From vaccination to infection : mechanistic studies of immune responses to SARS-CoV-2

Abstract

The emergence of a novel coronavirus, SARS-CoV-2, sparked a global health crisis, leading to the COVID-19 pandemic. Development and deployment of vaccines against COVID-19 elevated population-level immunity and reduced COVID-19-related morbidity and mortality worldwide. However, recurrent infections are frequent and the immune mechanisms conferring lasting protection remain elusive. In this thesis, I focused on characterizing how adaptive immune responses to COVID-19 vaccines evolve over time in terms of magnitude, quality and durability, and what immune mechanisms contribute to lasting protection from SARS-CoV-2 infection. The work was performed in a non-human primate (NHP) model, whose physiological and immunological similarity to humans provides essential translational insights about SARS-CoV-2 infection and prophylaxis.

In Paper I, I characterized the innate and adaptive immunity after unmodified mRNA vaccination. A low dose of COVID-19 mRNA vaccine elicited a type I interferon-related innate immune activation but did not elicit detectable virus-specific adaptive responses with a single dose. Two boost immunizations, one and six months after prime, were required for induction of robust B and T cell immunity. Increased avidity of serum antibodies after each dose indicated significant affinity maturation of the B cell response. Mechanistically, the low dose of mRNA vaccine disseminated to fewer draining lymph node clusters compared to a higher dose, suggesting that poor immunogenicity after the first vaccination is a result of restricted priming.

In Paper II, I evaluated the evolution of immune responses over three immunizations with a protein subunit COVID-19 vaccine, and their capacity to provide durable protection from SARS-CoV-2 infection. Each immunization expanded the neutralizing breadth towards different SARS-CoV-2 variants, while simultaneously promoting affinity maturation of virusspecific B cells. Vaccine-elicited immunity, particularly after three immunizations, conferred significant protection from SARS-CoV-2 infection. Both virus-specific neutralizing antibodies in the blood before infection as well as anamnestic immune responses in the lungs early after infection were associated with reduced viral replication, underscoring the importance of mucosal immunity for effective defense against respiratory viruses.

In Paper III, I continued to follow the NHPs from the previous study to investigate the protective effects of combined infection- and vaccine-derived immunity, also known as hybrid immunity. Pre-existing immunity, whether hybrid or a result of a past infection, reduced viral loads in the respiratory tract after a reinfection with a highly divergent forward drift SARS-CoV-2 variant XBB.1.5. Reinfection, but not intramuscular boost vaccination, significantly expanded lung tissueresident memory T cells and mucosal antibodies, which were associated with protection from infection in the lower respiratory tract. This positions infection-elicited tissue-resident memory T cells as one of the key players able to reduce recurrent infection rates at the mucosal sites.

Collectively, these studies provide a deeper understanding of immunity in response to COVID-19 vaccines and immunological mechanisms critical for control of SARS-CoV-2 infection, with possible implications for development of vaccines against respiratory viruses.