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Biological Research and Disease Studies / Vaccines and Immunoinformatics Approaches / Mosquito Borne Diseases and Control · Journal article
The Journal of Immunology · July 28, 2026
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This phase 1 open-label human challenge study in 14 dengue-naïve subjects documents that experimental DENV-4 infection elicits non-neutralizing antibodies with complement-fixing, phagocytosis-promoting, and (in a subset) NK cell-activating functions. The work is mechanistic and descriptive, establishing assay feasibility and immunological characterization; it does not measure clinical protection or compare protective capacity against disease outcomes.
Phase 1 open-label human challenge study. 14 dengue-naïve subjects enrolled in an open-label phase 1 study.. Intervention: Subcutaneous inoculation with slightly attenuated live DENV-4 strain H-241. n = 14.
Infected subjects generated DENV-4-specific complement-fixing antibodies and anti-NS1 antibodies that facilitated monocyte-mediated phagocytosis of target cells DENV-4-specific antibodies mediated NK cell activation in a subset of subjects
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This work provides mechanistic characterization of non-neutralizing antibody responses to DENV-4 in humans and validates laboratory assays for future studies. The authors note that neutralizing antibody titers do not reliably predict disease outcome, but this study does not yet establish whether non-neutralizing antibodies correlate with protection or risk; readers should view this as foundational methodology for larger, outcome-focused trials.
Phase 1 open-label human challenge study in a small, dengue-naïve cohort characterizing immune mechanistic endpoints (non-neutralizing antibody functions) without a comparator or clinical outcome measure.
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This work provides mechanistic characterization of non-neutralizing antibody responses to DENV-4 in humans and validates laboratory assays for future studies. The authors note that neutralizing antibody titers do not reliably predict disease outcome, but this study does not yet establish whether non-neutralizing antibodies correlate with protection or risk; readers should view this as foundational methodology for larger, outcome-focused trials.
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Abstract Introduction Primary infection with one of the four dengue viruses (DENV-1—4) induces serotype-specific antibodies (Abs) that confer durable protection and cross-reactive Abs that offer transient immunity. While neutralizing Ab titers are commonly used to assess protection, they do not reliably predict disease outcome, and the role of Abs that mediate non-neutralizing effector functions remains poorly understood. We present an approach to evaluate the non-neutralizing Ab (nNAb) response to experimental DENV infection in humans. Methods In a phase 1 open-label study, 14 dengue—naïve subjects were subcutaneously inoculated with a slightly attenuated, live DENV-4 strain, H-241. Plasma was collected from pre- and 6 months post-infection to measure Ab-dependent complement deposition, Ab-dependent cellular phagocytosis, and Ab-dependent cellular cytotoxicity (ADCC). All assays used target cells infected with DENV or transfected to express DENV-derived surface-bound NS1 protein. Results Infected subjects generated DENV-4-specific complement-fixing Abs and anti-NS1 Abs that facilitated monocyte-mediated phagocytosis of target cells. DENV-4-specific Abs also mediated NK cell activation in a subset of subjects. Conclusion Future work will focus on extending this functional study to recipients of a tetravalent vaccine followed by DENV-1 challenge to investigate how nNAbs correlate with disease protection/risk, and broaden our understanding of immune defense against dengue beyond neutralizing Abs. Funding Source DOD Topic Categories Viral Immunology (VIR)
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