Preexisting Enhancing Antibodies in Vaccinated Participants Accelerate Dengue Virus 1 Infection Following Live Virus Human Challenge

Abstract

Abstract Dengue Human Infection Models (DHIM) are needed to down-select dengue vaccine candidates and establish tetravalent efficacy before advanced clinical field trials. As part of a randomized heterologous prime-boost vaccine strategy, participants received a tetravalent dengue (TDEN) Purified Inactivated Vaccine (PIV) prime followed by a TDEN Live Attenuated Vaccine (LAV) boost at 28, 90 or 180 days. Vaccinated participants (n = 6) aged 18–50 years, with detectable pre-challenge TDEN antibody titers, and flavivirus-naïve control participants (n = 4) were inoculated with DENV-1 strain 45AZ5, 27–65 months following booster dosing. Daily quantitative PCR detected DENV-1 RNA in nine of 10 participants (5/6 vaccinees and 4/4 controls). The mean onset of RNAemia occurred on day 5 (range 5–6) in vaccinees versus day 8 (range 7–10) in controls, P = 0.007, with a trend towards reduced RNAemia duration in vaccinees (8.2 days vs. 10.5, P = 0.056). Mild to moderate symptoms, leukopenia, and transaminitis were commonly observed. Severe adverse events were detected only in vaccinees, including fever > 102.1°F (n = 3) and headache (n = 1), with one transient Grade 4 AST. Immunologic and transcriptomic analyses revealed vaccinees developed rapid and more robust upregulation of pathogen-induced gene markers of inflammatory innate and effector responses, in the setting of pre-existing antibodies and in vitro evidence of antibody-dependent enhancement, compared to naïve controls. We conclude that TDEN-PIV-primed, TDEN-LAV-boosted participants were unprotected against DENV-1 infection and further, showed increased clinical, immunologic, and transcriptomic evidence of inflammation potentially mediated by preexisting infection-enhancing antibodies. ClinicalTrials.gov identifier: NCT04786457.