Molecular analysis of the human antibody repertoire elicited after vaccination against Yellow Fever Virus

Abstract

Yellow fever virus (YFV) vaccine (17DD, 17D, 17D-213) is a live-attenuated vaccine that constitutes the main countermeasure against the yellow fever disease. Despite its efficacy, availability, and good vaccination coverage, YFV remains a persistent threat due to recurrent outbreaks in endemic regions. It is already known that previous infections or vaccinations elicit humoral immunity that may affect both vaccine outcomes and the course of future exposures to antigenically related viruses, such as dengue (DENV) and zika (ZIKV). In the present study, the antibody repertoire of subjects revaccinated against YFV was analyzed to better understand the impact of the co-circulation of DENV and ZIKV in an endemic area, on YFV vaccine outcomes and the existence of cross-reactive antibodies to the three viruses. To address this goal, this study is divided into two chapters. The first chapter presents an analysis of the molecular dynamics of the antibody repertoire after YFV revaccination of four donors. Combining serological analysis and B cell receptor sequencing (BCR-seq) methods, we found that YFV booster induces a modest antibody response followed by rapid temporal decay revaccinated individuals. Antibody kinetics in these individuals can be correlated with a rapid expansion of pre-existing lineages as well as newly generated lineages that are mostly dominated by IgA. We also identified expanded lineages containing high CDRH3 amino acid sequence identity to DENV and/or ZIKV characterized antibodies, suggesting the influence of the flavivirus co-circulation in the vaccine outcomes. The second chapter of the study describes the composition of the IgG serological antibody repertoire and its relationship to B- cell clonal expansions after 6 months in the subjects revaccinated against YFV. Using a proteomic approach (Ig-seq) combined with BCR sequencing data (BCR- seq) of the antibody transcripts, we show that secreted antibody molecules reactive to DENV2 and ZIKV comprise a substantial fraction of the serological repertoire, with an average of ~35% of these antibody lineages pre-existing from the YFV vaccination. We compared these antibody lineages which were identified at transcriptomic and proteomic level and we observed significative diferences in the somatic hypermutation rates (SHM), gene usage and CDRH3 lenght. Taken together, we found evidence that flavivirus co-circulation and pre-existing humoral immunity may influence the complexity, quality and persistence of the YFV vaccine antibody responses.