A revised model for immune imprinting by influenza virus

PROJECT SUMMARY Immune imprinting by influenza virus has been described as a lifelong bias in immune memory of, and protection against, influenza strains encountered in early childhood. It has become an increasing focus in the field of influenza research. Immune imprinting has been thought to reflect unique events associated with early life infections and is viewed primarily as a function of B cell memory. In this proposal, we will test that many of the findings that have been attributed to the earliest infections can in fact be explained to a significant degree by an alternate mechanism involving CD4 T cell specificity and functionality that occurs during the first infection and that biases the responses to all influenza infections that occur thereafter. The proposed model, drawn from much of our accumulated research, will be tested by a series of experiments whose goal is to determine whether establishing pre-existing immunity with exclusive and selective lung- initiated CD4 T cell priming, followed by virus infection challenge, will mimic many of the features of immune imprinting. Novel molecular and intranasal vaccine strategies will be used to selectively prime the respiratory tract and CD4 T cell compartment for selected influenza epitopes by delivery into the respiratory tract. We will test whether priming subtype-specific HA CD4 T cell responses and CD4 T cells specific for epitopes that are conserved across influenza A subtypes can mimic influenza imprinting with regard to the biases in CD4 T cell and B cell responses and protection that occur upon influenza virus challenge. These issues will be addressed through completion of two Specific Aims: Specific Aim 1. Derive and test constructs encoding influenza-CD4 peptide epitopes and evaluate epitope specific priming via intranasal vaccine platform Specific Aim 2. Test of CD4 T recall responses to infection, antibody responses and protection Collectively, completion of these experiments have the potential to fundamentally change our understanding of what has been viewed as significant obstacle in human protective immunity to influenza and will offer strategies to overcome the deficiencies in the host that lead to the deleterious effects of imprinting.