Characterising lung tissue pathology and immunity in vaccinated and unvaccinated rhesus macaques challenged with SARS-CoV-2

Thesis

Much has been learned about how SARS-CoV-2 drives lung immunopathology. However, studies of post-mortem human lung tissue have confounding factors including different viral loads, infection timepoints and treatments. Animal studies allow us to standardise these factors, examine a wider range of pathological states and study the impact of vaccination on protection against or enhancement of lung pathology. As human studies can only collect tissue samples post-mortem, the impact of vaccination on the in-situ tissue response to infection has not been studied.

Using spatial transcriptomics and multiplex immunofluorescence, we characterise the immune mechanisms driving pathology and protection in the lung across vaccine and challenge scenarios in rhesus macaques challenged with SARS-CoV-2. Lung tissue from vaccinated (DNA, mRNA, viral vector and formalin-inactivated vaccines), unvaccinated, and re-challenged macaques were studied. Lesioned and non-lesioned regions of lung tissue were selected for analysis in order to link results with the pathological context in-situ.

Rhesus macaques had a spectrum of pathology outcomes depending on the level of immunity conferred by prior infection or vaccination. Rhesus macaques recapitulated several mechanisms of severe human COVID-19 disease, particularly when lesioned areas were focused on. In contrast, non-lesioned regions could not be used to effectively separate high and low pathology animals, demonstrating the importance of pathology-guided spatial analysis. We did not find any evidence of vaccine-associated enhanced disease (VAED) in vaccinated animals with high pathology.

CD4+ T cells were found in greater numbers in the lung tissue of vaccinated or previously-challenged NHPs and activated CD4+ T cells were more prevalent in the most protected group, vaccinated with the viral vector vaccine. CD8+ T cells and APCs were found to correlate with histopathology scores in lesioned areas and may co-localise spatially, suggesting ongoing antigen presentation to CD8+ T cells in more severe disease. These associations warrant further investigation for mechanistic insights

Authors: Gartlan, C

• DOI: 10.5287/ora-ngnz0pngn
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: lung; pathology; immunology; vaccines; COVID-19; SARS-CoV-2