Examining Preexisting Immune Mediators that Augment Immune Responses to Drifted Influenza Exposure

Thesis (Ph.D.)--University of Washington, 2018Influenza A annually infects 5-10% of the world’s human population resulting in an estimated one million deaths, severely afflicting the elderly population in particular. Influenza causes annual epidemics and re-infects previously exposed individuals because of antigenic drift in the surface glycoprotein hemagglutinin (HA). Due to antigenic drift, the immune system is simultaneously exposed to both novel and conserved parts of the influenza virus via vaccination and/or infection throughout life. Additionally, over time humans experience a gradual deterioration of the immune system, termed immunosenescence. Preexisting immunity and immunosenescence has long been known to influence subsequent hemagglutination inhibitory antibody (hAb) responses. However, the resulting immunological contributors that either dampen or enhance hAb responses are not fully understood. Here, we address basic questions regarding what preexisting immune components effect subsequent responses and how we can enhance and optimize responses to influenza in the face of preexisting immunity and immunosenescence. Therefore, to begin to address what preexisting immune components augment responses, both detrimentally and constructively, we adapted and characterized two sequential infection and vaccination mouse models with strikingly different hAb outcomes. We found that this differential response was due to disparities in T cell reactivity between the two mouse models. With both mouse models established we then used depletion and transfer methodologies to isolate the impact of immunological memory components on subsequent responses. Increased hAb responses were memory CD4+ T cell and B cell dependent, whereas dampening hAb responses were found to be due to a lack conservation between MHC Class II reactivity. We then characterized these different responses finding increased hAb responses corresponded to increased germinal center B and T follicular helper cells. We then reversed dampened hAb responses employing this knowledge by engineering conserved CD4+ T cell reactivity. These results suggest conserved MHC Class II restricted epitopes within HA are critical for memory B cells to adapt to drifting influenza and could be leveraged to boost subsequent hAb responses. Last, we used an adjuvant paired with the seasonal vaccine to elicit enhanced hAb responses in an immunosenescent mouse model, characterizing and evaluating protective responses. Collectively, we demonstrate that cognate memory B and T cells synergize to update the B cell repertoire to drifting influenza exposure while lack of cognate T cell help leads to a less protective response and inclusion of adjuvant in seasonal vaccination elicits enhanced hAb responses in an immunosenescent mouse model