Immune repentance: forgiving the original antigenic sins of B and T cells

Immune challenges, such as infections or vaccinations, result in the formation of immunological memory that can provide enhanced protection against future pathogen exposures. Diseases such as chicken pox or measles, for example, permanently shape the adaptive immune system and establish long-lived molecular recognition of the disease causative agents. However, in some cases, prior interaction with certain pathogens impairs the immune response mounted against genetically distinct strains. An individual's immune history, defined as the sum of all past and current immune challenges, contributes to the defense against future secondary immune challenges (e.g., reinfection). This concept, also referred to as original antigenic sin (OAS), has been traditionally described in the context of impaired protection against seasonal influenza infections, but has now emerged as a relevant consideration in both the global vaccination efforts against SARS-CoV-2 and reinfection with its evolving variants. For example, infection with H1N1 influenza strains has been reported to impact neutralizing antibody titers against future infections with genetically distinct influenza strains in mice and humans. These fundamental principles of OAS are relevant to the current SARS-CoV-2 vaccination strategies, as current vaccines use the genetic sequence of the spike protein derived from the original SARS-CoV-2 virus first detected in late 2019, despite increased prevalence and dominance of new variants of SARS-CoV-2 possessing mutations in their spike protein. This implies that future exposure of viral variants in immunized individuals may result in reduced vaccine efficacy and protection from infection. B and T cells play a crucial role in generating vaccine- and infection-mediated adaptive immunity and undergo a sophisticated generation and maintenance process termed clonal selection. B and T cells work together to produce high-affinity and virus-neutralizing antibodies, which are crucial to resolve infections. Understanding the molecular mechanisms underlying the selection of B and T cells is necessary to both profile how immune challenges permanently shape our immune system and how vaccines can be optimized to provide long-lasting and effective protection regardless of previously encountered immune challenges. Previous OAS studies have been largely based on population-level readouts from circulating serum, thereby ignoring the contribution of individual clones and the selective pressures which govern them. The selection of individual B and T cell clones, however, is what dictates the ability to generate broadly neutralizing antibodies against both previously encountered viruses and future unseen variants. It is therefore necessary to investigate how OAS imprints the adaptive immune response at the single-clone level to elucidate how vaccines confer broad protection against mutating viral populations. In this proposal, I will first investigate how immune histories alter the clonal selection of B and T cells during primary and subsequent immune challenges. A multidisciplinary approach of experimental and computational immunology methods will provide a mechanistic understanding of how OAS shapes the adaptive immune response at both the global and single-cell resolution. Second, I will use murine models of infection and immunization, transgenic mice enabling lineage tracing, and single-cell immune repertoire profiling, to further explore vaccination strategies that overcome the effect of OAS and achieve immune repentance of individual clones. Immune repentance refers to the molecular forgiveness of immune impairment resulting from previously encountered immune challenges. This will involve addressing how factors such as viral genomic sequence (e.g., SARS-CoV-2 boosters encoding either alpha, delta, or chimeric spike protein variants), dosing schedules, vaccination composition (e.g., protein vs mRNA), and heterologous vaccine administration routes (e.g., intranasal vs subcutaneous) interact with pre-existing B and T cell immunological memory. Finally, the elucidated molecular mechanisms underlying the clonal selection of virus-specific B and T cells from our proposed murine models will be investigated using human samples following SARS-CoV-2 infections and immunizations.