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1
Introduction
Protecting health is a major priority of society, families, and individual
parents. Over the past 100 years there has been a revolution in the ability
to protect health in the developed world, where there are resources to en-
able this to happen. In 1900, among every 1,000 babies born in the United
States, 100 would die before their first birthday, and five before 5 years of
age (Guyer et al., 2000). By 2007, fewer than seven were expected to die
before their first birthday, and only 0.29 per 1,000 before 5 years of age
(HHS, 2010). Diseases severe enough to kill children and adults can also
leave survivors disabled in some way, and as mortality has fallen, so has
the chance of severe disability from these diseases.
Among the dangers for children and adults that have greatly diminished
over the past century are infectious diseases. For bacterial diseases, antibi-
otics have been developed to treat infections before permanent harm can
occur. For many viral and bacterial diseases, vaccines now exist.
In the early 20th century, smallpox (which has 30 percent mortality
and a very high rate of disfigurement and other less common sequelae
including blindness and encephalopathy) and rabies (virtually 100 percent
fatal) could be prevented with immunization (CDC, 2001, 2008). With the
fast growing understanding of microbes and immunity from 1920 onward,
the development of immunizations became a race to “conquer” infectious
disease. Beginning with the combination diphtheria, pertussis, and tetanus
immunization during World War II and most recently with immunization to
prevent cervical cancer (the human papillomavirus vaccine), immunizations
have changed our expectations for child and adult health. Infections are less
of a terror, and children are expected to survive to adulthood.
27
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28 ADVERSE EFFECTS OF VACCINES: EVIDENCE AND CAUSALITY
Vaccines function by stimulating the immune system and prompt -
ing a primary immune response to an infecting pathogen or to molecules
derived from a particular pathogen. The immune response elicited by this
primary exposure to vaccine pathogen creates immunological memory,
which involves the generation of a pool of immune cells that will recognize
the pathogen and mount a more robust or secondary response upon subse-
quent exposure to the virus or bacterium. In successful immunization, the
secondary immune response is sufficient to prevent disease in the infected
individual, as well as prevent the transmission of the pathogen to others.
For communicable diseases, immunizations protect not only the individual
who receives the immunization, but also others with whom he or she has
contact. High levels of vaccination in a community increase the number
of people who are less susceptible or resistant to illness and propagation
of the infectious agent. Unvaccinated individuals or those who have not
developed immunity to this pathogen are afforded an indirect measure of
protection because those with immunity reduce the spread of the pathogen
throughout the entire population. The larger the proportion of people with
immunity, the greater the protection of those without immunity. This effect
is called “herd immunity.” Herd immunity is an important phenomenon
as immunization programs rarely achieve 100 percent immunization in
a population; and in some cases, previously vaccinated persons may not
exhibit effective immunity and disease may result from exposure to the
pathogen. For protection, immunization of not only ourselves but also our
neighbors is important.
The overwhelming safety and effectiveness of vaccines in current use in
preventing serious disease has allowed them to gain their preeminent role
in the routine protection of health. Before an immunization is introduced
for population-wide use, it is tested for efficacy and safety. However, im-
munization is not without risks. For example, it is well established that
the oral polio vaccine on rare occasion causes paralytic polio and that
vaccines sometimes lead to anaphylactic shock. Given the widespread use
of vaccines; state mandates requiring vaccination of children for entry into
school, college, or day care; and the importance of ensuring that trust in im-
munization programs is justified, it is essential that safety concerns receive
assiduous attention.
Congress passed the National Childhood Vaccine Injury Act (NCVIA,
P.L. 99-660) in 1986. The legislation was intended to bolster vaccine re-
search and development through federal coordination of the vaccine ef-
forts in government and by providing relief to vaccine manufacturers who
reported at the time that financial burdens from awards in the tort system
threatened their financial viability. The legislation was also intended to ad-
dress concerns about the safety of vaccines by instituting a compensation
program financed by an excise tax on covered vaccines, setting up a passive
surveillance system for vaccine adverse events, and by providing informa-
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29
INTRODUCTION
tion to consumers (CDC, 2010). Key provisions of the 1986 legislation
include
• The establishment of the National Vaccine Program Office, which
coordinates immunization-related activities between all Depart-
ment of Health and Human Services (HHS) agencies including the
Centers for Disease Control and Prevention (CDC), the Food and
Drug Administration, the National Institutes of Health, and the
Health Resources and Services Administration (HRSA).
• The requirement that all health care providers who administer
vaccines provide a vaccine information statement (VIS) to the vac-
cine recipient, or his or her parent or legal guardian, prior to each
dose. Each VIS contains a brief description of the disease as well
as the risks and benefits of the vaccine. The CDC develops VISs
and distributes them to state and local health departments as well
as individual providers.
• The requirement that health care providers must report certain
and are encouraged to report other adverse events (health effects
occurring after immunization that may or may not be related to
the vaccine) following vaccination to the Vaccine Adverse Event
Reporting System.
• The creation of the National Vaccine Injury Compensation Pro-
gram (VICP) to compensate those injured by vaccines on a no-fault
basis. Importantly, this compensation system has two parts:
○ The Secretary of Health and Human Services has created a
Vaccine Injury Table (Table) that “lists and explains injuries/
conditions that are presumed to be caused by vaccines. It also
lists time periods in which the first symptom of these injuries/
conditions must occur after receiving the vaccine. If the first
symptom of these injuries/conditions occurs within the listed
time periods, it is presumed that the vaccine was the cause of
the injury or condition unless another cause is found” (http://
www.hrsa.gov/vaccinecompensation/table.htm) and compensa-
tion is awarded.
○ Individuals who assert that they suffered an injury from a
vaccine that is not on the Table (“off-Table” or “causation-in-
fact”) must pursue their claim before Special Masters, who are
appointed by the United States Court of Federal Claims, which
hears any appeals. Claimants bear the burden of proving that
the vaccine caused their injury, although the burden of proof
is lower than that in the tort system.
A key component of the legislation, found in Sections 312 and 313,
required the HHS secretary to consult with the Institute of Medicine (IOM)
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30 ADVERSE EFFECTS OF VACCINES: EVIDENCE AND CAUSALITY
to review the scientific literature on vaccine safety. Two reports were issued
(IOM, 1991, 1994). These reports contain a framework for causality as-
sessment of vaccine adverse events.1 The reports addressed the vaccines
covered by the VICP up to that point: diphtheria and tetanus toxoids and
whole cell pertussis vaccine and other tetanus toxoid–containing vaccines;
measles, mumps, and rubella (MMR) vaccines; Haemophilus influenzae type
B vaccine; hepatitis B vaccine; and both inactivated and oral polio vaccines.2
The reports informed the secretary’s review of the Vaccine Injury Table. The
reports have also been referenced extensively as a source of definitive scien-
tific understanding of the evidence by Special Masters in decisions regarding
injuries not listed on the Vaccine Injury Table.
The IOM was subsequently asked to review specific vaccine safety
concerns in a series of reports requested by the CDC. These reports (IOM,
2001a,b, 2002a,b, 2003a,b, 2004a,b) included causality assessments simi-
lar to the previous IOM reports, but included other conclusions and recom-
mendations regarding research, communications, and policy review.
CHARGE TO THE COMMITTEE
In 2009 HRSA requested that the IOM convene a committee of experts
to review the epidemiological, clinical, and biological evidence regarding
adverse health events associated with specific vaccines covered by the VICP.
The committee was charged with developing a consensus report with con-
clusions on the evidence bearing on causality and the evidence regarding
the biological mechanisms that underlie specific theories for how a specific
vaccine is related to a specific adverse event. The vaccines to be reviewed
include varicella zoster vaccine, influenza vaccines (but not 2009 H1N1
vaccine), hepatitis B vaccine, human papillomavirus vaccine, tetanus-con-
taining vaccines other than those containing the whole cell pertussis com-
ponent, MMR vaccine, hepatitis A vaccine, and meningococcal vaccines. It
is expected that the report will provide the scientific basis for review and
adjudication of claims of vaccine injury by the VICP.
HRSA presented a list of specific adverse events for the committee to
review (see Table 1-1). The selection criteria were described at the first
committee meeting (Johann-Liang, 2009) as including the vast majority of
adverse events in the claims for compensation. The committee added ad-
verse events to the list if it identified epidemiologic studies or case reports
1 Adverse events are distinguished from adverse effects in that an event is something that
occurs but may not be causally associated, whereas an adverse “effect” implies causation. All
adverse effects are adverse events, but not all adverse events are adverse effects.
2 Vaccines are included in the VICP if they are recommended by the CDC for routine admin-
istration in children and are subject to an excise tax. Adults who experience an adverse reac-
tion to one of these “childhood” vaccines are also covered by the program.
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TABLE 1-1 Adverse Events Included in the Vaccine Chapters
DT–, TT–,
and aP– Injected-
MMR Varicella Influenza Hepatitis Hepatitis HPV Containing Meningococcal Related
Vaccine Vaccine Vaccine A Vaccine B Vaccine Vaccine Vaccines Vaccine Events
Adverse Event Chapter 4 Chapter 5 Chapter 6 Chapter 7 Chapter 8 Chapter 9 Chapter 10 Chapter 11 Chapter 12
●
Disseminated Oka VZV
without Other Organ
Involvement
●
Disseminated Oka VZV
with Subsequent Infection
Resulting in Pneumonia,
Meningitis, or Hepatitis
●
Vaccine Strain Viral
Reactivation without Other
Organ Involvement
●
Vaccine Strain Viral
Reactivation with
Subsequent Infection
Resulting in Meningitis or
Encephalitis
●
Measles Inclusion Body
Encephalitis
● ● ● ● ●
Encephalitis
● ● ● ● ● ●
Encephalopathy
●
Infantile Spasms
31
continued
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TABLE 1-1 Continued
32
DT–, TT–,
and aP– Injected-
MMR Varicella Influenza Hepatitis Hepatitis HPV Containing Meningococcal Related
Vaccine Vaccine Vaccine A Vaccine B Vaccine Vaccine Vaccines Vaccine Events
Adverse Event Chapter 4 Chapter 5 Chapter 6 Chapter 7 Chapter 8 Chapter 9 Chapter 10 Chapter 11 Chapter 12
● ● ❍ ● ●
Seizures
❍ ●
Meningitis
●
Cerebellar Ataxia
● ●
Ataxia
● ●
Autism
● ● ● ● ● ● ● ●
Acute Disseminated
Encephalomyelitis
● ● ● ● ● ● ● ●
Transverse Myelitis
❍ ❍ ❍ ❍
Optic Neuritis
❍ ● ● ●
Neuromyelitis Optica
● ● ● ● ● ● ●
Multiple Sclerosis
●
First Demyelinating Event
● ● ● ● ● ● ● ●
Guillain-Barré Syndrome
● ● ● ● ● ● ●
Chronic Inflammatory
Disseminated
Polyneuropathy
● ●
Opsoclonus Myoclonus
Syndrome
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● ● ●
Bell’s Palsy
● ● ● ●
Brachial Neuritis
●
Amyotrophic Lateral
Sclerosis
❍ ●
Small Fiber Neuropathy
● ● ● ● ● ● ● ●
Anaphylaxis
●
Chronic Urticaria
●
Serum Sickness
●
Asthma
❍
Erythema Nodosum
● ●
Systemic Lupus
Erythematous
● ●
Vasculitis
● ●
Polyarteritis Nodosa
●
Psoriatic Arthritis
●
Reactive Arthritis
●
Rheumatoid Arthritis
●
Juvenile Idiopathic
Arthritis
● ● ● ● ●
Arthropathy
(Arthralgia and Arthritis)
33
continued
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TABLE 1-1 Continued
34
DT–, TT–,
and aP– Injected-
MMR Varicella Influenza Hepatitis Hepatitis HPV Containing Meningococcal Related
Vaccine Vaccine Vaccine A Vaccine B Vaccine Vaccine Vaccines Vaccine Events
Adverse Event Chapter 4 Chapter 5 Chapter 6 Chapter 7 Chapter 8 Chapter 9 Chapter 10 Chapter 11 Chapter 12
● ● ●
Type 1 Diabetes
●
Hepatitis (Autoimmune)
●
Myocarditis
●
Pancreatitis
● ●
Hepatitis
●
Thromboembolic Events
❍ ●
Stroke
●
Hypercoagulable States
●
Myocardial Infarction
●
Chronic Fatigue Syndrome
●
Chronic Headaches
● ● ● ●
Fibromyalgia
●
Sudden Infant Death
Syndrome
●
Hearing Loss
❍
All-Cause Mortality
●
Oculorespiratory Syndrome
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●
Thrombocytopenia
●
Immune Thrombocytopenic
Purpura
●
Complex Regional Pain
Syndrome
●
Deltoid Bursitis
●
Syncope
NOTE: Adverse events indicated by “❍” were added to the list by the committee.
35
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36 ADVERSE EFFECTS OF VACCINES: EVIDENCE AND CAUSALITY
for an adverse event not originally assigned by HRSA. These additions were
all-cause mortality and seizures following influenza vaccine; optic neuritis
following MMR, influenza, hepatitis B, and diphtheria, tetanus, and pertus-
sis (DTaP) vaccines; neuromyelitis optica and meningitis following MMR
vaccine; erythema nodosum following hepatitis B vaccine; and stroke and
small fiber neuropathy following varicella vaccine.
The committee was also tasked with addressing, as time and evidence
allowed, general considerations. These included: underlying (susceptible)
populations, “immune dysfunction,” vaccine administration issues, appro-
priate time intervals for anaphylaxis and autoimmune diseases, and sequen-
tial vaccination issues. The committee addressed some of these, as described
in Chapters 4–12. It is important to note that the committee was not tasked
with assessing the benefits (effectiveness) of vaccines or any policy issues
related to vaccination. The task is clearly focused on an assessment only of
the risk of vaccines.
COMMITTEE PROCESS
The committee was composed of individuals with expertise in pediat-
rics, internal medicine, neurology, immunology, immunotoxicology, neu-
robiology, rheumatology, epidemiology, biostatistics, and law. Appendix F
includes biographical sketches of the committee members. The committee
met eight times between April 2009 and March 2011. The committee held
open sessions at three of these meetings. Appendix G includes agendas of
these open meetings. The committee’s methodology and approach to their
task is described in Chapter 2.
OUTLINE OF THE REPORT
Chapter 2 details the committee’s methodology. Chapter 3 discusses
generally possible mechanisms of vaccine injury. Chapters 4–11 present the
evidence reviewed by the committee for each of the eight vaccines covered
and the conclusions it reaches. Chapter 12 presents causality assessments
for adverse events that can occur with any injected vaccine regardless of
the vaccine antigen and components. The committee discusses some special
considerations of its work in Chapter 13.
REFERENCES
CDC (Centers for Disease Control and Prevention). 2001. Vaccinia (smallpox) vaccine rec-
ommendations of the Advisory Committee on Immunization Practices (ACIP), 2001.
Morbidity & Mortality Weekly Report 50(RR-10).
CDC. 2008. Human rabies prevention. Morbidity & Mortality Weekly Report 57(RR-3):1-36.
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37
INTRODUCTION
CDC. 2010. History of vaccine safety. http://www.cdc.gov/vaccinesafety/Vaccine_Monitoring/
history.html (accessed August 1, 2011).
Guyer, B., M. A. Freedman, D. M. Strobino, and E. J. Sondik. 2000. Annual summary of
vital statistics: Trends in the health of Americans during the 20th century. Pediatrics
106(6):1307-1317.
HHS (U.S. Department of Health and Human Services). 2010. Deaths: Final data for 2007.
National Vital Statistics Reports 58(19).
IOM (Institute of Medicine). 1991. Adverse effects of pertussis and rubella vaccines: A report
of the committee to review the adverse consequences of 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 vaccine and autism.
Washington, DC: National Academy Press.
IOM. 2001b. Immunization safety review: Thimerosal-containing vaccines and neuro-
developmental disorders. Washington, DC: National Academy Press.
IOM. 2002a. Immunization safety review: Hepatitis B vaccine and demyelinating neurological
disorders. Washington, DC: The National Academies Press.
IOM. 2002b. Immunization safety review: Multiple immunizations and immune dysfunction.
Washington, DC: National Academy Press.
IOM. 2003a. Immunization safety review: SV40 contamination of polio vaccine and cancer.
Washington, DC: The National Academies Press.
IOM. 2003b. Immunization safety review: Vaccinations and sudden unexpected death in
infancy. Washington, DC: The National Academies Press.
IOM. 2004a. Immunization safety review: Influenza vaccines and neurological complications.
Washington, DC: The National Academies Press.
IOM. 2004b. Immunization safety review: Vaccines and autism. Washington, DC: The
National Academies Press.
Johann-Liang, R. 2009. Charge to the Institute of Medicine Committee to Review Adverse
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