Immunomodulating factors of host response to infectious disease and vaccination

Abstract

How our immune system responds to infection or vaccination depends on both the immune stimulus and the state of our immune system. This observation stems from known differences in how we, our friends and family, and others around the globe respond to infections including SARS-CoV-2 and HIV-1, and why vaccinations elicit different levels of protection across a population. Yet, we do not fully understand how co-infection impacts our immune responses to novel pathogens, why we have different symptoms after infection, or how to best tune our immune responses towards a common cause. Understanding these immune factors will inform prognostication of immune responses and guide future design of immune stimuli to cultivate clinically beneficial responses. In order to address these gaps in the field, I have utilized three model systems across my thesis project. The first model is a cohort of people living with HIV-1 (PLWH) who acquired SARS-CoV-2 early in the pandemic. This group was compared with people without HIV-1 (PWOH) in order to understand the impact of HIV-1 co-infection on the body’s ability to generate a humoral immune response to SARS-CoV-2. The second model is a cohort of people who had acquired SARS-CoV-2 and continued to test positive for a prolonged time. This group was compared to people who acquired SARS-CoV-2 but quickly converted from positive to negative direct antigen tests. The goal is to understand the humoral and cellular immune response differences to SARS-CoV-2 that could account for the different testing outcomes. The third model is an HIV-1 vaccine study in which healthy adults received vaccinations differing only in the adjuvant component. These results inform the impact of vaccine adjuvants on antibody quantity and quality. Results from this body of work suggest context and coordination modulate the immune response to infection and vaccination. In the first research chapter, PLWH who acquired SARS-CoV-2 (a) exhibited a trend toward decreased magnitude of SARS-CoV-2-specific antibodies, despite modestly increased overall response rates when compared with PWOH; (b) recovered from symptomatic outpatient COVID-19 with comparatively diminished immune responses; and (c) lacked a corresponding increase in SARS-CoV-2 antibodies with increased COVID-19 severity when asymptomatic versus symptomatic outpatient disease was compared. Together these results suggest PLWH harbor an immune system requiring a higher level of antigenic stimulation to mount a comparable immune response to PWOH. In the second research chapter, people who acquired SARS-CoV-2 and shed viral particles for only a short period of time (non-PVS) mounted a more coordinated immune response into the convalescent period anchored on the nucleoprotein-specific antibody response, antibody dependent cellular cytotoxicity response, and CD4+ T cell response. Finally, in the third research chapter, HIV-1 vaccination using several different adjuvants demonstrated the superiority of the response magnitude for one adjuvant, 3M-052, and revealed a qualitative maturation required with repeated vaccination in order to elicit Fc-mediated effector functions. These results provide insight into the ability to tune the quantity and quality of the immune response with future vaccine design. Insights gained from this thesis project serve to advance our understand of host-specific differences modulating immune responses to infection and adjuvant-specific differences modulating host responses to vaccination. In both cases, systems immunology frames a suite of discrete immune measurements that must be analyzed in concert to reveal the complex interactions within our bodies. As scientific measurements continue to advance, so too must our analytical methods to make sense of it all. If we can understand our immune system, we can control our immune system. If we can control our immune system, we can improve the human condition.