Structure-function analysis of infection- and vaccine-induced B-cell repertoires

Abstract - Overall Influenza virus evolves in response to pressure from herd immunity, resulting in progressive variation of viral antigenicity and limiting vaccine efficacy. The goal of this Program project is to establish a secure mechanistic foundation for novel vaccination strategies that might confer long-lasting immunity in face of rapid antigenic variation of currently circulating subtypes and in anticipation of potential introduction of zoonotic subtypes into the human population. The breadth of expertise in our four collaborative Projects and three scientific Cores and Results from the current and previous grant cycles allow us to pursue the following Specific Aims. (1) Can a suitable vaccination strategy modify or redirect immune "imprinting" -- the observed influence of an individual's history of infection of vaccination on their response to an antigenically drifted strain or novel subtype? We will determine the full scope of the human humoral response to vaccination in individuals of all ages (infants to seniors) and hence of varying exposures, and we will carry out, in non-human primates (NHPs), experiments to compare imprinting by infection and vaccination. (2) We have found (in mice) a strong effect of the anatomical location of immunization with protein antigen on the response to a subsequent immunization. We will determine whether this effect extends to infection and whether it is also true in NHPs. Experiments in mice will determine whether components of TFH cell memory are similarly localized and test the contribution of conserved T-cell epitopes to humoral imprinting. (3) We will design novel vaccine antigens to extend previous studies of human immune responses (focused on hemagglutinin) to influenza neuraminidase (NA) and to determine the importance of T-cell epitope diversity for design of optimized immunogens. We will also create a model for co-evolution of virus (immune escape) and humoral immunity (antibody affinity maturation) using directed molecular evolution in the laboratory.