Development of a pan-sarbecovirus vaccine by adenoviral vector capsid display

Thesis

In 2019, SARS-CoV-2 became the third highly pathogenic betacoronavirus to emerge in human populations in the 21st century, causing the global COVID-19 pandemic. The circulation of diverse SARS-CoV-2-like sarbecoviruses in animal reservoirs presents an ongoing threat of future spillover events. Vaccines that offer broad ‘strain-agnostic’ protection against these viruses could potentially mitigate the severity of a future pandemic.

In this thesis, I investigated the strategy of adenoviral vector capsid display in order to develop a candidate pan-sarbecovirus vaccine. Adenoviral vectors elicit robust cellular immunity but modest antibody responses compared to virus-like particles (VLPs) or mRNA-lipid nanoparticles. To overcome this limitation, chimpanzee adenovirus vectors were modified in order to use the adenoviral capsid as a scaffold for the VLP-like display of sarbecovirus antigens. Genetic insertion of foreign sequences into the adenoviral hexon protein enabled the display of conserved epitopes from the spike S2 subunit, while entire Receptor-Binding Domain (RBD) antigens could be conjugated to the adenovirus capsid using a Tag/Catcher system. Capsid display vaccines were highly immunogenic in animal models, enabling potent humoral responses to displayed antigens while maintaining cellular immunity to an encoded transgene. Subsequently, chimpanzee adenoviral vectors encoding the conserved nucleoprotein antigen were used to display protein immunogens containing diverse RBD proteins from all major sarbecovirus lineages. These vectors directed robust cross-reactive T cell responses against the nucleoprotein and elicited broad neutralisation of diverse sarbecoviruses, including divergent isolates not included in the immunogen design such as SARS-CoV-1.

This work combines the strengths of VLP and adenoviral vector vaccines into a single vaccine platform that elicits broad cellular and humoral immunity across the sarbecovirus sub-genus. The further development of broadly protective vaccines could help alleviate the ongoing pandemic risk posed by circulation of preemergent sarbecoviruses in animal reservoirs.

Authors: Sampson, AT

• DOI: 10.5287/ora-qq9amndyq
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: sarbecovirus; vaccine; adenoviral vector; SARS-COV-2; betacoronavirus; virus-like particle
• Subjects: Vaccine development; Immunology; Virology; Vaccination