Effect of prior flavivirus immunity on the adaptive response to the yellow fever 17D vaccine

Santos del Peral, Antonio (2024): Effect of prior flavivirus immunity on the adaptive response to the yellow fever 17D vaccine. Dissertation, LMU München: Medizinische Fakultät

Abstract

The yellow fever 17D vaccine (YF17D) is the most effective of all flavivirus vaccines. Given the widespread prevalence of flaviviruses, YF17D is frequently administered to individuals with pre-existing cross-reactive immunity, potentially influencing immune responses. Here, I investigated the impact of pre-existing flavivirus immunity induced by the tick-borne encephalitis virus vaccine (TBEV) on the response to YF17D vaccination in 250 individuals up to 28 days post-vaccination (pv). Previous TBEV vaccination did not influence the early neutralizing response to YF17D, predominantly driven by the IgM antibody fraction. TBEV pre-vaccinated individuals, however, developed high amounts of cross-reactive IgG antibodies with limited capacity to neutralize YF17D. In contrast, TBEV-unvaccinated individuals elicited a non-crossreacting but efficiently neutralizing response. Utilizing recombinant YF17D envelope protein mutants displaying different epitopes, I identified quaternary dimeric epitopes as the main target of neutralizing antibodies and the fusion loop epitope (FLE) as the focus of cross-reactive antibodies. TBEV pre-vaccinated individuals expanded anti-FLE IgG antibodies that can cause antibody-mediated enhancement (ADE) of dengue virus infection in vitro. Flow cytometric analysis consistently showed a greater expansion of antigen-specific memory B cells in TBEV-pre-vaccinated individuals following YF17D vaccination. Furthermore, TBEV pre-vaccinated individuals displayed a diverse antibody response, covering a wide range of specificities beyond cross-reactive epitopes shared by TBEV and YF17D. TBEV-induced antibodies enhanced YF17D vaccine immunogenicity, resulting in higher antibody titers and a more robust antigen-specific CD4 T cell response, measured in an ex vivo restimulation assay on day 28. In contrast to the significant differences in serum antibody titers, TBEV pre-vaccination had no impact on the longitudinal dynamics of bulk and tetramer-specific CD4 and bulk CD8 T cell responses, as assessed through multiparametric spectral flow cytometry. Genomic DNA bulk B cell receptor (BCR) sequencing indicated limited clonal expansion in the bulk repertoire and reduced diversity by days 7 and 14 post-vaccination, consistent with the B cell population kinetics observed through flow cytometry. In conclusion, the YF17D vaccine elicits both humoral and cellular immune responses that culminate in the generation of protective immunity. Pre-existing TBEV immunity does not impact the timing of the cellular immune response, but it significantly boosts YF17D immunogenicity and modifies the immunodominance of YF17D epitopes. This shift redirects the response in TBEV-pre-vaccinated individuals from a finely tuned, non-cross-reactive neutralizing response to a cross-reactive response focused on the FLE, with the potential to enhance dengue virus infection.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften ; 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Fakultäten: Medizinische Fakultät
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 15. April 2024
• 1. Bericht­erstatter:in: Rothenfußer, Simon