Infection history shapes envelope-specific IgG repertoires with convergent neutralization from multiple lineages in secondary dengue 2259474

Abstract Introduction Dengue virus (DENV1-4) infects an estimated 400 million people annually. Severe disease is often linked to antibody-dependent enhancement (ADE) during secondary infection, whereby cross-reactive, non-neutralizing antibodies facilitate viral entry. While primary infection elicits protective serotype-specific and enhancing cross-reactive antibodies, secondary infection is thought to elicit broadly neutralizing antibodies that confer heterotypic protection. However, it remains unknown whether post-secondary plasma neutralization is driven by a few dominant clonotypes or distributed across diverse broadly neutralizing lineages. Methods We applied high-resolution proteomic analysis of DENV envelope (E) dimer-specific circulating immunoglobulin (IgG) at post-secondary late convalescence (4-6 months post-illness) to quantitatively profile the plasma antibody repertoire with monoclonal resolution in participants of a pediatric hospital-based study in Nicaraguan (N = 3 DENV2, N = 4 DENV3). Recombinant monoclonal antibodies (mAbs) were constructed from the most abundant serological lineages for epitope mapping and neutralization assays. Results Across five donors, >87% of E-specific IgG lineages were cross-reactive and >67% neutralized at least two serotypes. Of these, 64% cross-neutralized DENV1-4 with geometric mean NT50 values between 0.19 — 1.4 µg/mL. Analysis of abundant IgG lineages from two donors, either secondary DENV2 or DENV3 infection, revealed distinct epitope profiles on the E dimer despite similar cross-neutralizing activity. Conclusion Our findings demonstrate functional convergence to DENV cross-neutralization despite divergent epitope profiles in donors with different secondary DENV infection histories. Together, this suggests that DENV cross-neutralizing antibodies are abundant in post-secondary plasma, and that there are several mechanisms and lineages that enable broad neutralization of DENV1-4. Funding Source National Institute of Health R21AI176011 and National Institute of Allergy and Infectious Disease P01AI106695 Topic Categories Viral Immunology (VIR)