0. Epidemiological aspects of Vaccine Preventable Diseases (VPD)
Biagio Pedalino

1. What’s so special about VPD?

2. Vaccines: what are they?
A vaccine is a biological preparation (microorganism, toxoid, subunit)
Stimulates the body's immune system to create antibodies against this microorganism
A vaccine aims to safely protect a healthy individual/population from a particular infection
Vaccines need to be assessed before and after licensing

3. Objectives of the presentation
To define key aims and effects of different vaccination programmes
To identify key principles in vaccination programme evaluation
Disease surveillance
Vaccine uptake (coverage)
Vaccine effectiveness
Vaccine safety

4. Aims of vaccination programmes
To protect those at highest risk
(selective vaccination strategy) or
To eradicate, eliminate or control disease
(mass vaccination strategy)

5. Selective vaccination strategy
Vaccine given specifically to those at increased
risk of disease
High risk groups
e.g. pneumococcal, meningococcal
Occupational risk
e.g. hepatitis B, influenza
Travellers
e.g. yellow fever, rabies, hepatitis A
Outbreak control
e.g. hepatitis A, measles

6. Selective vaccination strategy
Vaccine targeted at a specific group (although risk of disease affects another)
Girls and young women (~13-26 yrs)
e.g. HPV, rubella
Pregnant women
e.g. tetanus (neo-natal tetanus)

7. Mass vaccination Eradication Elimination Control
Infection (pathogen) has been removed worldwide e.g. smallpox
Elimination
Disease has disappeared from one area but may remain elsewhere, e.g. polio, measles
Control
Disease no longer constitutes a significant public health problem in certain countries, e.g. neo-natal tetanus

8. Progress Toward Polio Eradication
Decrease of >99% from > cases in to <2000 cases in 2008
35,251 cases
Polio cases have decreased by over 99% since 1988, from an estimated more than cases to 1919 reported cases in 2002 (as of 16 April 2003). 2 14

9. How do mass vaccination programmes impact the disease?
Reduce size of susceptible population
Reduce number of cases
Reduce risk of infection in population
Reduce contact of susceptibles to cases
Lengthening of epidemic cycle (“honeymoon phase”)
Increase mean age of infection 2

10. All susceptible

11. Basic reproductive number: R0=4

12. Mass vaccination

13. Mass vaccination

14. Effective reproductive number: R < 1

15. Impact of mass vaccination programme Annual measles notifications & vaccine coverage Poland
Source: National Institute of Public Health – National Institute of Hygiene, Warsaw, Poland

16. Objectives of the lecture
To understand key aims and effects of different vaccination programmes
To understand key principles in vaccination programme evaluation, specifically
Disease surveillance
Vaccine uptake (coverage)
Vaccine effectiveness
Vaccine safety

17. Considerations behind the epidemiology of vaccine-preventable diseases
Surveillance reflects programme
vaccination history and disease dynamics (e.g. change age of vaccination; change number of doses)
Immunization is population-based
role of herd immunity
Vaccine efficacy needs monitoring

18. Surveillance of VPD Pre-implementation Post implementation
estimate burden
decide vaccination strategy
Post implementation
monitor impact and effectiveness
Nearing elimination
identify pockets of susceptibles
certification process

19. Impact of mass vaccination programme Annual measles notifications & vaccine coverage Poland
Source: National Institute of Public Health – National Institute of Hygiene, Warsaw, Poland

20. Surveillance of VPD
Disease incidence (before and after introduction of vaccine)
Vaccine uptake (coverage)
Vaccine effectiveness
Serological surveillance
Adverse events
Knowledge and attitudes

21. Key data to collect for surveillance of vaccine preventable diseases
Person
Age
Place
Residence
Time
Date of disease onset
Date of specimen collection
Vaccination status
Vaccine failure or failure to vaccinate?

22. Additional data for diseases of special interest or being eliminated
Person
Age, gender, profession, etc.
Place
Residence, possible sites of exposure, hospital, etc.
Time
Date of rash onset, location during possible exposure period, location during infectious phase, etc.
Vaccination status
Number of doses
Date of doses

23. Disease incidence Main sources of data Other sources
statutory notification
laboratory reporting
death registrations
Other sources
hospital episodes
sentinel GP reporting
paediatric surveillance

24. Surveillance of vaccine coverage
Number of vaccines distributed
Number of vaccines administered
sampling population assessment, e.g. cluster
total population assessment (administrative)
Number of doses of vaccine given/used
Total (target-)population

25. Use of administrative coverage data
Usually total population
Monitor trends over time
Look for pockets of poor coverage
Compare with disease epidemiology
Estimate vaccine effectiveness

26. Efficacy, effectiveness, herd immunity and impact
is the direct protection to a vaccinated individual as estimated from clinical trial
Effectiveness
is an estimate of the direct protection in a field study post licensure
Herd immunity
is an indirect effect of vaccination due to reduced disease transmission
Impact
is the population level effect of a vaccination programme. This will depend on many factors such as vaccine coverage, herd immunity and effectiveness
In fact there are two components of vaccine protection - direct and indirect effect.
Direct effect is the prevention of infection by the vaccine in a vaccinated individual
Indirect effect is the effect of the vaccine at the population level. With increasing coverage, there is a fall in the number of cases and thus sources of transmission in a given population and thus a reduction in the risk of infection in the community - so called herd immunity
Measures of VE (i.e. RCT) are usually randomised at an individual level to eliminate the indirect effect and thus measure only the direct effect of the vaccine, whereas effectiveness trials measure both direct and indirect effects with the unit of allocation groups of individuals

27. Vaccine evaluation Pre-licensing Post-licensing Vaccine efficacy:
randomised, blinded, controlled clinical trials
Vaccine efficacy:
protective effect idealised conditions
Randomised Controlled Trials (RCT), simple interpretation
observational studies
Vaccine effectiveness:
protective effect under ordinary conditions of a public health programme
prone to bias, more complex interpretation
RCT = randomized, controlled trial

28. Efficacy versus effectiveness
Vaccine efficacy Preventable fraction among exposed (Vaccinated)
Study conditions
Independent of vaccine coverage
Vaccine effectiveness Preventable fraction in the population
Field conditions
Later on VE is used interchangeably for efficacy and effectiveness. This could be confusing. 28

29. Factors influencing field vaccine efficacy (effectiveness)
Host
age at vaccination (e.g., measles, influenza)
immune status (e.g., measles)
number and timing of doses (e.g., Hepatitis B)
years since vaccination (e.g., pertussis)
Vaccine
production
storage (e.g., temperature, light)
transportation
route of administration
Agent
strains included in the vaccine formulation 29

30. Methods to assess VE Pre-licensure:
randomised control trial (RCT)
Post-licensure: observational/field investigation
cohort study / case-control study
screening method
household contact study
There are several methods to measure VE.
As already mentioned RCT can be used to measure VE (usually prelicensure phase 3a) or vaccine effectiveness (usually phase 4post licensure and increasingly prelicensure phase 3b)
Observational studies are assessments of VE in the field post-licensure, which are are often undertaken in outbreak settings.
There are several methods which we will explore. They can be serological and/or epidemiological. Epidemiological methods include the rapid screening or case population method, cohort studies, family contact studies based on calculating household secondary attack rates, case-control methods and cross-sectional mthods such as EPI cluster sampling technique.

31. Calculating the vaccine efficacy in the field: Reference method
Proportion of cases potentially avoided among vaccinated
Preventable fraction among exposed to a vaccine
Formula
VE = (ARNV - ARV) / ARNV (Cohort study)
VE = 1-OR (Case control study)
Require a confidence interval
Nous allons voir les mesures dans trois contextes différents

32. Vaccinated Unvaccinated 0,9 VE = = 78% ARV = 2/10 = 0,2
ARU = 9/10 = 0,9
Unvaccinated
0,9 – 0,2
0,9
VE =
= 78%

33. Calculating the vaccine efficacy in the field: Rapid screening method
PCV: Proportion of cases vaccinated
PPV: Proportion of the population vaccinated
VE: Vaccine efficacy
Orenstein WA et al. Field evaluation of vaccine efficacy. Bull World Health Organ 1985; 63:

34. Cases may be vaccinated or
Impact of vaccine coverage on vaccination status of cases assuming VE < 100%
Vaccine Coverage
100 %
Cases may be vaccinated or
unvaccinated
All cases vaccinated;
All are primary or
secondary vaccine
failures
All cases
unvaccinated
No vaccine has 100% efficacy 34

35. Potential pitfalls.... case definition vaccine history
case ascertainment
comparability of vaccinated/unvaccinated groups

36. Methodological issues: case definition
Lower specificity: case definition based only on clinical criteria may result in false-positive diagnoses
ARV > ARU
VE (%) = (ARU-ARV) X 100
ARU
artificial reduction in VE
Ideally the case definitions should be both sensitive and specific, but specificity is a more crucial factor than sensitivity.
However if the case definition is non-specific, then background illness may be misclassified as cases. If these false positives distribute equally between vaccinated and unvaccinated, then the AR will rise disproportionately in vaccinated compared to the unvaccinated. Remembering the equation results in an increase in RR - thus resulting in a falsely low estimate of VE.
Sensitivity is important to gain a more precise estimate. Low sensitivity lowers the power of the study, but does not alter the point estimate, providing the sensitivity is the same for vaccinees and non-vaccinees (which we deal with under case-ascertainment) - as you lose both vacc and unvacc cases.

37. Methodological issues: case definition
Changes in mumps vaccine effectiveness
Case definition
Diagnosis
by school nurse
ARV
18%
(12/67)
ARU
28%
(77/272) VE
37%
However when parents were interviewed and a clinical case definition was used which was more specific (parotitis for more than 2 days) - then relatively more cases were excluded from the vaccinated group resulting in an increase in the estimated VE to 52% (more accurate).
Kim Farley et al 1985 AJE

38. Methodological issues: case definition
Changes in mumps vaccine effectiveness
Case definition
Diagnosis
by school nurse
Parotitis > 2 days
ARV
18%
(12/67)
12%
(8/67)
ARU
28%
(77/272)
25%
(68/272) VE
37%
52%
However when parents were interviewed and a clinical case definition was used which was more specific (parotitis for more than 2 days) - then relatively more cases were excluded from the vaccinated group resulting in an increase in the estimated VE to 52% (more accurate).
Kim Farley et al 1985 AJE

39. Methodological issues: vaccine history ascertainment
avoid misclassification of vaccination status
equal effort to confirm vaccination status among cases and non-cases
vaccination histories should be documented using GP, clinic, vaccination cards or computer records
persons with missing vaccination records should be excluded

40. Vaccine effectiveness: post licensure monitoring of VE
Maintenance of VE
Problems in vaccine delivery
cold chain failure, schedule violation, n° of doses, vaccine strain substitution
Epidemiological factors
pathogen changes
Methodological bias
selection bias, confounding, chance effects
Low protective efficacy
bad batch, different target population, alternative patterns of use, vaccine strain used
Increasingly vaccine effectiveness studies are being assessed pre-licensure as part of randomised vaccine effectiveness trials (called phase 3b trials). With measurement of VE under ordinary conditions of PH program
The traditional approach has been to evaluate vaccine effectiveness (VE in the field) post licensure (known as phase 4): to ensure that VE is maintained once a vaccine is introduced into PH practice. This may involve pre-planned evaluations or it may involve outbreak investigations which is often an outbreak in a highly vaccinated population. This may be due to several reasons:
Problems in vaccine delivery. A breach in the cold chain due to failure to store a vaccine at the appropriate temp.
Epidemiological factors: There may be changes in the pathogen, for example antigenic shift of influenza resulting in a decrease in current VE
Methodological bias
Low protective efficacy: The vaccine may have been administered to a different target population. For example pneumococcal vaccine phase 3 VE trials were conducted among young, healthy populations such as students. However. the vaccine post-licensure was targeted at the elderly, where VE was then found to be lower. Alternative patterns of use such as the simultaneous use of vaccines or other medicines may affect VE in PH practice eg following the death of a peace corps worker from rabies, who had been given rabies vaccine while taking chloroquine, it was realised that chloroquine inhibits the immune response to id admininstered rabies vaccine.

41. Herd immunity Definition Depends on:
Resistance of a group to a disease to which a large proportion of the members are immune
Decreases the probability of contacts between infected patients and susceptible individuals *
Depends on:
Infectiousness of the agent
Hepatitis A lower than measles
Population density
Target herd immunity for measles control
95% in general
May be lower in lower population density areas
* Adapted from Fox, et al. Am J Epidemiol. 1971; 94:179-89

42. What is different about surveillance of vaccine preventable diseases?
It’s not just about the disease
Decision making is a complex issue
Objectives change at different stages
It includes vaccine effectiveness
Adverse events following immunization (AEFI) - Vaccine safety issues
Case definitions have to change as the epidemiology changes
Surveillance methods have to change as the epidemiology changes
Follow-up of cases in more detail (remember vaccination status)
Vaccination programs have indirect effects
Surveillance includes Coverage
Surveillance includes Attitudes
N. Crowcroft
Agency for Health Protection and Promotion, Ontario, Canada

43. Questions?
Acknowledgments:
EPIET Vaccination module
HPA Immunisation Training (Richard Pebody, Nick Andrews, John Edmunds, Natasha Crowcroft, Mary Ramsay)
Revised by: Richard Pebody 2007, Pawel Stefanoff 2008, Marion Muehlen 2009, 2010, Biagio Pedalino 2011, 2012
Reference
Orenstein W. Assessing vaccine efficacy in the field. Epidemiological Reviews 1988