Humoral Immune Responses to COVID-19 Vaccines in Nonhuman Primates and Humans

Abstract

The emergence of SARS-CoV-2 has highlighted the need for and the power of vaccines against infectious diseases. SARS-CoV-2 is the third novel coronavirus to emerge into the human population in the span of 17 years following SARS-CoV-1 in 2002 and MERS-CoV in 2012. SARS-CoV-2 is the first for which there are licensed vaccines. Over the years, vaccinology has changed, including new vaccine platforms (e.g., mRNA or Adenoviral vectored) and adjuvants (e.g., Matrix-M or AS03) for vaccines. SARS-CoV-2’s emergence created a unique opportunity to study immune responses to vaccines using these new platforms and adjuvants. Additionally, the prolonged pandemic highlights how vaccines can lose efficacy against variants of a rapidly evolving virus. By interrogating the humoral immune responses to vaccination against or infection with SARS-CoV-2, we can further understand protective efficacy, breadth, potency, and evolution of humoral immune responses more broadly. In chapter two we characterized the humoral immune responses in nonhuman primates (NHPs) vaccinated against or infected with SARS-CoV-2 and their cross-reactivity to other coronaviruses. We demonstrated that sera from NHPs vaccinated with Adenovirus Type 26 (Ad26) based SARS-CoV-2 vaccine or infected with SARS-CoV-2 bound other coronavirus Spike glycoproteins though there was little to no cross neutralization. In chapter three we tested a protein-based nanoparticle vaccine for COVID-19 in NHPs. Our studies showed that after three doses there was a substantial induction of binding and neutralizing antibody responses to SARS-CoV-2 variants including Omicron BA.1 and robust protection against challenge with SARS-CoV-2 Delta. Finally, in chapter four we investigated the immune mechanisms of increased serum neutralization breadth over time in humans vaccinated with Ad26.COV2.S. We found that levels of somatic hypermutation (SHM) increased in Spike-specific peripheral B cells over an extended period of time. These data imply continued affinity maturation in individuals vaccinated with Ad26.COV2.S for at least eight months. The data presented in this thesis furthers our understanding of how ancestral strain matched vaccines against SARS-CoV-2 can induce humoral responses against SARS-CoV-2 variant strains and even other coronaviruses. These findings have implications for ongoing COVID-19 vaccination campaigns and future infectious disease vaccine development.