Developing multiviral nanoparticle vaccines to facilitate proactive vaccinology

Thesis

Vaccines are a critical public health intervention and have substantially reduced human suffering. The importance of vaccination was demonstrated during the COVID-19 pandemic, where the rapid introduction of safe and efficacious vaccines substantially reduced mortality and morbidity. Innovation is still required to further enhance the speed of vaccine production for protection against newly arising pathogens with pandemic potential. In the 21st century, three lethal zoonotic coronavirus outbreaks (SARS-CoV, MERS-CoV, and SARS-CoV-2) have already been recorded and several zoonotic coronaviruses have been recognized as future threats. In this thesis, I develop a vaccine technology that elicits a broadly protective immune response against a group of coronaviruses to enable proactive vaccine development. I use SpyTag to facilitate the purification and nanoassembly of a panel of receptor-binding domains (RBDs) from different coronaviruses. I examine patient-derived monoclonal antibodies raised against SARS-CoV-2 and identify cross-reactive antibodies that target evolutionarily conserved regions. I then produce a Quartet of tandemly linked coronavirus RBDs as a single polyprotein. I show that immunization with these Quartets as soluble proteins or displayed multivalently on the SpyCatcher003-mi3 Nanocage (Quartet Nanocages) elicits a potent immune response across a group of evolutionarily related coronaviruses. This response includes raising neutralizing antibodies against viruses absent from the vaccine. I demonstrate that Quartet Nanocages raise a broad immune response in mice that have been pre-biased towards a specific virus. I create a Quartet Nanocage vaccine that induces neutralizing antibodies against newly arisen viral variants with potent immune evasion. I produce a Quartet using coronaviruses identified prior to the COVID-19 pandemic and demonstrate that this vaccine raises a potent immune response against SARS-CoV-2. These results highlight the potential of the Quartet Nanocage strategy as a tool for proactive vaccinology, where vaccines are developed against zoonotic pathogens before human transmission has even occurred.

Authors: Hills, RA

• DOI: 10.5287/ora-o12bq8jzn
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: coronavirus vaccines; pandemic preparedness; cross-reactive immunity; nanoparticle vaccines; protein engineering; SARS-COV-2; public health; proactive vaccinology; COVID-19; vaccine development; global health; biotechnology
• Subjects: Biotechnology; Immunology; Biochemistry