1. 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. 2 Vaccine Safety in LMIC Current 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 America  Meningitis A vaccine in Africa WHO Blueprint Project will recommend development of infrastructure in countries where new vaccines are to be introduced PREVENT

3. 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

4. Example: Malaria

5. 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

6. 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 market  CDC: “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

7. Another Example of the Need for Country/Region Specific Data: BCG vaccine in HIV infected children  High risk of disseminated BCG identified late.

8. 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 countries  GBS is a very rare disease  Most 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

9. 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 countries  To justify the establishment of sustainable infrastructure for a global collaboration which would include developed, middle income and low income countries.

10. Participating Countries BUT - No Low Income Countries Included

11. 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.

12. Data Needs: Does INDEPTH Have the Necessary Data? vaccine Data Hospital And/or Clinic Diagnoses Survey Outcome Data Demographic Data on A 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. 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 safety  Provide Region/Country specific safety data  Provide environment for international collaborative studies of rare events  Develop “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

14. Current status Proposal developed, “letter of interest” submitted to and under review by the BM Gates Foundation for a five year project  To 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 safety  To assess the program and propose models for funding sustainable infrastructure for ongoing assessment of vaccine safety in LMIC. PREVENT

15. 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 comments  Outcomes 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

16. 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