A Proposal for a Collaboration with INDEPTH to Engage in Evaluations of

Vaccine Safety

Presented by

Steven Black, MD

on behalf of PREVENT (PRogram Enhancing Vaccine Epidemiology Networks

and Training)

PREVENT

2

Vaccine Safety in LMICCurrent Status

• Most LMIC countries have limited capacity to implement epidemiological vaccine safety studies In the past, most countries have relied on assessments from

developed countries, where vaccines have been usually licensed initially, or in results from passive surveillance

Passive reporting of AEs alone is not adequate to assess vaccine safety

• Increasing trend towards introduction of new vaccines into LMIC before they are licensed in Europe or the U.S. Rotavirus vaccine in Latin AmericaMeningitis A vaccine in Africa

• WHO Blueprint Project will recommend development of infrastructure in countries where new vaccines are to be introduced

PREVENT

PREVENT Rationale: New Vaccines for LMIC

Many vaccines will likely be introduced in the next decade into LMIC: Typhoid conjugate, Malaria, Cholera Dengue Improved TB vaccines.

Vaccines are in development for other diseases such as hookworm infection, Chagas, sleeping sickness, and others.

3

PREVENT

Example: Malaria

Lessons Learned from Past Vaccine Safety Concerns

• Safety scares can derail new valuable vaccine programs before they are fully implemented

• There is a need for infrastructure and know how

Without a ready infrastructure, responding to scares/ safety issues could take so long that the program could severely damaged by the time an analysis is done.

Prior studies have not built sustainable infrastructure

There is a Need for Country/Region Specific Data: Example: History of Rotavirus Vaccines

• Following licensure of the first rotavirus vaccine in 1998, post-licensure studies showed an attributable risk of intussusception of 1/10,000 vaccinees*In 1999 the manufacturer removed RotaShield from

the market - No rotavirus vaccine was available in any country for at least 5 years…

• Recently, studies in Mexico and Australia, an association was found with a risk of 1:100,000 doses, but the vaccines remained in the marketCDC: “Safety evaluations (and eventually

benefit risk assessments) should be applicable to the specific Region/Country in which the vaccine is being used “

*Kramarz et al., 2001, Murphy et al, 2001

Another Example of the Need for Country/Region Specific Data:

• BCG vaccine in HIV infected childrenHigh risk of disseminated BCG identified

late.

An Example of International Collaborative Vaccine Safety Studies: GBS and H1N1

• Multiple H1N1 influenza vaccines developed/distributed worldwide for pandemic use in 2009-10

• H1N1 vaccines used extensively in population groups not often vaccinated against influenza

• Limited capacity for epidemiological vaccine safety studies in many countriesGBS is a very rare diseaseMost countries do not have sufficient population to

reliably study such a rare event• H1N1 vaccine safety concerns provided opportunity to

demonstrate feasibility of a global collaborative vaccine safety consortium using a standardized protocol

International Collaboration:Proof of concept Study of GBS and H1N1

• Immediate objectives: To pilot an international collaborative approach

towards the implementation of a simple and reliable epidemiological study methodology

To investigate the association between GBS and H1N1 pandemic vaccines

• Final Goal: The validate that this collaborative approach should

be generalizable to other countriesTo justify the establishment of sustainable

infrastructure for a global collaboration which would include developed, middle income and low income countries.  

Participating CountriesBUT - No Low Income Countries Included

Vaccine Safety Assessment in LMIC: The Potential Role of INDEPTH

• Vaccine safety assessment requires stable infrastructure with ability to collect outcome and exposure information after vaccine introduction

• Requires the ability to perform collaborative studies across countries

• Requires epidemiologic expertise to perform the studies, publish them, and explain the results to the local population and MOH.

• INDEPTH has the epidemiologic infrastructure, epidemiologic expertise and the appropriate geographic diversity for the vaccines that are likely to be introduced.

Data Needs: Does INDEPTH Have the Necessary Data?

vaccineData

Hospital And/or Clinic Diagnoses

Survey Outcome Data

Demographic Data onA Population

Exposure information at a minimum for cases

Outcome or Possible“Adverse Event”

NOTE:

•With all three, can calculate rates and attributable risk

•Can do case series with Outcome alone or case control with Outcome and Demographics

13

(PRogram Enhancing Vaccine Epidemiology Networks and Training)

• The Brighton Collaboration has implemented PREVENT to facilitate development of infrastructure for vaccine safety assessment Demonstrate capacity of the INDEPTH and similar

networks to effectively evaluate vaccine safetyProvide Region/Country specific safety dataProvide environment for international collaborative

studies of rare eventsDevelop “best practice” models for evaluations in

LMIC. • PREVENT working group includes: Steve Black ( University of Cincinnati); Jan Bonhoeffer

(Brighton Collaboration); Miriam Sturkenboom (Erasmus University); Hector Izurieta (US FDA), Robert Chen (US CDC); Kayla Laserson (INDEPTH)

PREVENT

Current status

• Proposal developed, “letter of interest” submitted to and under review by the BM Gates Foundation for a five year projectTo develop best proactive models for assessing the

safety of vaccines in LMIC targeted for new vaccine introduction

To develop training programs for the conduct of such studies

To conduct pilot studies to evaluate vaccine safetyTo assess the program and propose models for funding

sustainable infrastructure for ongoing assessment of vaccine safety in LMIC.

PREVENT

Next steps• Conduct pilot assessments at interested sites to assess how

INDEPTH resources can best to used to assess vaccine safety Draft protocol submitted at this meeting for commentsOutcomes to be evaluated in pilot (NOT for vaccine effect)

Common not severe outcomes ( eg fever) Rare outcomes ( possibly seizure or meningitis) Mortality Known “true negative” outcome (to assess bias).

Different case ascertainment methods: HDSS versus hospital based case finding

Different analytic approaches to be considered Cohort Case only methods such as case series

PREVENT

Conclusions

• Increasing focus on development of vaccines targeting the developing world requires safety evaluation infrastructure in the same geographic area.

• In addition, globalization of vaccine manufacturing, requires globalization of safety evaluation.

• Potential variability in susceptibility to adverse events requires a diverse population to evaluate vaccine safety

• INDEPTH would seem to be an ideal platform on which to build this new capacity

• The PREVENT collaboration is proposed to further this end.

• We look forward to a fruitful collaboration with interested INDEPTH sites.

PREVENT