We recommend efforts to develop and standardize assays for antibodies to NA, and to evaluate and correlate the subtype ELISAs with a gold standard functional assay, e.g. a neuraminidase inhibition method.

Sero-epidemiology research is important for pandemic preparedness. Such research should include studies to understand pre-pandemic antibody levels in human populations in key areas to HA and NA proteins, and investigating potential cross-protection provided by human anti-HA or anti-NA antibodies against the avian strains.

A longer-term goal is to develop simpler serologic assays for field use. It seems most prudent and practical to do this work on assay development and standardization in centralized reference laboratories, but we ultimately need to develop techniques that can be transferred to field laboratories.

We discussed the need to investigating immune correlates of protection extensively. A much broader and deeper understanding of the human immune response to flu infection in general, as well as to vaccines is needed, based on using modern immunologic techniques. Examples include subtype-specific ELISAs and new assays, focusing on trying to better understand protection and cross-protection by antibodies to these proteins; and the role of IgG and IgA in serum and mucosal sites that have specificity for these proteins in protection.

We conclude that it is important to use the many new methods now available to probe human immune responses against primary and secondary flu infections with non-pandemic strains. These studies would give us a repertoire of methods to apply immediately to evaluate host responses in a pandemic setting. Examples of this kind of work include better characterizing flu-specific memory T cells and B cells, and aspects of trafficking of immune cells that can be studied now, such as lung trafficking and trafficking to mucosal epithelium. What is the role of cross-protective immunity by T cells that recognize various flu proteins? We can now study all of these questions in new ways.

Applying new immunologic assays to understand protective immunity requires their use in the context of prospective studies, using clinical endpoints and viral shedding to define a true correlate of protection, as opposed to just to measuring an immune response in the absence of information about viral replication.

We recommend efforts to improve understanding of the consequences of antigenic drift in H5 strains. New tools should be used to better understand the immunopathogenesis of complex and fatal flu infections, not just in the pandemic setting, where obtaining samples may be difficult, but also during annual epidemics. New tools and a better network for sharing patient samples for testing would enable us to better analyze the mechanisms that lead to these unusual situations.

Additional research to evaluate flu vaccine immunity is necessary. This work should be based on some of the same concepts discussed for assessing the response to natural infection and defining protective immunity. In this case, the goal should be to develop a panel of standardized immunologic assays that can be used as background information for designing pandemic vaccines that would engender the best repertoire of immune responses in the shortest time after vaccination.

In this context, we recommend comparing the capacities of existing inactivated, live attenuated, and vectored vaccines for inducing humoral and cellular and mucosal immunity,



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