Wednesday, May 8, 2024
5/8/2024
PROJECT SUMMARY/ABSTRACT Seasonal influenza A viruses (IAVs) cause several million infections each year in the United States and have significant economic and health impacts. The rapid evolution of IAVs yields antigenically distinct viruses each year. Vaccine strains are chosen several months prior to the start of the season, but given the high rate of viral evolution, predominant strains can change between when vaccine strains are chosen and the start of the season. This poses as a major challenge in designing effective vaccines. A better understanding of how antigenic variants arise will improve the ability to anticipate antigenically distinct IAVs. At the global level, there is a clear pattern of recurring selective sweeps where antigenically novel variants that escape pre-existing humoral responses dominate in circulation. However, at the individual host level, stochastic effects appear to play a greater role in shaping IAV evolution. Yet antigenic mutants must arise amongst individuals to circulate globally. Data from the Lowen laboratory and other groups suggest that transmission may play a role in selecting for IAVs. Based on these data, I hypothesize that selection of IAV antigenic mutants in the context of pre-existing immunity acts inefficiently within hosts but efficiently during transmission between hosts. I will be using genetically barcoded influenza A/Texas/50/2012 (H3N2) virus (Tx/12) to address this hypothesis. Tx/12 is a well-studied virus that was the chosen vaccine strain for the 2014-2015 influenza season. The circulating H3N2 viruses during this season however were antigenically mismatched to the vaccine Tx/12 strain. This resulting vaccine escape was a result of the F159S mutation in the hemagglutinin (HA) glycoprotein. I will use genetically neutral barcoded Tx/12 wild type and HA F159S viruses in pre-immunized guinea pigs (i.e., pre-immune) to determine how both deterministic and stochastic effects shape the antigenic evolution of IAV. I have rescued non-barcoded Tx/12 wild type and HA F19S virus using reverse genetics. I have shown that both viruses grow robustly in guinea pigs and the HA F159S virus is antigenically distinct from the wild type virus in the guinea pigs. I have also designed and begun cloning the genetic barcodes in the HA genes of both viruses and started evaluating the vaccine to induce partial pre-existing immunity to Tx/12 wild type virus in guinea pigs. In Aim 1, I will examine the efficiency of selection within pre-immune hosts. I will alter the time of introduction of the antigenic mutant and its frequency in the population. I will monitor wild type and antigenic mutant barcode frequencies and diversity to measure genetic bottlenecks under these conditions. In Aim 2, I will examine the efficiency of selection between hosts. I will alter whether the donor or recipient animal has partial pre-existing immunity to Tx/12 wild type and monitor barcode frequencies and diversity of both viruses in donor and recipient animals. Through these experiments, I will further our fundamental understanding of the evolutionary processes that govern IAVs which can aid in better anticipating seasonal variants when designing vaccines.
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