associated with increases in morbidity and mortality.
Vaccination is the primary means of reducing the impact of influenza. The
effectiveness of influenza vaccines depends, in part, on the match between the
viral strains used to produce them and the strains that actually circulate in the
subsequent influenza season. The Advisory Committee on Immunization Prac-
tices (ACIP) currently recommends influenza vaccination for persons 6 months
of age and older who are at increased risk for complications of influenza, all
persons 50 to 64 years old, and health care workers and others who can routinely
transmit influenza to those at high risk for complications (CDC, 2003c). Persons
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IMMUNIZATION SAFFI Y REVIEW
considered to be at high risk for complications from influenza include persons
aged 65 years or older; residents of nursing homes and chronic care facilities;
children and adults with chronic lung, heart, kidney, metabolic, or immune system
disorders; and women who will be in the second or third trimester of pregnancy
during influenza season. The ACIP encourages, when feasible, the use of influ-
enza vaccine for children 6 to 23 months of age.
The majority of influenza vaccines currently approved for use in the United
States are inactivated ("killed virus". A live attenuated intranasal influenza
vaccine was just approved by the FDA in June 2003 for use in the United States
in healthy individuals aged 5-49 years (DHHS, 2003~. Current vaccines are
trivalent, produced using strains of influenza A(HlNl), influenza A(H3N2), and
influenza B viruses. Because of the continuing antigenic changes in these viruses,
new influenza vaccines are formulated each year based on information on the
viral strains that circulated during the previous season or are circulating at the
time in other parts of the world.
Adverse Neurological Events
The adverse events considered in this report GBS, MS, and optic neuritis-
are primarily diseases involving demyelination of nerve cell axons in either the
central (CNS) or peripheral (PNS) nervous systems.
GBS is an acute, immune-mediated paralytic disorder of the peripheral ner-
vous system. Estimates of the annual incidence of GBS range from 0.4 to 4.0
cases per 100,000 population, with most studies pointing to a level of from 1 to 2
cases per 100,000 (Hughes and Rees, 1997; Magira et al., 2003~. GBS occurs
throughout the year, and in the United States the condition is more likely to occur
in adults than in children (Asbury, 2000~.
About two-thirds of GBS cases occur several days or weeks after an infec-
tious event (Hughes and Rees, 1997), commonly a diarrhea! illness or a virus-like
upper-respiratory infection. From 20 percent to 40 percent of all GBS cases are
associated with Campylobacter jejuni infections (Buzby et al., 1997~. Exposure
to certain vaccines has also been associated with an increased risk for GBS. The
potential association between GBS and influenza vaccines, most notably the 1976
swine influenza vaccine, has been widely studied and is the subject of this report.
The characteristic clinical feature of GBS is an acute, rapidly progressive,
symmetrical weakness, with loss of deep tendon reflexes, possible tingling in the
feet and hands, and muscle aches (myalgia). Approximately 85 percent of patients
will return to normal functioning within 6 to 9 months, but some patients experi-
2Inactivated influenza vaccines licensed for use in the United States for the 2002 influenza season
included FluShield (Wyeth Lederle); Fluvirin (Evans Vaccines, Ltd.); and Fluzone (Aventis Pasteur).
As of November 2002, Wyeth ceased producing FlueShield. The live attenuated vaccine FluMist is
manufactured by MedImmune Vaccines, Inc and marketed by Wyeth Vaccines.
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EXECUTIVE SUMMARY
7
once relapses or a prolonged disease course with residual neurological deficits
(Asbury, 2000; Joseph and Tsao, 2002~. The mortality rate is 3-5 percent, with
patients succumbing to undetected respiratory failure, malfunction of the auto-
nomic nervous system, or to complications of immobility such as sepsis or
pulmonary embolism (Joseph and Tsao, 2002~.
MS affects between 250,000 and 350,000 people in the United States and is
the most common inflammatory demyelinating disease of the CNS (Keegan and
Noseworthy, 2002~. Its incidence and manifestations vary within the population.
The relapsing-remitting form, for example, occurs predominantly in females
(~1.6:1), but follows a more severe clinical course in males (Noseworthy et al.,
2000~. The incidence of the disease is highest in persons between the ages of 20
and 40 years, but it is also diagnosed in children as young as 2 years and in older
individuals. The prevalence of the disease is between 50 and 250 cases per
100,000 population in high-risk areas such as the Scandinavian countries or the
northern United States, whereas it is less than 5 cases per 100,000 in Africa and
Japan (Waubant and Stuve, 2002~.
Clinically, MS is characterized by a variety of neurological signs and symp-
toms, reflecting the occurrence of inflammatory demyelinating lesions through-
out the CNS. Common presenting symptoms include focal sensory deficits, focal
weakness, a loss of vision, double vision, imbalance, and fatigue. The severity of the
disease can range from subclinical forms that are diagnosed only after death from
other causes to hyperacute forms that lead to death within the first few months after
disease onset. The cause of MS remains elusive, but disease susceptibility appears
to involve both genetic and environmental factors. Genetic factors are reflected in
an increased risk of developing MS among family members of MS patients.
Optic neuritis is caused by an inflammation of the optic nerve, with lesions
occurring behind the orbit but anterior to the optic chiasm (IOM, 1994a). Symp-
toms include rapid vision loss, pain associated with eye movement, dimmed
vision, abnormal color vision, altered depth perception, and Uhthoff's phenom-
enon (visual loss associated with an increase in body temperature) (IOM,2001c).
The majority of cases resolve within a few weeks to months of onset. Optic
neuritis can occur as an isolated monophasic disease, or it may be a symptom of
other demyelinating diseases such as acute disseminated encephalomyelitis
(ADEM) or MS.
SCIENTIFIC ASSESSMENT
Causality
Guillain-Barre' Syndrome
For its review of the epidemiologic evidence regarding a possible association
between influenza vaccination and GBS, the committee separated studies concern-
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IMMUNIZATION SAFFI Y REVIEW
ing the vaccines administered during the 1976 National Influenza Immunization
Program from studies concerning influenza vaccines administered in subsequent
years. The committee reviewed studies that presented data for the nation as a
whole and studies based on data for individual states or for military personnel.
Case reports were also reviewed, but the committee concluded that reports to
VAERS and other case reports submitted to the committee are uninformative
with respect to causality, although they are useful for hypothesis generation. Case
reports help describe the domain of concerns, but the data are usually uncorrobo-
rated clinical descriptions that are insufficient to permit meaningful comment or
to contribute to a causality argument. The analytical value of data from VAERS
and other passive surveillance systems is limited by such problems as under-
reporting, lack of detail, inconsistent diagnostic criteria, and inadequate denomi-
nator data (Ellenberg and Chen, 1997; Singleton et al., 1999~.
1976 Swine Influenza Vaccine
Studies that examined the association between swine influenza vaccine and
GBS, including analysis and reanalysis of nationwide data (Schonberger et al
1979, Langmuir et al 1984), and state-based studies (Parkin et al., 1978; Marks
and Halpin, 1980; Breman and Hayner, 1984; Safranek et al., 1991) consistently
showed an increased risk of GBS for the vaccinated population (See Table 3~.
The committee concludes that the evidence favors acceptance of a causal
relationship between 1976 swine influenza vaccine and Guillain-Barre syn-
drome in adults. Concerns that the evidence of increased risk found in the
original analysis of the national data might have been a reflection of inaccuracies
in ascertainment of GBS cases have been addressed in subsequent studies by
detailed and systematic reviews of clinical data to verify GBS diagnoses.
Although the studies of GBS among military personnel (Johnson, 1982;
Kurland et al., 1986) do not show an association with the 1976 swine influenza
vaccine, these studies have limitations that led the committee to discount their
findings in its evaluation of the evidence. Military personnel represent a more
limited age range than the civilian population and are typically healthier on
average than civilians of comparable ages. In addition, information bias may
have been present because estimates of the number of vaccinations administered
and the number of people serving in the military were not validated and the
accuracy of the data sources was not reported. Thus, these studies are limited in
their ability to contribute to the causality argument.
Influenza Vaccines Used after 1976
The committee reviewed several population-based surveillance studies
(Hurwitz et al., 1981; Kaplan et al., 1982, Lasky et al., 1998), a study of military
personnel (Roscelli et al., 1991), and two unpublished studies that were discussed
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EXECUTIVE SUMMARY
9
by Chen (2003) at the committee's public meeting (see Table 4~. Their findings
were mixed. The studies differed in terms of their design, the case definitions for
GBS, their methods of case ascertainment, the size of the study populations, and
the influenza seasons covered. Compared with the 1976 immunization experi-
ence, vaccinations were administered over a longer period of time in the years
covered by these studies, making it more difficult to detect any increase that
might have occurred in a rare condition like GBS. Although immunization rates
were estimated to be much higher among U.S. Army personnel (Roscelli et al.,
1991), the relatively small size of the population vaccinated each year would
make detection of vaccine-attributable risk difficult. Because of the nature of
case reports, the information from VAERS added little to the committee's ability
to assess causality.
The committee concludes that the evidence is inadequate to accept or
reject a causal relationship between GBS in adults and influenza vaccines
administered after 1976 (that is, subsequent to the swine influenza vaccine
program).
Multiple Sclerosis
The committee examined reports on epidemiological studies of relapses
among MS patients following influenza vaccination; separately it examined a
smaller set of reports concerning the risk of MS onset. All these studies con-
cerned influenza vaccines used in various years, including the swine influenza
vaccines of 1976. The committee was also provided with VAERS summary
information (Haber, 2003~. Reports from passive surveillance systems like
VAERS are of little assistance in assessing causality.
On the basis of the Confavreaux study (2001) and the consistent findings
from the other studies (Miller et al., 1997; Mokhtarian, 1997; Bamford et al.,
1978; Myers et al., 1977), the committee concludes that the evidence favors
rejection of a causal relationship between influenza vaccines and relapse of
multiple sclerosis in adults. Uncontrolled studies and case series (De Keyser et
al., 1998; Salvetti et al., 1995; Sibley et al., 1976) provide similar findings, but
given their nature they are of limited value in assessing causality. The occurrence
of relapse is rare and the power to detect increased risk is limited.
Few studies have examined the association between influenza vaccination
and the onset of MS. Only one study (DeStefano et al., 2003) provided a thorough
description of the study methods and outcomes. It found no increase in the risk of
onset of MS associated with influenza vaccination, but in the absence of confir-
mation from other sources, the committee concludes that the evidence is inade-
quate to accept or reject a causal relationship between influenza vaccines
and incident MS in adults. However, the biological mechanisms involved in the
onset of MS are presumed to be related to those involved in relapse. With the
epidemiological data favoring the rejection of a causal relationship between
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IMMUNIZATION SAFFI Y REVIEW
influenza vaccines and relapse of MS, the committee sees no reason to suspect
that a causal relationship might exist between influenza vaccines and onset of MS.
Because the available studies did not consistently report ages (some did not
report age at all, and detail is lacking in studies that did report age, for example,
reporting average age without a range) and none of the studies specifically
included children, the committee could not reach a conclusion on causality in the
children's age group, but it also could not clearly define the lower age limit for its
conclusion in adults.
Optic Neuritis
With a single epidemiologic study available (DeStefano et al., 2003), the
committee concludes that the evidence is inadequate to accept or reject a
causal relationship between influenza vaccines and optic neuritis in adults.
VAERS data and case reports have limited value in assessments of causality.
Because the available studies that examined optic neuritis did not specifically
include children, the committee could not reach a conclusion on causality in the
children's age group, but also could not clearly define the lower age limit for its
conclusion in adults.
Other Demyelinating Neurological Conditions
Several case reports have been published mentioning the occurrence of other
neurological disorders (e.g., acute disseminated encephalomyelitis, transverse
myelitis) after influenza vaccination (Saito et al., 1980; Yahr and Lobo-Antunes,
1972; Bakshi and Mazziotta, 1996; Lamer and Farmer, 2000 ). Other neurologi-
cal conditions were reported from the surveillance system set-up during the 1976
National Influenza Immunization Program, but the data were not sufficient to
assess causality (Retailliau et al., 1980~. No other epidemiological studies were
identified. Based on the nature of case reports and the paucity of epidemiological
data, the committee concludes that the evidence is inadequate to accept or
reject a causal relationship between influenza vaccines and other demyeli-
nating neurological disorders.
Children and Influenza Vaccines
Influenza vaccine is generally administered to adults, and relatively few
studies have reported data concerning any neurological complications observed
in children. Currently, ACIP encourages influenza immunization for children
ages 6-23 months (CDC,2003c). A recommendation for annual routine influenza
immunization in that age group may be made within the near future (CDC,
2003c). Given concerns that demyelinating neurological disorders might follow
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EXECUTIVE SUMMARY
11
receipt of influenza vaccines, the committee describes the relevant data in chil-
dren, specifically focusing on the age group 6-23 months .
The published reports concerning the 1976 swine influenza vaccine and GBS
(Schonberger et al., 1979; Marks and Halpin, 1980; Breman and Hayner, 1984)
and the reports on the safety of trivalent inactivated influenza vaccine in children
(Neuzil et al., 2001; Gonzalez et al., 2000; Piedra et al., 1993) did not directly
examine the relationship between influenza vaccines and demyelinating neuro-
logical disorders in children. These studies use a broad and varied definition of
"children," and the small number of children in the studies limit the ability to
detect rare neurological outcomes, such as GBS and MS. The committee reviewed
one unpublished study that reported no cases of MS or other demyelinating
disorders in children (France, 2003), but the unpublished nature of the study and
the small number of cases limit its use in assessing causality. No published
studies directly examined receipt of influenza vaccines and the occurrence of
demyelinating neurological disorders in children. Thus, based on the lack of
direct published evidence on influenza vaccines and demyelinating neurological
disorders in children, especially those aged 6-23 months, the committee con-
cludes that there is no evidence bearing on a causal relationship between
influenza vaccines and demyelinating neurological disorders in children aged
6-23 months.
Biological Mechanisms
In its assessment of the possibility of a relationship between influenza vac-
cines and neurological complications, the committee hypothesized two general
ways vaccine could lead to neurological complications: immune-mediated pro-
cesses and neurotoxic effects.
Infection can induce immune-mediated tissue injury. In most cases, this
injury is short-lived and resolves as the immune system eliminates active infec-
tion. The injury is a consequence of the immune response to the foreign invader,
and when the invader is eliminated, the damaging immune process ceases. In
some diseases, however, infection appears to induce an injurious immune response
in the form of T and B cells that are directed, at least in part, against self antigens.
This autoimmune injury must be distinguished from immune-mediated injury
that results from persistent but undetected infection.
The two major mechanisms proposed to account for the activation of self-
reactive T and B cells and the induction of autoimmunity by infection are molecular
mimicry and bystander activation (see IOM 2002b for a complete review of this
issue). Molecular mimicry is a mechanism by which an antigenic epitope from an
infectious agent or other exogenous substance that is structurally similar to
(mimics) an epitope of a self-molecule has the potential to trigger the activation
of self-reactive, naive T or B lymphocytes. Bystander activation results when an
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IMMUNIZATION SAFFI Y REVIEW
infection creates environmental conditions that allow the activation of self-
reactive T and B cells that are normally held in check. For example, tissue
damage from an infection (or an inflammatory process) can lead to the liberation
or exposure of host antigens in a context that allows for presentation to, activation
of, and expansion of self-reactive lymphocytes.
It is conceivable that vaccine antigens could mimic self (host), that stimula-
tion from vaccines could trigger bystander activation just as an infectious organ-
ism does, and that either or both of these potentially damaging mechanisms could
possibly lead to the development of central or peripheral demyelinating disease.
There is no reason in theory why influenza virus antigens, or other substances in
the vaccines (e.g., residual traces of constituents from the production process),
could not function in this way. Thus, there is a theoretical basis for influenza
vaccines to induce immune responses that could possibly lead to demyelination.
As discussed in the subsequent section, however, the evidence in support of this
theory is limited, and some is indirect.
The following biological evidence relates to the theory that influenza vac-
cines could be associated with neurological complications:
· Bystander activation. Animal models (Hjorth et al., 1984; Ziegler et al.,
1983) show that under contrived experimental conditions inoculation with influ-
enza vaccines in combination with myelin antigens (as tissue or gangliosides)
leads to demyelinating diseases similar in many respects to GBS. Animal models
of MS-like CNS demyelination also exist but have not been linked to influenza
viruses or vaccines. In models of peripheral demyelination (EAN-like disease
and EN), influenza vaccines had adjuvant properties in the presence of neural
antigens. For this model to operate during routine human use of influenza vac-
cine, neural injury would have to be initiated during the immunization process to
release neural antigens with which the vaccine would act as adjuvant, or influ-
enza vaccines would have to contain myelin (which has not been shown) or other
components that mimic myelin.
.
Molecular mimicry. Evidence related to molecular mimicry is mixed.
1. No direct evidence shows that influenza antigens or other vaccine compo-
nents act as molecular mimics of self antigens in the nervous system.
Although two older studies demonstrated similarities in amino acid
sequences between the myelin protein P2 and the influenza A virus protein
NS2, there is no evidence that this sequence similarity leads to structural
similarity or that NS2 can elicit host autoantibodies. In addition, NS2 is
not likely to be found in influenza vaccines.
2. A strong set of data indicate that C. jejuni antigens can trigger GBS
through molecular mimicry. Influenza vaccines are made using viruses
cultivated in eggs, and eggs can be contaminated with C. jejuni. Although
the production of the 1976 swine influenza vaccine by four different
manufacturers with four different proprietary seed viruses and different
egg sources makes widespread C. jejuni contamination seem highly
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EXECUTIVE SUMMARY
13
unlikely, the available evidence cannot exclude the possibility that C. jejuni
antigens were present in the vaccines from all four manufacturers.
The committee concludes that there is weak evidence for biological
mechanisms related to immune-mediated processes, including molecular
mimicry and bystander activation, by which receipt of any influenza vaccine
could possibly influence an individual's risk of developing the neurological
complications of GBS, MS, or other demyelinating conditions such as optic
neuritis. In the absence of experimental or human evidence regarding the
direct neurotoxic effect of influenza vaccines, the committee concludes that
this mechanism is only theoretical.
SIGNIFICANCE ASSESSMENT
The committee considered the significance of the concern that influenza
vaccines might increase the risk of developing neurological complications such
as GBS or MS. The scientific assessment provided support for a link between
GBS and the 1976 influenza vaccines, but the evidence for other outcomes or for
vaccines for other years was inadequate to support a conclusion or favored no
association. Vaccination plays a key role in efforts to reduce the annual impact of
influenza infections, making it important that any vaccine-related risks be identi-
fied and evaluated.
Influenza vaccine is an essential tool for reducing the substantial burden of
morbidity and mortality associated with influenza infections each year. Not only
is the yearly disease toll high, but the prospect of an influenza pandemic is a
serious concern to many. If the viral strains used to produce the vaccine are
closely matched to the viral strains circulating during the influenza season, vacci-
nation may prevent illness (although not necessarily infection) in 70 to 90 percent
of healthy children as young as 6 months of age and healthy adults under age 65.
(CDC, 2002b). Vaccination is only 30 to 40 percent effective in preventing
illness in older and more frail individuals, but it is 50 to 60 percent effective in
preventing hospitalization and 80 percent effective in preventing deaths (CDC,
2002a).
Influenza vaccine must be given every year and is recommended for large
segments of the population, making it the one of the most widely used vaccines in
the United States. Because the vaccine is used so widely and may be recom-
mended for regular administration to young children, the possibility of vaccine-
related adverse events must be given serious consideration. In its scientific assess-
ment, the committee found support for a causal association between the vaccine
used in 1976 and GBS. But it found no support for an association with relapses of
MS, and inconclusive evidence regarding influenza vaccines used in other years
and other neurological conditions. The committee found no evidence bearing on
a causal relationship between influenza vaccines and demyelinating neurological
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IMMUNIZATION SAFFI Y REVIEW
disorders in children aged 6-23 months. GBS is a serious condition, but it is rare
and the additional risk related to vaccination in 1976 translated into fewer than
6 cases per million vaccinees (Langmuir et al., 1984~. By contrast, influenza
contributes to an annual average of 13.8 deaths per 100,000 (36,000 deaths,
majority are 65 years of age or older) and to an annual excess of 49 pneumonia
and influenza related hospitalizations per 100,000 (114,000 hospitalizations)
(Thompson et al., 2003; Simonsen et al., 2000~. It is important to fully understand
any risk for GBS or other neurological complication that might be associated
with influenza vaccination to ensure that it can be appropriately weighed against
the sizable burden of illness associated with influenza infections.
RECOMMENDATIONS FOR PUBLIC HEALTH RESPONSE
Policy Review
The committee does not recommend a policy review of the recommenda-
tions for influenza vaccination by any of the national or federal vaccine
advisory bodies on the basis of concerns about neurological complications.
Current and future immunization policies should continue to reflect the
benefits of influenza vaccination.
Research
With a vaccine as widely used as influenza vaccine, the committee considers
it important to pursue research and research-related activities aimed at ensuring
that any risk of GBS or other neurological complications is minimized.
Surveillance and Epidemiological Studies
Even though use of the vaccine generally appears to pose minimal risk of
adverse neurological events, the strong association between the 1976 vaccine and
GBS points to the need for appropriate vigilance through adequate surveillance
systems and for better tools to support studies of rare adverse events. The com-
mittee recommends increased surveillance of adverse events associated with
influenza vaccination of children, with particular attentiveness to detecting
and assessing potential neurological complications. Enhanced surveillance
should be in place before an ACIP recommendation is implemented for
universal annual influenza vaccination of young children.
Better methods are needed to identify and assess risks for rare outcomes such
as the neurological complications considered in this report. The scale of the 1976
vaccination program helped make detection of the link with GBS feasible. The
committee recommends efforts to develop techniques for the detection and
evaluation of rare adverse events and encourages the use of administrative
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EXECUTIVE SUMMARY
15
databases and the standardization of immunization records as part of this
effort.
Basic and Clinical Science
Despite improvements over the past 25 years in the broad understanding of
the pathogenesis of autoimmune diseases, and of GBS in particular, the exact
mechanisms by which the 1976 influenza vaccine precipitated this adverse out-
come remain unknown. To gain further insight into these mechanisms, the com-
mittee sees a need for additional basic and clinical research on influenza viruses,
the composition and immunological properties of the 1976 vaccine, immunologi-
cal responses to vaccines in general, and host characteristics that may affect
susceptibility to adverse events.
There is a need to better understand the immunological responses in recipi-
ents of the 1976 swine influenza vaccine who experienced GBS. One avenue of
inquiry should be the pathogenesis of influenza viruses in general and the swine
influenza strain (A/New Jersey/76) in particular to learn whether and how strains
might differ in their ability or predisposition to produce neurological injury. The
committee supports ongoing research aimed at better understanding the
pathogenesis of influenza and encourages efforts to anticipate which strains
might be more neurologically active.
Although the 1976 influenza vaccine was produced under atypical condi-
tions, with the four manufacturers given less time than usual while being asked to
produce much larger quantities than in previous years, there is no evidence that
the speed of manufacture or volume of production produced lapses that could
have led to a faulty vaccine. The increased risk of GBS associated with the 1976
swine influenza vaccine appeared consistent for vaccine from the four different
manufacturers, for the monovalent and bivalent vaccines, and for the whole- and
split-virus vaccines. The consistency of the risk across the sources and types of
vaccine argues against, but does not rule out, problems related to the manufactur-
ing process. Issues that might be investigated include whether there was some-
thing atypical about the nonviral components of the swine influenza vaccines
and, if so, identifying it and determining whether it can be controlled.
The use of eggs to produce vaccine-strain influenza virus suggests the possi-
bility that unrecognized antigens might have been present in the 1976 vaccine.
C. jejuni infection is a recognized risk factor for GBS, possibly acting through
molecular mimicry, and C. jejuni commonly infects chickens. Although the com-
mittee concluded that molecular mimicry is only theoretically possible as an
immune mechanism by which influenza vaccines may cause GBS, the evidence
that C. jejuni antigens can trigger GBS is strong, and the possibility cannot be
excluded that C. jejuni antigens were present in swine influenza vaccine from all
four manufacturers of the 1976 swine influenza vaccine. Although stocks of the
1976 vaccine are unlikely available, the committee recommends that if
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16
IMMUNIZATION SAFFI Y REVIEW
samples of the influenza vaccines used in 1976 are available, they should be
analyzed for the presence of C. jejuni antigens, NS1 or NS2 proteins, or other
possible contaminants. The 1976 vaccines should be compared with current
and other historical influenza vaccines.
Studies in animals (Hjorth et al., 1984; Ziegler et al., 1983) have provided at
least some basis for considering bystander activation as a potential mechanism by
which influenza vaccines could cause GBS or related neurological complications.
As it did in a previous report (IOM, 2002a), the committee recommends contin-
ued research using animal and in vitro models, as well as with humans, on
the mechanisms of immune-mediated neurological diseases that might be
associated with exposure to vaccines.
Genetic factors are known to be an important source of variability in the
responses of the human immune system and in the risks of autoimmune disease.
At present, understanding of the complex interactions among genetic variables
and environmental exposures, including vaccines and wild-type infectious organ-
isms, remains incomplete. The committee recommends continued research
efforts aimed at identifying genetic variability in human immune system
responsiveness as a way to gain a better understanding of genetic susceptibility
to vaccine-based adverse events.
Communication
A broader framework for influenza vaccine issues is critical for substantial
progress in vaccination rates to be achieved. A rigorous, systematic identification
of the influences that affect experts' and subpopulations' views and decisions
about vaccines is an important step toward developing such a framework
(Bostrom, 1997~. Despite the studies that have been conducted to date, a compre-
hensive context has not yet been compiled for the influenza vaccine. The com-
mittee recommends that research be supported to conduct investigations
that would deepen and expand the knowledge available from existing studies
and more effectively organize what is currently known from these and future
projects. Comprehensive influence diagrams of expert and at-risk populations'
views of the vaccine are needed to provide a broader context and reveal richer
insights than are possible from a review of currently available studies.
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EXECUTIVE SUMMARY
17
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18
IMMUNIZATION SAFFI Y REVIEW
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EXECUTIVE SUMMARY
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INFLUENZA VACCINES
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BOX 1
Previous Reports of the Immunization Safety Review Committee
Immunization Safety Review. Measles-Mumps-Rubella Vaccine and Autism (IOM, 2001a)
Immunization Safety Review: Thimerosal-Containing Vaccines and Neurod~evelopmental Disorders (IOM, 2001b)
Immunization Safery Review: Multiple Immunizations and Immune Dysfunction (IOM, 2002b)
Immunization Safety Review: Hepatitis B Vaccine and Demyelinating Neurological Disorders (IOM, 2002a)
Immunization Safety Review. SV40 Contamination of Polio Vaccine and Cancer (IOM, 2002c)
Immunization Safety Review. Vaccinations and Sudden Unexpected Death in Infancy (IOM, 2003)
For its evaluation of the question concerning influenza vaccines anc! neurological complica-
tions, the committee held an open scientific meeting in March 2003 (see Appendix B) to hear
presentations on issues germane to the topic. These presentations are available in electronic form
(audio files ant! 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 ant! 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 cau-
sality cleveloped by previous TOM committees (IOM, 1991; 1994a,b) convened uncler the con-
gressional mandate of P.~. 99-660 to address questions of immunization safety. The categories
of causal conclusions user! by the committee are as follows:
I. 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 immunization safety
hypothesis uncler review. That is, there is no presumption that a specific vaccine (or vaccine
component) does or floes not cause the adverse event in question. The weight of the available
clinical and epidemiologic evidence cleten~ines whether it is possible to shift from that neutral
position to a fancying for causality ("the evidence favors acceptance of a causal relationship") or
against causality ("the evidence favors rejection of a causal relationships. The committee does
not conclucle that the vaccine does not cause the adverse event merely if the evidence is inade-
quate to support causality. Instea(l, it maintains a neutral position, conclucling that the "evidence
is inadequate to accept or reject a causal relationship."
Although no fimn rules establish the amount of evidence or the quality of the evidence re-
quired to support a specific category of causality conclusion, the committee uses standard epi-
clemiologic criteria to guide its decisions. The most definitive category is "establishes causality,"
which is reserves! for those relationships in which the causal link is unequivocal, as with the oral
polio vaccine and vaccine-associatec3 paralytic polio or with anaphylactic reactions to vaccine
UNEDITED, UNCORRECTED PROOFS
Representative terms from entire chapter:
influenza vaccine
