INFECTION- AND VACCINE-INDUCED IMMUNE RESPONSES TO SARS-COV-2 AND OTHER HUMAN CORONAVIRUSES

Abstract

SUMMARY Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019 and spread across the world causing the COVID-19 pandemic. Unprecedented efforts by scientists across the world saw the development and approval of different mRNA and adenovirus-vectored vaccines targeting the spike protein of the virus to protect against infection and severe disease to varying degrees. However, while vaccine-induced responses have been extensively studied in the general population, responses in specific vulnerable groups such as immunodeficient patients (IDPs) are not fully understood. In addition, although an increasing amount of evidence demonstrates differential immunogenicity of the various vaccine platforms, the host and vaccine factors that underly these differences are not fully understood. A better understanding of the determinants of infection- and vaccine-induced immune responses in vulnerable groups and healthy comparators will inform improved next generation coronavirus vaccines. In this dissertation, I characterised immune responses following vaccination against SARS-CoV-2 in cohorts of IDPs, and healthy healthcare workers (HCWs). IDPs exhibited comparable T cell responses to HCWs but lower antibodies after vaccination although their profiles were more variable, and they were at greater risk of failing to generate immune responses after vaccination. This depended on the particular type of immunodeficiency they suffered from: primary or secondary. In IDPs, vaccine responses were also affected by vaccine type and age. In this cohort, frequency of spike-specific T cell induced by ChAdOx1-nCoV-19 were higher than those induced by BNT162b2 but equivalent to those seen in HCWs. When immune responses were analysed in hospitalised COVID-19 patients and mildly infected HCWs, the magnitude of the T cell responses induced correlated with disease severity. In cases of vaccine breakthrough infections, previous vaccination did not show ‘imprinting’ that would have stopped variant specific T cell immune responses. Investigation into the role of pre-existing anti-vector immunity on vaccine induced responses demonstrated significant cross-reactivity between pre-existing anti- human adenovirus 5 (HuAd5) and ChAdOx1-nCoV-19 vaccine vector immunity, with ChAdOx1-nCoV-19 vaccination inducing HuAd5 specific T cells and antibodies in vaccinated humans and in a mouse model. In the human study, ChAdOx1-nCoV-19-induced spike-T cell responses inversely correlated with levels of binding IgG antibodies against HuAd5 but correlated positively with HuAd5-specific T cells suggesting bystander T cell enhancement of the vaccine response. I used the mouse model to determine if pre-existing HuAd5-specific T cells contributed by bystander activation to the enhanced spike-specific T cell responses seen when IDPs were immunised with ChAdOx1-nCoV-19. Pre-existing anti-HuAd5 responses did not affect ChAdOx1-nCoV-19 induction of antibody to spike antigen although the T cell responses were variable between groups. A nucleoprotein mRNA vaccine study in mice demonstrated different patterns of T cell and antibody cross-reactivity between human Embecoviruses with significant nucleoprotein-specific T cell cross-reactivity between the human common cold coronaviruses, OC43 and HKU1 while antibody cross-reactivity was minimal. HCW sample screening revealed universal seropositivity to human common cold coronaviruses, but low or undetectable T cell responses. Following in vitro expansion and epitope mapping experiments, specific regions in human coronavirus nucleoproteins containing highly immunogenic cross-reactive T cell epitopes were identified. This study underscores the importance of tailored vaccination strategies to optimise immune responses in vulnerable groups and highlights that T cells targeting conserved epitopes in coronavirus proteins are possible vaccine targets for eliciting broadly protective immunity.