1. 1 Considerations in the Pre- and Early Pandemic Use of Influenza Vaccine Jesse L. Goodman, MD, MPH Center for Biologics Evaluation and Research, VRBPAC, February 27, 2007 Can we potentially help prevent this?

2. 2 Predicting risk-an uncertain science Probability, timing, severity and identity of future pandemic are unknown H5N1 persists – and other serotypes remain a threat Evidence of increased human-human transmission, perhaps accompanied by relevant changes in the virus, may presage the pandemic Waiting for such evidence may leave limited time for vaccine production and administration These uncertainties complicate strategy and planning

3. 3 Why consider immunization prior to (or early in) a pandemic? Production times are long (3-6 months with current methods) and capacity is limited Stockpiling has provided flexibility to consider early use Some evidence supports priming and cross-protection among some heterologous H5 strains, which may be increased with novel adjuvants Modeling suggests benefits to early use of a vaccine, even one with limited efficacy, and in single doses

4. 4 The first wave will be declining when vaccine becomes available JANFEBMARAPRMAYJUNJULAUGSEPOCTNOVDEC PREPARE SEED MONOVALENT PRODUCTION FILL/TEST FIRST VACCINE TO PEOPLE! IMMUNOGENICITY? OUTBREAK ACTIVE SAFETY/SAE DATA/HCDCONTINUED PHARMACOVIGILENCE (Licensed vs. EUA)

5. 5 Strategies to help speed vaccine production and availability –Make strains, reagents, testing faster –Use dose sparing strategies –More rapidly induce immunity? –Make vaccines with enhanced cross- protective properties? conserved genes, live vaccines –Use scalable and rapid production methods E.g. cell culture/recombinant protein/DNA –Increase manufacturing capacity and stockpiling

6. 6 Approaches to Pandemic Influenza Vaccine Timing: Overview –During a pandemic Pros - Clearest benefit/risk (though even with proven vaccine, strain could have unforeseen AEs) Con- too little, too late –In an “emerging” pandemic Vaccination can begin if stockpiled –Can target areas/individuals at high risk Even at reduced efficacy, models predict benefit –Temporizing strategy until matched vaccine available Benefit/risk ratio clearer than prepandemic use –Although feared pandemic still could “fizzle” Expensive, need large stockpile –Potential need to replace/rotate stockpiles

7. 7 Potential Approaches to Pandemic Vaccine Timing: cont’d. –Pre-pandemic Could be offered as option separately from or as part of annual immunization –Generally or to populations with increased risk If successful, could blunt or prevent pandemic –Human and economic benefits, requires less surge capacity, reduces need for emergency measures, production, stockpiles Strain mismatch likely, and may lead to reduced efficacy Uncertain pandemic risk raises additional safety concerns

8. 8 Priming and Cross Protection Natural infection provides long-term protection against that strain and variable protection against related strains Inactivated vaccine provides some protection beyond one flu season and against related strains which may be increased with live attenuated vaccines Preliminary animal, serologic and clinical studies of H5 vaccines provide evidence of variable cross-protection between heterologous strains, that may be enhanced by novel adjuvants, and also suggest that priming may be possible and durable Caveat: It is not clear how well matched strains need to be, or to what degree serologic studies predict protection - sequence based prediction is improving –Surrogates for protection are also not well defined (unknown for LAIV), and HAI and neutralizing assays are highly variable

9. 9 Models Suggest Potential for Significant Vaccine Effects: Impact of vaccine delay and of prevaccination Figure a, b: effects of mass vaccination beginning on day 30 (second bar down), 60 (blue) or 90 (green) after first case) for high/low transmissible virus Fig. c - Policy 21 = pre-vaccination of 20% of population (VE30%), prioritizing children, added to household quarantine, school closure, next day Rx and household Px - Ferguson, Cummings, Fraser, et al Nature 442, 448-452(27 July 2006)

10. 10 Many Unanswered Questions –How can we better measure and predict both protection and cross-protection? Hospitalization, death, contagion may be more relevant/achievable impacts vs. infection Can new or existing animal models contribute? –What dose and dose intervals are needed for priming? Boosting? –How durable will priming be? Are specific levels of Ab needed, and must they be maintained? –Caveats: many answers may be serotype, clade or even virus specific, and may defy prediction

11. 11 Data Needs How should we design trials to evaluate immunogenicity for pre-pandemic or early pandemic use? – opportunity is here now –What should standards be? Further scientific data and public discussion will be important in considering vaccine use in pre- and early pandemic settings –Substantial safety data will ultimately be needed in considering pre-pandemic approaches Today’s discussion is intended to further both the data gathering process and discussion.

12. 12 Thanks!