1. John R. LaMontagne Memorial Symposium on Pandemic Influenza Research April 4-5, 2005 Institute of Medicine Working Group Five: Immunology, Assay Standardization, and Correlates of Protection Research Recommendations

2. Develop, validate and standardize serologic tools for pandemic preparedness (1-2 yr) Improve neutralization assays for avian strains: Standard protocols, engineered inoculum (BSL-2), automation Improve HAI for detection of H5 antibodies Develop ELISA methods for HA subtypes Develop standardized purified/recombinant HA and NA proteins and reference serum panels Develop and standardize assays for anti-NA –Correlate subtype ELISA with ‘gold standard functional’ inhibition (NI) method

3. Seroepidemiologic research related to pandemic preparedness –Assess pre-pandemic antibodies to HA and NA –Investigate potential cross-protection provided by human anti-HA or anti-NA against avian strains Longer term goal: –Simpler serologic assays for field use

4. Investigate immune correlates of protection Goal: Characterize the human immune response to flu infection and vaccines using modern immunologic techniques Examples -Subtype-specific ELISA and neutralization assays for HA and NA to improve understanding of protection and cross- protection -Role of IgG/IgA in serum or at mucosal sites with specificity for HA or NA in protection -Use new methods for probing human immune responses to primary and secondary flu infection with non-pandemic strains in order to develop methods that can be applied immediately to studies in a pandemic setting -Characteristics of flu-specific memory T cells and B cells -Trafficking of immune cells to lung, mucosa, etc. -Cross-protective immunity by T cells against flu proteins

5. Apply new immunologic assays in prospective studies using clinical endpoints + viral shedding to define correlates of protection Improve understanding of consequences of antigenic ‘drift’ in H5 strains Use new tools to better understand immunopathogenesis in complex/fatal flu infection (epidemic and pandemic cases)

6. Additional research to evaluate flu vaccine immunity (2-5 yr) Goal: Develop panel of standardized immunologic assays for use in designing pandemic vaccines Compare capacities of inactivated, live attenuated and vectored vaccines to induce humoral, cellular and mucosal immunity, with primary and secondary vaccination and with varying routes of administration Immunogenicity and efficacy in infants, children, adults and the elderly Time to induction of protective response Persistence of immune response Generate experience with multiple pandemic vaccines to assess reactogenicity, immunogenicity, optimal dose and route of administration