Considerations in the Pre- and Early Pandemic Use of Influenza Vaccine

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Considerations in the Pre- and Early Pandemic Use
of Influenza Vaccine
Can we potentially help prevent this?

• Jesse L. Goodman, MD, MPH
• Center for Biologics Evaluation and Research,
  VRBPAC, February 27, 2007

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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

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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

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The first wave will be declining when vaccine
becomes available
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
NOV
DEC
PREPARE SEED
MONOVALENT PRODUCTION
FILL/TEST
OUTBREAK
FIRST VACCINE TO PEOPLE!
(Licensed vs. EUA)
IMMUNOGENICITY?
ACTIVE SAFETY/SAE DATA/HCD
CONTINUED PHARMACOVIGILENCE
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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

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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

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Potential Approaches to Pandemic Vaccine Timing
contd.

• 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

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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

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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)
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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

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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
• Todays discussion is intended to further both
  the data gathering process and discussion.

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Thanks!