Vaccine development and deep immune profiling in preclinical models of emerging outbreak viral pathogens

Emerging outbreak viral pathogens pose a significant threat to public health. Essential studies on the pathogenesis of and preventive tools for infectious threats often rely upon preclinical models to inform or supplant evaluations in humans. This thesis features studies characterising the immune responses after vaccination and infection in animal models, ranging from rodents to non-human primates, with a focus on two viral pathogens of epidemic/pandemic potential: Lassa virus (LASV) and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).
LASV is endemic to regions in West Africa and circulates in rodent populations. Upon transmission to humans, LASV infection may cause an acute febrile illness called Lassa fever. Within the last several years, outbreaks of Lassa fever - associated with increased disease severity and mortality - have been reported in regions of endemicity. In the first half of this thesis, I present my work on the development and evaluation of a ChAdOx1-vectored vaccine for the prevention of Lassa fever, ChAdOx1-Lassa-GPC. The testing of this vaccine began with immunogenicity studies in mice and progressed to efficacy evaluations in guinea pig and non-human primate challenge models of LASV infection. Collectively, the results from these studies indicate that ChAdOx1-Lassa-GPC elicits strong, polyfunctional Th1 and cytotoxic T-cell responses targeting the viral surface glycoprotein. Although antibody titres are high, they are non-neutralising, and exhibit the capacity to elicit a variety of Fc-driven effector functions. Importantly, immunisation with ChAdOx1-Lassa-GPC protected guinea pigs and non-human primates from direct challenge with a lethal dose of LASV and significantly reduced viral load in tissues.
SARS-CoV-2 emerged in Wuhan, China in late 2019 and has resulted in an on-going pandemic of a (primarily) respiratory disease, known as coronavirus disease-19 (COVID-19). Applying skills and techniques developed during prior studies on LASV, I subsequently shifted the focus of my thesis work to contribute to research efforts for SARS-CoV-2. Consequently, the second half of this thesis describes the immunological assessment of a COVID-19 vaccine, ChAdOx1 nCoV-19/AD1222 in rhesus macaques, first after intramuscular delivery and next after intranasal delivery. Results demonstrated the robust induction of humoral responses after vaccination, via both routes, and significant reductions in lower respiratory tract viral load and inflammation, which could be detected on a cellular level. Finally, a more detailed investigation of SARS-CoV-2 pathogenesis in rhesus macaques was carried out to profile age-related immune dynamics after infection in older versus younger animals. Overall, through the employment of various animal models, the data presented in this thesis have contributed to the advancement of two vaccine candidates to late stages of development and added to current understanding of host responses to infection.

Keywords: lassa virus
SARS-CoV-2
lassa fever
COVID-19
vaccine development
immune profiling
Advisor: Gilbert, S
Lambe, T
Munster, V