Variation among dengue virus-1 lineages affects the neutralization breadth of antibody responses elicited by infection and vaccination

Dengue virus (DENV) genetic diversity within serotypes may influence the breadth and durability of vaccine-induced immunity. We developed a panel of DENV-1 reporter virus particles encompassing ~ 74% of known global envelope protein diversity and evaluated neutralization using sera from tetravalent vaccine recipients, experimental DENV-1 challenge participants, and individuals with monotypic natural infection. Neutralization varied substantially among DENV-1 lineages and differed by exposure history. Several variants showed reduced neutralization following vaccination despite high overall antibody titers. Subsequent DENV-1 challenge broadened responses, which remained elevated through 180 days, whereas challenge of unvaccinated individuals produced lower potency and more lineage-specific decreases over time. Natural infection produced comparatively uniform neutralization across the panel. We used antigenic cartography to identify specific envelope amino acid positions associated with increased antigenic distance and reduced neutralization across vaccine and challenge sera. These findings demonstrate substantial within-serotype antigenic variation and support using diverse lineages to assess DENV vaccine-induced immunity.