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

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.