Immune profiling in subclinical secondary dengue-infected cases reveals adaptive immune signatures correlated to protection from severe dengue.

Development of strategies to prevent severe dengue has been challenging, partly by our incomplete understanding of a protective immune response after dengue virus (DENV) infection. To define adaptive immune signatures associated with protection from hospitalized dengue, we performed in-depth single-cell immunoprofiling and quantified DENV-specific T cells in subclinical or hospitalized dengue-infected children. Individuals with subclinical infection exhibit clonally expanded CD4+ TEMRA cells, increased frequency of DENV-specific CD4+ T cells, and demonstrate a gene expression signature of increased Treg functionality. Across all T cell subsets, subclinical cases upregulated a type I IFN response gene signature. In contrast, expanding CD8+ EM cells from hospitalized patients express more inhibitory markers and fewer cytotoxic proteins. In addition, hospitalized dengue is characterized by high frequencies and clonally expanded immunoglobulin G (Ig)G1-expressing plasmablasts. These findings identify candidate correlates of protection and support a rationale for T cell-directed interventions for dengue disease.