Shared germline-biased plasmablast clonotypes shape early neutralizing antibody responses during acute Chikungunya virus infection

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Introduction: Chikungunya virus (CHIKV) infection causes acute febrile illness and severe joint inflammation, with some patients progressing to chronic arthritis. Early isotype-switched neutralizing antibody (nAb) responses have been associated with protection from chronic arthritis, but the cellular and molecular features of these early responses remain poorly defined. Methods: We performed single-cell sorting of plasmablasts (PBs) from patients with acute CHIKV infection and generated 94 human monoclonal antibodies (mAbs). These were evaluated for binding to CHIKV-infected Vero cells and to purified CHIKV, neutralizing activity, isotype distribution, somatic hypermutation (SHM), and immunoglobulin gene usage. PB-derived antibodies were compared with CHIKV-specific memory B cell (MBC)-derived antibodies from seropositive individuals. Results: Over one-third of PB-derived mAbs recognized CHIKV-infected Vero cells, and most were class-switched. Among these, 12 bound to purified CHIKV, and 6 of them showed neutralizing activity. All PB-derived nAbs had germline-like sequences with little to no SHM, and four displayed shared clonotypic features, including a conserved `WEL' motif in the CDRH3 region. Conversely, CHIKV-specific MBC-derived nAbs showed diverse but often higher levels of SHM, consistent with affinity maturation. Discussion: Together, our findings suggest that early nAb responses generated during acute CHIKV infection are germline-biased with overlapping features suggestive of convergent clonotype responses, providing a cellular and molecular basis of the early protective humoral immunity.

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