Abstract Introduction Pre-existing dengue immunity shapes subsequent immune responses, which can either be protective or pathogenic, though the underlying mechanisms remain poorly defined. Using a live attenuated monovalent DENV3 vaccine, we investigated how baseline immunity shapes cytokine, plasmablast, and clinical biomarker responses. Methods Participants were classified as naïve, heterotypic to a single serotype, or polytypic based on screening neutralizing antibodies, then restratified using area under the curve of viremia by qRT-PCR. We profiled 30 cytokines by Luminex and assessed plasmablast responses by ELISpot alongside standard clinical biomarkers. Results Low-viremia participants, most of whom had polytypic immunity, had early increases in innate cytokines, such as IL-6, IL-7, GM-CSF, and IFN-γ, followed by downregulated TNF-alpha and IL-2R and elevated MCP-1, lymphocyte, and monocyte counts, consistent with efficient viral control. The intermediate-viremia group showed early elevations in IFN-α and Th1-associated cytokines, followed by expansion of DENV3-reactive IgG+ and IgA+ plasmablasts, and IP-10 and IL1-RA induction, indicating a coordinated antiviral response with moderate inflammation. High-viremia participants, who mostly had heterotypic immunity, had more delayed increases in DENV-specific IgG+ plasmablasts and broader and more sustained elevations in proinflammatory and tissue-activating cytokines, such as G-CSF, VEG-F, and MIP-1 chemokines. Conclusion Pre-existing dengue immunity coupled with post-vaccine viremia delineates individuals into distinct profiles. We observed transient innate activation and controlled inflammation in low viremia participants, a coordinated adaptive response in the intermediate viremia group, and low-level but broad and persistent inflammation in the high viremia group. Understanding these profiles can help refine dengue interventions to improve safety and protective efficacy. Funding Source This research was supported by the Intramural Research Program of the National Institutes of Health (NIH) as well as NIH Bench-to-Bedside Program Funds - Award # 994875, the NIH Director’s Challenge Innovation Award, ReVAMPP grant 1 U19 AI181960-01, and P Topic Categories Viral Immunology (VIR)
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