Orthoflavivirus-wide B-cell cross-reactivity following TAK-003 vaccination reveals synergistic immune interactions with YF-17D

Antigenic similarities between orthoflaviviruses result in highly cross-reactive immune responses in humans. Immune interactions between different strains and serotypes are not widely studied but of interest as they may contribute to cross-protection or immunopathology. Defining these complex relations is of particular interest for orthoflavivirus vaccines to ensure their efficacy and safety. As flaviviruses are expanding geographically, vaccines will be administered in populations with very different flavivirus exposure backgrounds. We chose to study immune interactions between the yellow fever 17D vaccine (YF-17D) and the tetravalent dengue vaccine (TAK-003), both offered in high and low flavivirus exposure areas. We longitudinally analyzed serum IgG and B-cells responses including dengue virus (DENV) and YF-17D neutralization in 19 TAK-003 vaccinees with complex orthoflavivirus immune backgrounds, of which 9/19 were previously YF-17D vaccinated. Our results show that TAK-003 increased DENV structural and non-structural antigen-specific serum IgG titers and circulating B-cell clones, but B-cells cross-reacting with structural antigens of other orthoflaviviruses, including Zika, West-Nile, Tick-borne and Japanese encephalitis and yellow fever virus, were preferentially boosted. Individuals with prior YF-17D vaccination displayed higher B-cell frequencies that were also more cross-reactive, compared to YF-17D naïve individuals. TAK-003 induced detectable DENV neutralization titers in both groups and boosted YF-17D neutralizing titers in YF-17D vaccinated individuals. Our results show that dengue vaccination had an orthoflavivirus genus-wide impact on envelope cross-reactivity and revealed a potential synergistic effect between YF-17D and TAK-003. This knowledge is critical to inform vaccine policy makers.