Establishment of ‘natural antibodies’ during primary dengue infection

Dengue virus (DENV) poses a major global health burden, with limited vaccine availability and concerns that immunization of dengue-naïve individuals may exacerbate disease severity due to antibody-dependent enhancement. This challenge highlights the need for deeper insight into primary immune responses. Using a controlled human challenge model, we conducted a longitudinal analysis of B-cell receptor repertoire dynamics during primary DENV1 infection. Our study reveals that the acute-phase response is dominated by memory-derived B-cell clones, indicating pre-existing cross-reactive immunity. Concurrently, we identified highly public, convergent B-cell clones arising from naïve B cells, characterized by shared sequence features across individuals. These clones exhibit atypical maturation kinetics: while they switch to the IgG isotype during the convalescent phase, they retain germline-like sequences with limited somatic hypermutation. This suggests that affinity maturation is delayed compared to canonical responses. Our findings provide mechanistic context for previous reports of natural antibody responses in dengue and refine current models of how neutralizing and potentially enhancing antibodies emerge following primary infection. By resolving the timing and origin of early B-cell responses, this work contributes to a more precise framework for understanding flavivirus immunity. These insights may guide vaccine design strategies that aim to elicit protective immunity without enhancing the risk of severe disease.