Studies on Vaccine Safety

Dr. Digambar Ambikar

Dr. Digambar Ambikar 1

• A vaccine is a biological preparation that
improves immunity to a particular disease.
• Vaccines are among the most cost-effective
and prevalent public health interventions.
• Morbidity & mortality declined where
immunizations are practiced.
• Vaccine safety is prime for:
- Public
- Manufacturer
- Immunization providers
- Recipients of vaccines
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• No vaccine is completely safe or completely
effective, while all known vaccine adverse events are
minor and self-limited, some vaccines have been
associated with rare but serious health effects.
• Knowledge and research capacity has been limited
by:
– Inadequate understanding of biologic mechanisms
underlying adverse events.
– Insufficient information from case reports & case
series.
– Limitations of existing surveillance systems to provide
evidence of causation.
• To overcome these limitations, Epidemiology is vital
in providing scientific methodology for assessing
vaccine safety.
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• IMPORTANCE OF VACCINE SAFETY
• Decrease in disease risks and increased attention on
vaccine risk.
• Public confidence in vaccine safety is critical
- Higher standard of safety.
- Vaccines are generally healthy.
- Lower risk tolerance= Need to search for a rare
reaction
- Vaccination is universally recommended and
mandated.
• Ongoing safety monitoring needed for the
development of the sound policies and
recommendations.
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• METHODS OF MONITORING VACCINES SAFETY

• There are two methods of monitoring vaccines:

1. Pre-licensure
2. Post-licensure

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• PRE-LICENSURE MONITORING
• Vaccines like other pharmaceutical products,
undergo extensive safety and efficacy evaluations
in the laboratory.
• Pre-licensure studies are carried out on :
- Animals
- Humans

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• Prelicensure human studies
• Phase I, II, III trials
• Common reactions are identified
• Vaccines are tested in thousands of persons
before being licensed and allowed on market
• Most trials involve patients but screening and
prevention involves healthy volunteers

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• If the vaccine is shown to be safe and effective in
Phase- III, the manufacturer applies for a license
from the FDA.
• The FDA licenses the vaccine itself and licenses
the manufacturing plant where the vaccine will
be made.
• During the application, FDA reviews:
1. The clinical trials results
2. Product labeling
3. The manufacturing plant
4. The manufacturing protocol
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• POST-LICENSURE MONITORING
• Identifies rare reactions
• Monitor increases in known reactions
• Identify risk factors for reactions
• Identify vaccine lots with unusual rates or types of
events
• Identify signals

• Phase IV studies can be an FDA requirement for

licensure.
• These trials include tens of thousands of volunteers
and may address questions of long-term
effectiveness and safety or examine unanswered
questions identified in Phase III clinical trials
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• VAERS

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• VAERS ADR REPORTING FORM

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• ADE CLASSIFICATIONS
• Adverse events following vaccination can be
classified by:
• Frequency (Common, Rare)
• Extent(Local, Systemic)
• Severity(Hospitalization, Disability and Death)
• Causality and Preventability (Intrinsic to vaccine,
faulty production or faulty administration)

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• CLASSIFICATION
• Adverse events are divided after vaccinations
into:
1. Vaccine-induced
2. Vaccine-potentiated
3. Programmatic error
4. Coincidental

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1. Vaccine-induced
Due to intrinsic characteristic of the vaccine
preparation & individual response of the vaccine,
these events would not have occurred without
vaccination.
E.g., vaccine-associated paralytic poliomyelitis after
oral polio vaccine.
2. Vaccine-potentiated
Would have occurred anyway, but were precipitated
by the vaccination.
E.g., first febrile seizure in a predisposed child.
3. Programmatic error
Due to technical errors in vaccine preparation,
handling, or administration.
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4. Coincidental
Associated temporally with vaccination by chance
or due to underlying illness.

• METHODOLOGIC PROBLEMS
1. Signal Detection
2. Assessment Of Causality
3. Exposure
4. Outcome
5. Analyses, Confounding & Bias
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 1. SIGNAL DETECTION
• Vaccines are biologic rather than chemical in
nature.
• Variation in rate of adverse events by
manufacturer or even lot might be expected.
• Surveillance systems need to detect such
potential aberrations in a timely manner.
• Many vaccinations are administered to
individuals: simultaneously or as combination
vaccine, unless the number of persons who also
receive that exact permutation of vaccine
exposures is known, it may be difficult if not
impossible to know if an aberration has occurred.
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• Vaccine safety surveillance systems:
• Examine multiple exposures (e.g., different
vaccine antigens, manufacturers, lot numbers)
and multiple disease outcomes.
• Monitor both previously known and previously
unknown adverse events

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 2. ASSESSMENT OF CAUSALITY
• Vaccine-specific clinical syndrome.
e.g.myopericarditis in healthy young adults -
smallpox vaccine : must be identified for
assessing any adverse event caused by vaccine.
• Information useful for assessing causality in
individual case reports includes:
1. Previous general experience with vaccine
- Duration of licensure
- Number of vaccinees, whether similar events
have been observed among other vaccinees or
nonvaccinees
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2. Alternative etiologies.
3. Individual characteristic of the vaccinees that
may increase the risk of the adverse event.
4. Timing of events.
5. Characteristic of the event (e.g., laboratory
findings)
6. Re-challenge.

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3. EXPOSURE
• Misclassification of exposure status occur if there
is poor documentation of vaccinations.
- Increases in number of licensed vaccines
- Relative lack of combination vaccines
• Leads to vaccination history misclassifications.

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4. OUTCOME
• Events being assessed are frequently extremely
rare (e.g., encephalopathy, GBS).
• So identifying cases for interpretation of study
findings is a major challenge.
• Many adverse events caused by vaccines are
poorly defined clinical syndromes.(e.g.,
encephalopathy, GBS)
• The poor understanding & lack of diagnostic tools
for these syndromes limits clinical &
epidemiologic studies of these illnesses.
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5. ANALYSES, CONFOUNDING & BIAS
• Since vaccines can lead to series of outcomes, cohort
studies can be considered.
• In this adverse events & person-time risks are
evaluated.
• When outcomes are rare, these studies become time
consuming and expensive.
• Case-control studies are also carried out in case of
rare adverse effects.
• Once a vaccine is licensed, it is unethical to withhold
the vaccine in subsequent randomized trials as a
means to minimize confounding and bias.
• To minimize recall bias, it is best to rely on data
sources that gather information on outcomes and
vaccine exposure independently.
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• AD HOC EPIDEMIOLOGIC STUDIES
• Ad hoc epidemiologic studies are employed to
assess signals of potential adverse events caused
by :
• Spontaneous reporting systems
• Medical literature
• Other mechanisms.
• Cohort, case–control studies : used to gather
information to measure or compare risks of an
adverse event following vaccination with risk in
the absence of vaccination.
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• AUTOMATED LARGE-LINKED DATABASES

• Automated large-linked databases provide a

more cost-effective and flexible framework.
• Ad hoc epidemiologic studies is needed in
settings without automated large-linked
databases or where the power of the automated
large-linked databases may be inadequate to
answer a question in a timely manner.
• Eg: VSD by CDC

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• VACCINE SAFETY DATALINK(VDC)

• In 1990, CDC established the Vaccine Safety

Datalink (CDC) project to improve scientific
understanding of vaccine safety.
• This project involves partnerships with 10 large
managed care organizations(MCOs) to monitor
vaccine safety.
• Each participating organization gathers data on
vaccination (vaccine type, date of vaccination) ,
medical outcomes(outpatients visits, inpatients
visits, urgent care visits), birth data and census
data.
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• Clinical immunization safety assessment network

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