Infection at mucosal surfaces: SARS-CoV-2

The pandemic caused by the SARS-CoV-2 virus has had a profound international impact, causing widespread morbidity and mortality as well as substantial indirect secondary consequences of the restrictions implemented to constrain the virus. During 2020 the University of Oxford developed a SARS-CoV-2 vaccine using a simian adenoviral vector (ChAdOx1 nCoV-19). Pre-clinical studies demonstrated reduced viral load in lower respiratory tract samples in vaccinated animals, but no difference in the upper respiratory samples. In the first part of this thesis, I investigate the impact of ChAdOx1 nCoV-19 vaccination on SARS-CoV-2 infection in the upper respiratory tract and stool of trial participants.
Vaccine trial participants aged 18 and over from 19 UK study sites were randomised to receive the ChAdOx1 nCoV-19 vaccine or a comparator vaccine (MenACWY). From May 2020 to June 2021 participants were asked to perform weekly self-swabs of their nose and throat in addition to attending their study site for swabbing if they experienced any primary SARS-CoV-2 symptoms (fever of 37.8C or above, cough, shortness of breath, ageusia, anosmia). Samples underwent NAAT testing and were retrieved for genome sequencing. A selected group of trial participants were asked to provide stool samples during acute SARS-CoV-2 infection.
Adherence to weekly sampling was high and over 10% of participants tested positive during the study period. Infections in vaccinated participants were less likely to be symptomatic, were less severe, had higher cycle threshold values and a shorter duration of NAAT positive swabs compared to controls. A novel variant B.1.1.7 with notable spike protein mutations emerged during the study period for which vaccine efficacy for primary symptomatic Covid-19 infection was lower at 58.3% (95% CI 29.1-75.5) than for a preceding, common variant, B.1.177 (80.7%, 95% CI 67.1-88.6). Symptomatic infection was more likely to be associated with detectable RNA in stool however vaccination status was not related with detectable RNA in stool. There was no demonstrable difference in amino acid or nucleotide substitutions between sequences obtained from control or vaccinated participants for infections caused by B.1.177 or B.1.1.7. Intrahost viral diversity was detected in 90% (135/150) sequences with 93% of iSNVs occurring in only a single participant. This work demonstrates the impact of ChAdOx1 nCoV-19 vaccination on viral dynamics and efficacy against B.1.1.7 and emphasises the value of intensive surveillance of vaccine trial participants.
In Part 2 of this thesis (concerning work conducted prior to the SARS-CoV-2 pandemic, presented in Appendix 4), I investigate the population dynamics of Salmonella Typhi using a controlled human infection model. Participants were exposed to equal proportions of two genetically similar but distinct strains and 50% of individuals were diagnosed with typhoid. Both strains were detected at diagnosis from all participants who became bacteraemic showing no evidence of a single cell bottleneck. This study illustrates how co-infection within a controlled human infection model may be used to develop further understanding into the fundamentals of population pathogenesis.

Keywords: vaccination
COVID-19
SARS-CoV-2
Advisor: Pollard, A
Ramasamy, M
Golubchik, T
MacLennan, C
Moxon, E