Characterization of Non-Neutralizing Antibody Responses in a Dengue Virus-4 Human Challenge Model 2243013

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)