Impact of Prior Dengue Infection on the Severity and Outcomes of Subsequent Infections: A Meta-Analysis of the Placebo Arm of Clinical Trials

ImportanceThe increasing incidence and prevalence of dengue in Latin America is well-documented. Historical case-control series also highlight that secondary infections are a risk factor for severe dengue, hospitalization, and death. This has generated alarm among some sectors of the population and the scientific community. However, there has been no examination based on the results of randomized clinical trials that analyzes the risk of severe events in individuals with and without prior dengue infection. ObjectiveTo evaluate the association between serologically confirmed prior dengue infection (DVC) and the subsequent risk of DVC, severe dengue (DS), dengue hospitalization (DHOSP), dengue-related death, and all-cause mortality. MethodsA systematic review and meta-analysis were conducted following PRISMA guidelines. Studies were searched in PubMed, CINAHL, Medline, Cochrane Library, and Web of Science, including only phase III randomized clinical trials of vaccine efficacy with data on participants in the placebo groups and information on previous infections. Random-effects models were applied to calculate combined odds ratios (OR), and heterogeneity among studies was assessed. ResultsA total of four studies corresponding to three phase III clinical trials were included. Participants with prior infection had a lower likelihood of developing DVC during follow-up (OR: 0.85; 95% CI: [0.75; 0.98]; p=0.024) and the same risk of dengue hospitalization as those without prior dengue (OR: 1.18; 95% CI: [0.92; 1.53]; p=0.198). However, they had a higher rate of DS during follow-up (OR: 2.91; 95% CI: [1.23; 6.87]; p=0.015). No dengue-related deaths were observed in any of the clinical trials during follow-up. ConclusionsPrior dengue infection significantly reduces the risk of DVC and increases the risk of DS, although it does not significantly affect the risk of dengue hospitalization or dengue-related death during follow-up. The findings of this study highlight the need to reconsider the value of prior infection as an independent risk factor.