Vaccines are not without risk but the risks of vaccine-preventable diseases far outweigh the risks of vaccination. Clinical trials are required to evaluate vaccine safety and efficacy prior to licensure. Rare adverse events may require very large clinical trials to detect. After licensure, ongoing monitoring through observational studies is important to further evaluate safety. Immunization providers play an important role in ensuring vaccine safety through proper vaccine handling, administration, reporting of side effects, and patient education.

1. Vaccine
Pharmacovigilance
Rajiv Ahlawat
Department of Pharmacy Practice, NIPER, Mohali

2. Vaccination is
the top Public
Health
achievement of
the 20th
Century
MMWR 1999; 48:241

4. Vaccine-Preventable Diseases:
Baseline 20th Century & Current Morbidity
Number of Cases
Disease Baseline 2010* % Decrease
Smallpox 48,164 0 100.00
Diphtheria 175,885 0 100.00
Measles 503,282 57 99.99
Mumps 152,209 2,528 98.34
Pertussis 147,271 21,291 85.54
Polio (par.) 16,316 0 100.00
Rubella 47,745 6 99.99
CRS 823 0 100.00
Tetanus 1,314 8 98.39
Hib 20,000 16 99.92
MMWR 1999;48:245, 2011;59:1700

5. Vaccine provide by Govt. of India
Govt. of India is providing vaccination to prevent 7
vaccine preventable diseases(VPDs)namely,
– Diphtheria,
– Pertussis,
– Tetanus,
– Polio,
– Measles,
– Hepatitis B
– BCG
– JE vaccination
– Hib (given as pentavalent containing Hib+DPT+Hep B)

6. Other vaccines….
• Pneumococcal vaccine
• Rotavirus vaccine
• Hepatitis A
• MMR
• Influenza
• Meningococcal
• Cholera
• JE
• HPV
• Varicella
• Typhoid

7. Definition
• According to the CIOMS/WHO Working Group on Vaccine
Pharmacovigilance,
Vaccine pharmacovigilance is defined as “the science and
activities relating to the”
– Detection,
– Assessment,
– Understanding and
– Communication
of adverse events following immunization and other
vaccine- or immunization-related issues, and to the
prevention of untoward effects of the vaccine or
immunization”

8. Importance of Vaccine Safety
• Decreases in disease risks and increased
attention on vaccine risks
• Public confidence in vaccine safety is critical
• Low tolerance for vaccine risks
–Higher standard of safety is expected
–Vaccinees generally healthy (vs. ill for
drugs)
–Lower risk tolerance = need to search for
rare reactions

9. Steps of vaccine Pharmacovigilannce
Test hypothesis through appropriate epidemiological
methods
Develop hypothesis about causal association between an
AEFI and vaccination
Detect signal Suggesting AEFI is related to vaccine

10. Which AEFIs should be reported?
• Serious AEFI
• Signal and events associated with newly
introduced vaccine
• AEFI that may have been caused by an
immunization error
• Significant events of unexplained cause
occurring within 30 days after a vaccination
• Events causing significant parental or
community concern
• Swelling, redness, soreness at the injection site
IF it lasts for more than 3 days or swelling
extends beyond nearest joint

11. Adverse event following immunization
(AEFI)
• Vaccine product-related reaction
– Extensive limb swelling following DTP vaccination.
• Vaccine quality defect-related reaction
– Failure by the manufacturer to completely inactivate a lot of
inactivated polio vaccine leads to cases of paralytic polio
• Immunization error-related reaction
– Transmission of infection by contaminated multidose vial
• Immunization anxiety-related reaction
– Vasovagal syncope in an adolescent during/following
vaccination
• Coincidental event
– Example: A fever occurs at the time of the vaccination (temporal
association) but is in fact caused by malaria.

12. Types of ADR
• Very common ≥ 10%
• Common (frequent) ≥ 1% and < 10%
• Uncommon (infrequent) ≥ 0.1% and < 1%
• Rare ≥ 0.01% and < 0.1%
• Very rare < 0.01%

13. Determining causality
Difficulties in determining causation between events that are linked in
time are common to all drug and vaccine safety monitoring systems.
This is particularly challenging in the case of vaccines, because:
• Information on “dechallenge and rechallenge” is usually missing,
• Vaccines are given to most of the country’s birth cohort at an age
when coincidental disease are likely, Several vaccines are likely to
be administered at the same immunization visit,
• Vaccine storage, handling, transport and administration must
adhere to specific conditions.
• Any of these, if not done correctly, can result in an adverse event.
The possibility of immunization errors therefore must be
investigated.

14. Rate of ADR occurrence
• Observed rate
– Total number of cases reported per 1000 vaccinated children
– Detect in clinical trial or post licensure vaccine safety
• Background rate
– Not related to vaccine
– Occur per 1000 unvaccinated children
– Record prior or simultaneously to vaccination
• Vaccine reaction rate
– Related to vaccine
– Detected in placebo controlled randomized clinical trial, or
passive surveollance or post licensure studies
– Observed rate – background rate

15. Other factors to consider when
comparing rates of AEFIs
• Vaccines Manufaturer
• Age- child vs adloscents
• Vaccine dose- primary vs booster
• Case definition- standard
• Surveillance method- method of
surveillance
• Background condition-background rate of
certain events may differ between
communities

16. Problem
Imagine that rumours begin to circulate about a vaccine
when cases of convulsions following immunization occur
amongst vaccinated infants. The background rate of
convulsions in this population is 1:1,000 infants. The
observed rate in vaccinated infants is 1.2:1,000. What is
the vaccine attributable rate derived from these figures?
– A. 2 additional cases of convulsions in every 1,000
vaccinations, compared with the background rate.
– B. 2 additional cases in every 10,000 vaccinations, compared
with the background rate.
– C. 1.2 additional cases in every 1,000 vaccinations, compared
with the background rate.
– D. 1.2 additional cases in every 10,000 vaccinations, compared
with the background rate.

17. Rotavirus vaccine• Pre-licensure literature noted a suspicion of an increased risk
of intussusception.
• After RotaShield® was licensed for routine use by the public
(approximately one million children vaccinated within the first
nine months licensure) the American vaccine safety
surveillance, Vaccine Adverse Event Reporting System
(VAERS), began to receive reports of intussusception following
administration of the vaccine.
• About 100 (0.01%) of the one million children vaccinated
developed intussusception, 16 a potentially life-threatening
bowel obstruction that occurs for unknown reasons in about
one child per 10 000, regardless of whether or not they have
received a vaccine.
Because of the uncertainty about the relationship between
RotaShield® and intussusception cases following vaccination,
the manufacturer voluntarily took the product off the market in

18. Risk of acquiring illnesses following
infection versus risk following vaccination

19. Source for vaccine safety

20. Risk/benefit assessment
• Required to strengthen the confidence in immunization
programmes.
• Address the population at risk (not the individual at risk),
• Take into account contextual issues (economics, availability of
alternative vaccines, sociopolitical and cultural factors),
• Be prompted by a newly identified risk, but must remain
holistic (e.g. take into account the entire safety profile of a
vaccine, not only the specific information relating to the event
that was detected),
• Run in parallel to active enquiry, cooperation and exchange of
information.

21. Problem
During a mass measles campaign for 7.5 million
children aged from 9 months to 14 years, a 7
year old child developed encephalopathy,
convulsions and died.
– Should the measles campaign be suspended?
– Does the need for action to protect children from
possible vaccine related harm in this situation
outweigh the need for further investigation, or
vice versa?

22. Options for action could include discontinuing the immunization
campaign, withdrawing a vaccine batch, and improving staff
training and communication.
Withdrawing a vaccine lot:
– Advantages: reduces fear of vaccine, renews confidence in
the vaccine or the campaign,
– Disadvantages: cost, potential compromise of the
campaign, loss of confidence in vaccine quality.
Audit injection practices of health workers to identity sources of
immunization errors; investigate the need for improved training
and education.
It is essential to indicate the quality and quantity of any future
evidence necessary to trigger reconsideration of the issue, and
how the outcomes of any actions will be monitored and
assessed.

23. Risk benefit evaluation
• In the country of Kanindistan, there are 5 million children
between the ages of 1–5, and the annual mortality in this age
group is 120/100,000.
• In a mass vaccination campaign, all suitable children between
the ages 15 years are to be vaccinated against Japanese
Encephalitis Virus (JEV). Three million children have been
vaccinated in the first 2 weeks, during which 140 deaths have
been reported following vaccination.
• In the year before the vaccination campaign the risk of
children in the same age range dying of naturally acquired JEV
infection was 5.25/100,000.
Evaluate this information, to determine whether the
risk/benefits of the JEV vaccination campaign outweigh the risks
of the disease.

24. Comparing mortality rates of
unvaccinated vs. vaccinated children.
• With 3 million children vaccinated, the
expected mortality in this group in a 2 week
period is:
3,000,000 x 120/100,000 x 2/52 = 138
• The number of deaths (140) is slightly higher
than this figure.

25. Comparing the risk of children dying from
Japanese Encephalitis (JE) with the excess
mortality among vaccinated children.
• (140 – 138) / 3,000,000 = 1/1,500,000
vaccinated children.
• The risk of dying from the disease
(5.25/100,000) is greater than the excess
mortality associated with the vaccination
(1/1,500,000).

26. Problem
• The country of Rubovia has a population of 60
million and the annual incidence of Guillain Barre
syndrome is 2/100,000 individuals.
• In an immunisation campaign, 5 million adults were
immunised with an influenza A vaccine. In the 8
weeks following immunisation 26 of them
developed Guillain Barre syndrome.
Calculate the vaccine attributable rate of Guillain
Barre syndrome per 100,000 immunised individuals.

27. The expected incidence of Gullain Barre
syndrome in a population of 5million
people in an 8 week period is:
5,000,000 x 2/100,000 x 8/52 =16 (15.4)
The number observed is 26, therefore
the excess is 26 – 16 = 10
The excess incidence is 10/5,000,000 =
0.2/100,000 vaccinated individuals.

28. Role of disease burden studies in the development and
introduction of new and underutilized vaccines
Disease-Burden Studies
Disease Epidemiology
• Geographical distribution
• Age groups
• Seasonality, risk factors
Vaccine
Design
Clinical Evaluation
• Study sites
• Vaccination schedules
& Strategies
Vaccine Utilization
• Target groups
• Impact
• Cost-effectiveness

29. Clinical trials and assessment of
vaccine safety

30. Steps on Vaccine Development1
• Recognize the disease as a distinct entity
• Identify etiologic agent
• Grow agent in laboratory
• Establish in animal model for disease
• Identify an immunologic correlate for immunity to the disease- usually
serum antibody
• Inactivate or attenuate the agent in the laboratory- or choose antigens
• Prepare candidate vaccine following GOOD manufacturing Procedures
• Evaluate candidate vaccine(s) for ability to protect animals

31. Steps on Vaccine Development2
• Prepare protocol(s) for human studies
• Apply to MCC for investigational New drug (IND)
approval
• Phase I human trials- Safety and immugenicity,
dose response
• Phase II trials- Safety and immugenicity
• Phase III trials- Efficacy

32. Steps on Vaccine Development3
• Submit Product Licensure Application MCC approval
• Advisory Committees review and make recommendations
• Marketing Post- Licensure Surveillance for safety and effectiveness
(Phase IV)
• Long and Complicated process
 Usually takes 10-15 years
 Many vaccine candidates fail for every success
 Costs: $ 100- $ 700 million per successful vaccine

33. Vaccine Evaluation
Pre-licensing
Randomised, Blinded,
Controlled Clinical Trials
Vaccine efficacy:
Protective Effect under
Idealised Conditions
RCT: controlled experiments,
simple interpretation
Post-licensing
Observational Studies
Vaccine effectiveness:
Protective Effect under
Ordinary Conditions of a
public health programme
prone to bias, more complex
interpretation

34. Basic Calculation of VE
% reduction in attack rate of disease in vaccinated (ARV)
compared to unvaccinated (ARU) individuals
VE (%) = (ARU-ARV) X 100
ARU
Where
and
Consequently, VE = 1-RR (preventive fraction)
ARU
ARU
1
ARV
ARU
 RR

35. 0,9 – 0,2
0,9
VE = = 78%
Vaccinated
IV = 2/10 = 0,2
IU = 9/10 = 0,9
Unvaccinated
Basic Calculation of VE

36. Methods to Assess VE
• Pre-licensure:
 Randomised control trial (RCT)
• Post-licensure:
Observational/Field investigation
• Screening method
• Cohort study
• Household contact study
• Case-control study

37. Observational study: Screening Method
• Used with Routine Surveillance Data
Take population vaccine coverage (PPV)
Compare with coverage in cases (PCV)
VE = 1 - PCV x (1-PPV)
(1-PCV) x PPV

38. Sample Sizes Needed During Clinical Trials to Detect
Increases in Rates of
Rare Vaccine Adverse Events
Rates of Event (%) Sample Size* No. Potentially Affected
Annually1
0.1 vs. 0.2 50,000 4,000
0.1 vs. 0.3 17,500 8,000
0.05 vs. 0.1 100,000 2,000
0.01 vs. 0.02 500,000 400
0.01 vs. 0.03 175,000 800
* Two-arm, power=80%, alpha (2 sided)=5%
1 If the entire birth cohort (approx. 4 million children) received the vaccine each year
Adapted from Ellenberg SS: Safety considerations for new vaccine development. Pharmacoepidemiol Drug
Safety 10(5):411-5, 2001

39. Vaccine Rare ADRs
Oral polio vaccine (OPV) VAPP very rare (0.0002% – 0.0004% or 2 – 4/1,000,000)
Measales Febrile seizure (uncommon at 0.3% or
1/3000)Thrombocytopenic purpura(very rare at 0.03%
or 1/30,000)
BCG Fatal dissemination of BCG infection (very rare at
0.000019% – 0.000159% or 0.19 – 1.56/1,000,000)
IPV Not Known
Haemophilus influenzatype b conjugate
(Hib)
Not Known
Pneumococcal conjugate, (PCV-7), (PCV-
10)
Not Known
Hepatitis B (HepB) Not Known
Inactivated polio vaccine (IPV) Not Known
Rotavirus Not Known
Vaccine safety . Safety profile of vaccine.
https://extranet.who.int/vaccsafety/en/vaccine/learning/learning/module1/index.html. Accessed on 13 March 2012.

40. Vaccines are Not Without Risk
• No vaccine is 100% safe
• No vaccine is 100% effective
• All vaccines have possible side effects, most mild, rarely
severe
• The risk of disease far outweighs the risk of vaccine

42. The Provider’s Role
• Immunization providers can help to ensure
the safety and efficacy of vaccines through
proper:
–vaccine storage and administration
–timing and spacing of vaccine doses
–observation of precautions and
contraindications

43. The Provider’s Role
• Immunization providers can help to ensure
the safety and efficacy of vaccines through
proper:
–management of vaccine side effects
–reporting of suspected side effects to
VAERS
–vaccine benefit-risk communication

44. Precaution
• A condition in a recipient which may
increase the chance or severity of an
adverse event, or
• May compromise the ability of the
vaccine to produce immunity

45. Invalid Contraindications to Vaccination
 Mild illness
 Mild/moderate local reaction or fever
following prior dose
 Antibiotic therapy
 Disease exposure or convalescence
 Pregnancy in the household
 Premature birth
 Breastfeeding
 Allergies to products not in vaccine
 Family history unrelated to
immunosuppression

46. Vaccine-Associated Paralytic Polio (VAPP)
 OPV is a live attenuated virus
 1 out of 2.4 million doses VAPP
 1997 a IPV/OPV schedule
 2000 an all IPV schedule recommended in US

47. Thank you

48. • Hib (given as pentavalent containing
Hib+DPT+Hep B)
• DPT (Diphtheria, Pertussis and Tetanus Toxoid)