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Dengue virus envelope protein (E) forms homodimers on the virion surface and elicits both neutralizing and non-neutralizing antibodies from IgG-secreting cells (IgG-SC). How the developing antibody response at the monoclonal level contributes to protection is unknown. We profiled single IgG-SC responses in a Cambodian pediatric cohort by measuring affinity and serotype cross-reactivity of secreted antibodies from patients with subclinical or hospitalized dengue during acute DENV1 or DENV2 infection. Using droplet-based microfluidic imaging, we analyzed over 3,300 single IgG-SC. Hospitalized patients exhibited significantly lower numbers of IgG-SC, despite comparable IgG secretion rates and similar frequencies of DENV E-specific antibody-secreting cells relative to subclinical cases. In hospitalized patients, the affinity of IgG-SC for the DENV1 E-dimer was 3-fold lower compared to subclinical cases. Notably, antibodies recognizing quaternary epitopes\u2014binding E-dimers but not monomers\u2014were detected exclusively in subclinical cases, whereas hospitalized patients predominantly produced monomer-reactive antibodies. These findings suggest that dengue severity may be linked to the inefficient generation of sufficient numbers of high-affinity, broadly reactive antigen-specific IgG-SC during post-primary infection.<\/jats:p>","DOI":"10.1371\/journal.ppat.1014552","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T17:44:01Z","timestamp":1790876641000},"page":"e1014552","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Quantitative and qualitative differences in anti-Envelope IgG-secreting cells distinguish subclinical and hospitalized dengue in a Cambodian pediatric cohort"],"prefix":"10.1371","volume":"22","author":[{"given":"Amandine","family":"Trouchet","sequence":"first","affiliation":[{"name":"Institut Pasteur, Universit\u00e9 Paris Cit\u00e9, INSERM UMR1222, Antibodies in Therapy and Pathology","place":["Paris, 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