IMMUNE CORRELATES OF PROTECTION AGAINST INFLUENZA A VIRUSES IN SUPPORT OF PANDEMIC VACCINE DEVELOPME

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IMMUNE CORRELATES OF PROTECTION AGAINST INFLUENZA
A VIRUSES IN SUPPORT OF PANDEMIC VACCINE
DEVELOPMENTFDA/NIH/WHO Public Workshop,
December 10-11, 2007Bethesda, MD

• Workshop Organizers
• OVRR/CBER Jerry Weir, Hana Golding, Maryna
  Eichelberger
• Maureen Hess
• NIAID/NIH Kanta Subbarao, Catherine Luke
• WHO David Wood, Martin Friede

Hana Golding, Ph.D., DVP/OVRR/CBER
VRBPAC February 21, 2008
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Current State of Efficacy Evaluation of Pandemic
Influenza Vaccines

• Current situation (limited human-to-human
  transmission of avian influenza) is not conducive
  to traditional vaccine clinical efficacy trials.
  Therefore, evaluation of pandemic influenza
  vaccines is relying on immunological measures
  borrowed from seasonal influenza vaccines.
• The principal correlate of influenza vaccines
  efficacy is Haemagglutination inhibition (HI)
  antibody titer as a read-out

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Challenges in Efficacy Evaluation of Pandemic
Influenza Vaccines

• Is it appropriate to extrapolate what we know
  from seasonal influenza vaccination to pandemic
  influenza vaccines, when most of the populations
  are lacking pre-existing immunity? Higher
  pathogenicity of H5N1?
• Is an HI titer (or any antibody measurement)
  appropriate to predict clinical benefit from new
  types of influenza vaccines such as
• Live attenuated vaccines
• Plasmid DNA vaccines
• VLP and Vector vaccines
• How do we establish the protective levels
  associated with newly defined immunological
  endpoints and accurately quantify the responses
  following vaccination?

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GOALS OF THE PUBLIC WORKSHOP

• Identify the gaps in our knowledge and abilities
  in addressing the unique challenges encountered
  in the development and evaluation of vaccines
  intended to protect against pandemic influenza
• Facilitate implementation of global research
  agenda to improve efficacy assessment of pandemic
  influenza vaccines

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Session I Correlates of protection against
seasonal influenza (Chair Robert Couch)

• This session included descriptions of humoral and
  cell-mediated responses to influenza, with an
  emphasis on immune mechanisms that contribute to
  protection against influenza infection or
  disease.
• Both antibody and T cell responses contribute to
  protection against seasonal influenza. Meta
  analysis of human challenge studies support the
  conclusion that HI antibody titer of 140 is
  associated with gt50 reduction in the risk of
  contracting influenza infection or influenza
  disease.

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Session II Immune responses to avian influenza
infections and vaccines against novel influenza
viruses in humans (Chair Jacqueline Katz)

• This session included a description of the
  genetic and antigenic heterogeneity of H5N1
  viruses and antibody responses in poultry
  workers.
• Immune responses to several avian influenza
  vaccine candidates (inactivated LAIV) were
  presented from clinical studies performed in the
  US as well as in Europe.
• Dr Fred Hayden (WHO) described the South East
  Asia Influenza Clinical Research Network that
  will facilitate international collaborative
  epidemiology and immunologic studies of pandemic
  influenza.

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Session III Assays to evaluate vaccine
immunogenicity (Chair Maria Zambon)

• This session included a discussion of the
  limitations of current assays to detect antibody
  responses to HA and NA, and described new assays
  to evaluate cell mediated immunity and
  M2-specific antibody responses. Novel assays that
  use pseudotyped viruses and H5N1 genomic phage
  display libraries were also described.
• The traditional HI tests based on chicken or
  turkey RBC are not optimal for anti-H5N1 HI.
  Horse RBC seems to have more sialic acid a2-3
  linked glycans, the preferred receptors for H5N1
  strains. Horse HI needs validation

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Session IV Correlates of Protection against
Avian Influenza potential insights from animal
studies (Chair Kanta Subbarao)

• In this session animal models for pandemic
  influenza were described. Results of wild-type
  virus challenge in mice and ferrets to determine
  the immunogenicity and efficacy of new vaccines
  were presented.
• These animal models provided important
  information about vaccine immunogenicity and
  correlates of protection, including heterologous
  protection.
• Vaccine effects included reduced viral loads in
  URT and lungs, lower morbidity and less lung
  pathology.
• Lethality is often not an optimal endpoint for
  vaccine effect and/or dose finding.

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Workshop Outcome Identified gaps and general
recommendations-1

• It may be premature to extrapolate what we know
  from seasonal influenza vaccination to pandemic
  influenza vaccines. Particularly the use of a
  given antibody end-point to predict pandemic
  vaccine efficacy.
• Use of HI may not be appropriate for all types of
  pandemic influenza vaccines. Additional
  immunogenicity measurements need to be defined
  and the protective levels associated with the
  newly defined endpoints determined.
• Novel assays should be developed to measure
  mucosal immunity, cell-mediated responses, and
  antibody responses to NA and other targeted
  antigens.

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Workshop Outcome Identified gaps and general
recommendations-2

• Animal models (mice and ferrets) can provide
  important insight regarding correlates of
  protection against emerging avian strains
• In order to facilitate the standardization of
  assays to evaluate and compare vaccine
  responsiveness there is an immediate need for
  standard reference reagents, low pathogenicity
  viral stocks, working cell banks, and shared
  SOPs.
• Programmatic approach to pandemic vaccine trials,
  with use of standardized assays should facilitate
  comparison of vaccine candidates and expedite
  pivotal studies, licensure, and pre-pandemic
  preparedness