Dengue virus is especially pernicious compared with many other viruses, as secondary infections can actually be worse than the first one. Now, a new phase 1 trial involving controlled infections in volunteers provides a treasure trove of details about how preexisting immunity and anti-dengue antibodies affect the nature of secondary infections with dengue. The findings are among the first to glean insights using a large controlled human challenge, and could inform future therapeutics and the design of more broadly protective vaccines. Secondary infections with dengue are often the most severe ones, as preexisting antibodies can boost viral counts and raise the risk of severe symptoms. This has frustrated the development of badly needed vaccines for dengue. Furthermore, it’s been challenging to understand how pre-infection affects dengue outcomes, as animal models have many limitations and patients usually don’t present until after viral counts have peaked. In this study, Camila Odio and colleagues recruited 45 healthy adults who had either zero, one, or more than one prior infection with any of the four strains of dengue virus (DENV1-DENV4). The volunteers received injections of a live, weakened strain of DENV3 in a challenge study, allowing the researchers to fully interrogate dengue immunity dynamics in humans in a safe and controlled setting. The team made various discoveries: for example, they found that people whose antibodies boosted the replication of the virus had the highest viral counts and waning of CD8-bearing T cells and antibodies. Meanwhile, people who had higher amounts of antibodies against the viral nonstructural protein 1 displayed more balanced immune responses and lower viral counts. “Collectively, this work confirms multiple hypotheses generated by natural history studies and reveals the optimal conditions for inducing potent and persistent immunity against DENV1 to DENV4,” Odio et al. conclude.
For reporters interested in trends, a July 2025 study in Science Translational Medicine involving some of the same authors identified a class of anti-dengue antibodies that correlated with broad protection and lower disease risk in a cohort of children: https://www.science.org/doi/10.1126/scitranslmed.adq0571
Science Translational Medicine
Dengue virus controlled human challenge reveals that preexisting immunity shapes viral replication and broadly protective responses
28-Oct-2026