Epidemiological aspects of Vaccine Preventable Diseases (VPD) Biagio Pedalino

What’s so special about VPD?

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

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

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

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

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)

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

Progress Toward Polio Eradication Decrease of >99% from >350 000 cases in 1988 to <2000 cases in 2008 35,251 cases Polio cases have decreased by over 99% since 1988, from an estimated more than 350 000 cases to 1919 reported cases in 2002 (as of 16 April 2003). 2 14

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

All susceptible

Basic reproductive number: R0=4

Mass vaccination

Mass vaccination

Effective reproductive number: R < 1

Impact of mass vaccination programme Annual measles notifications & vaccine coverage Poland 1960-2000 Source: National Institute of Public Health – National Institute of Hygiene, Warsaw, Poland

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

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

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

Impact of mass vaccination programme Annual measles notifications & vaccine coverage Poland 1960-2000 Source: National Institute of Public Health – National Institute of Hygiene, Warsaw, Poland

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

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?

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

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

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

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

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

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

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

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

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.

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

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%

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; 63:1055-68

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

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

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.

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

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

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

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.

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

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

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