A systematic review of dengue controlled human infection studies: safety, viral kinetics and immunology

BACKGROUND: The immunopathogenesis of dengue infection and immune correlates of protection are uncertain, no therapeutic anti-viral is available, and the long-term risks of severe breakthrough infection after vaccination remain of concern. Dengue controlled human infection models (DCHIM) have found increasing utility and have the potential to address these unmet needs. We reviewed the clinical, biochemical and immunologic features of modern day DCHIMs. METHODS: A systematic review protocol was developed and registered with PROSPERO [CRD42024558534]. We searched MEDLINE, Cochrane and Embase for controlled human infection studies using attenuated dengue virus strains from January 2000 - December 2025. No restriction was placed on study setting (dengue endemic/non-endemic) or whether the study was conducted in seronegative or seropositive individuals. The primary outcome was the proportion of inoculated participants who developed viraemia ('attack rate'). RESULTS: Our search yielded 1181 results, and identified 11 published studies, recruiting 248 participants aged 18-55 years. All studies were performed in non-dengue endemic areas and were models of primary dengue. Four studies challenged previously vaccinated individuals, and one utilised DCHIM to assess antiviral efficacy. Attenuated dengue virus strains of all four DENV 1-4 serotypes were utilised as challenge agents. Attack rate across all serotypes was 50-100% in seronegative participants and 0-83% in previously vaccinated participants and was strain-dependent. Clinical and biochemical features of dengue fever varied between strains, with peak viral load and probability of fever being highly correlated (r = 0·91, p < 0·01). There were no serious adverse event reported, and 9 (4%) participants met protocol criteria for hospitalisation. Viral and/or immune evidence of disease enhancement was observed in 5/81 (7%) of challenged seropositive participants. CONCLUSION: DCHIMs of primary dengue are a valuable and safe tool that has supported vaccine development. Further work is needed to expand DCHIMs to endemic settings and as a model of secondary dengue.