2. What is vaccination?
• Vaccination is the administration of antigenic material (the vaccine) to
produce immunity to a disease.
• Vaccines can prevent or ameliorate the effects of infection by a
pathogen.
• Vaccination is considered to be the most essential and cost-effective
method of preventing infectious diseases.
3. Where the vaccination is needed?
• Morbidity and mortality attributable to vaccine-preventable diseases
are declined.
• High rates of vaccination, low incidence of vaccine preventable
disease and adverse events after immunization has been the matter
of concern.
4. Safety of Vaccines
• An extensive review of vaccine safety by Institute of medicine(IOM)
found that knowledge & research capacity has been limited due to:
Inadequate understanding of biologic mechanisms underlying
adverse event
Insufficient information from case reports and case series
Inadequate size and length of follow-up many population
based epidemiologic studies
Limitations of existing surveillance systems to provide
persuasive evidence of causation
• The IOM concluded if research capacity and accomplishments are not
improved, future reviews of vaccine safety will be handicapped
5. Clinical Problems in
Pharmacoepidemiological Research
Policy Issues
• Physico-chemical properties
• Lower risk tolerance of vaccines
e.g. the event that occur at ~ 1/1000000-1/10000000 doses, such as
acute encephalopathy after whole cell pertussis vaccine, GBS
(Group-B Streptococcal) after swine influenza vaccine .
• Exposure of vaccines to large number of people by public health
authorities - Mandatory vaccination
• Herd immunity.
• Exposure to vaccine universally “first do no harm”, it applies more
in public health than in clinical medicine
• Eg: Cutter incident - the administration of inactivated polio vaccine
to about 4 lakh persons resulted in 260 polio cases.
6. Error in production
• Eg:polio vaccine contaminated by simian virus 40
• Exposure of high levels of ethyl mercury from thimerosal preservative
in vaccine – highlights the importance of safety concerns the basis of
strict regulatory control by FDA & WHO.
• Vaccine safety studies have narrow margins for error-high standards
of accuracy & timeliness are needed
• Vaccines generally have few alternative strains or types-decision to
withdraw a vaccine or switch between strains depends on risk benefit
perspective
• Eg:the decision of license withdrawal of Mumps vaccines containing
the Urabe strain due to the risk of vaccine associated Meningitis
without an alternative in UK.
7. • Certain countries have compensation programme for persons injured
by vaccination
• Eg: In US vaccine injury table contains vaccine which contains data
necessary for the assessment of adverse events caused by specific
vaccines
• Periodic revision of vaccine injury table leads to the manufacturers the
importance of improving the quality of vaccines
• Recommendations for the use of vaccines depends on the balance of
risk & benefits
• Research in vaccines safety help to distinguish true vaccine reactions
from coincidental events
• It helps to maintain public confidence in immunization
8. Clinical Issues
• Evaluation of safety & efficacy in laboratory for vaccines is equally
important as other pharmaceutical products before licensure.
Phase 1 trial
• Require subjects in tens
• Detect extremely common adverse events
Phase 2 trial
• Enroll hundreds of subjects
• Helps in concluding
• The relationships between concentration of antigen
• No of vaccine components
9. Phase 3 trial
• Sample size - larger.
• Based on efficacy considerations.
• Inferences on safety depends on sample sizes & duration of observation.
• Formulation techniques
• Effect of successive doses
• Profiles of common reactions
Management, prevention or treatment of vaccine adverse event-
rudimentary stage.
Subspecialties with adequate referral base & research funds are
needed
10. Methodological Problems
1. Signal Detection
• Surveillance systems help in detecting the adverse events of
vaccines in timely manner.
• Vaccine safety Surveillance system should examine multiple
exposures and multiple disease outcome
• The sensitivity and specificity depends on the goal of
surveillance.
• Sensitivity- detection of a previously unknown illness or
syndrome
• Specificity- tracking a known disease
11. 2) Standard Definitions and Evaluative Protocols
– Case Definitions are used at the time of reporting or at the time of analysis
to improve specificity.
• Application of definitions at the time of reporting:
o Reduces the no of reports processed
o Lowers the operating cost .
o Sensitivity of surveillance –low.
• If the reporting form is open ended-
o sensitivity of surveillance greater.
o Cost will be higher.
• Advancement of scientific knowledge will be hindered in
immunization safety due to lack of standard case definitions
12. 3) Assessment of causality
Assessment of vaccine associated adverse events is not
possible unless …
o A vaccine specific clinical syndrome is observed
o Recurrence upon rechallenge
o Vaccine specific laboratory finding
• Epidemiologic studies are necessary to assess whether
vaccinated persons are at higher risk than unvaccinated
persons if adverse event occur in absence of vaccination.
13. 4) EXPOSURE
• Documentation of exposure status is important to
prevent misclassification
• Poor documentation due to
o Substantial mobility between health care providers
o Substantial difficulty may be encountered in ascertaining
vaccination status- In older persons
• Immunization card recorder
14. 5) OUTCOME
• Assessing the rare events due to vaccination is major challenge
• According to Institute of Medicine committee a study may be
technically feasible but logistically infeasible
• The other difficulty in assessing the rare events in populations
less frequently exposed is inadequate study power.
15. 6) Analysis, Confounding and Bias
• Childhood vaccines are administered on schedule, here age is
the confounding factor.
• Factors which are difficult to control leads to delayed
vaccination or non vaccination.
• eg: low socio economic status.
16. Currently Available Solutions
Pre-licensure
• Separate, large scale, long term, randomised experimental
trials-needed to better assessment of serious vaccine risks.
• Broadening the assessment of pre and post licensure is
necessary.
• Data & safety monitoring boards (DSMBs) represents
another area of potential improvements in the pre-licensure
process.
17. Post Licensure
1. Spontaneous Reporting Systems(SRS):
• Informal or formal passive surveillance or SRS have been the
corner stone of most vaccine safety monitoring system due to
low cost of operations.
• Vaccine manufacturers also maintain SRS for their products,
which are usually forwarded to appropriate national
regulatory authorities.
18. • Administration of vaccines →healthcare providers +surveillance
system/regulatory agency →develops vaccine adverse event
reporting system (VAERS).
• To increase sensitivity VAERS form is designed & computerized to
permit narrative descriptions of adverse events .
• Reporting forms containing check-off boxes for specific events with
accompanying case definitions have been developed in certain
countries.
• A field guidelines for implementation of monitoring of adverse
events following immunization (AEFI) has recently been developed
by WHO.
19. 2) Classifications & Case Definitions
• Vaccine adverse events can be classified into :
• Frequency (common, rare)
• Extend (local or systemic)
• Severity
• Causality
• Preventability
20. Recent classification divides adverse events after vaccinations
into:
1. Vaccine-induced
2. Vaccine-potentiated
3. Programmatic error
4. Coincidental
Dutch system-classification of reports:
1.Simple-a single vaccine injection & a single major reaction
2.compound-a single vaccine injection & more than one major reaction
3.Multiple->1vaccine injection in the same person & 1 major reaction
4.Compound multiple->1 vaccine injection in the same person & >1
major reaction
21. 3) Standardized Clinical Assessment Protocols &
Centers:
4 Assessment of Causality:
Depends on :
1. Strength of association
2. Analytic bias
3. Biologic gradient /dose response
4. Statistical significance
5. Consistency
6. Biologic plausibility/coherence
22. 5) Signal Detection
• Identifying a potential new vaccine safety problem (signal) requires a mix of
clinical intuition& epidemiologic expertise.
• VAERS is one of the largest registries for rare vaccine adverse events in the
world.
• Eg; bell’s palsy was detected in recipients of a new Swiss intranasal influenza
vaccine.
• Due to its ease of implementation & interpretation, the proper reporting rate
ratio (PRR) method is the most widely used disproportionality measures in
VAERS for prospective and retrospective signal generation.
23. 6) Mass Immunization Campaigns
• Whenever a very large number of vaccine doses are administered over a well
defined short time interval, results in more prominent clusters of vaccine
adverse events.
• Surveillance of vaccine adverse events around the time of mass immunization
campaigns have been extremely useful in generating signals, either positive (eg
: GBS after polio vaccine) or negative ( eg: GBS after meals)
• VAERS type of data has helps to identify potential risk factors for vaccine
adverse events.
24. 7) Clinical Trials
A) Post-licensure clinical trials
• Optimization of vaccine use is done by clinical trials after licensure
to assess the effect of changes in
• Vaccine formulation
• Vaccine strain
• Age at vaccination
• The number and timing of vaccine doses
• Simultaneous administration
• Interchangeability of vaccines from different manufacturers
25. B) Phase 4 Surveillance Studies
• Improves the ability to detect adverse events that are not detected
during pre-licensure trials
C)Ad-Hoc Epidemiologic Studies
• Assess signals of potential adverse events generated by spontaneous reporting
systems, the medical literature or other mechanisms
• Eg of ad-hoc follow up studies to signals of vaccine safety issues are SIDS
after DTP vaccination.
D) Automated Large-linked Databases
• Development of automated large link data bases may permit improved ability
to monitor the safety of such post-licensure changes in vaccine without
conducting such clinical trials
26. Methodological Approaches
1. Exposures
• Vaccination records: helps to find out the exposure of vaccine in each
individual.
• The data can be easily retrieved & reviewed for any study design.
• Automated vaccination records :
• Ease the logistics of organizing the studies.
• Assess the accuracy of automated data in each study
27. • When persons receive the vaccination from a variety of providers, their
exposure status may be misclassified. This error could be minimized if a
Centralized National Vaccination Registry were implemented to track all
vaccination from birth.
• Vaccine Identification Standards Initiative (VISI) – organized by CDC to
improve the accuracy and efficiency of transfer of vaccine identification
information.
2. Outcomes
• To ensure both high sensitivity & specificity, a sequential approach is
required.
• E.g. for a study of neurologic illness following DTP immunization-
medical records of these patients reviewed to see if they met the case
definition. For outcomes with insidious onset like multiple sclerosis
sources of information need to be collected & analyzed.
28. 3) Analysis
• The case cross over or case series approaches are gaining popularity
in vaccine safety studies
4) Bias
• To minimize it is best to rely on data sources that gather information
on outcomes and vaccines exposure independently.
