Dengue Viruses and Lifelong Immunity: Reevaluating the Conventional Wisdom

(See the major article by Waggoner et al on pages 986–93.) For decades, efforts to develop a vaccine for dengue, a mosquito-borne disease caused by 4 distinct virus serotypes (DENV-1–4), have been guided by 2 key tenets: (1) that the immunity induced by exposure to a single DENV serotype is complete and lifelong [1, 2] and (2) that a DENV vaccine must be tetravalent and therefore convey protection against all 4 DENV serotypes, because of the risk of severe disease associated with secondary infections [3]. Recent phase 3 trials of a tetravalent dengue vaccine demonstrated limited protective efficacies against some serotypes despite high measured titers of type-specific neutralizing antibodies [4–6]. These results once again highlight the limitation of measuring serum neutralizing antibodies as a correlate of protection [7], but they also suggest the possibility that infection does not provide lifelong sterilizing immunity [8, 9] and, by extension, that a person can be infected with the same serotype more than once. Observations from previous cohort studies [10, 11] had alluded to this possibility, but until now the smoking gun of virologically confirmed repeat infections in the same person with the same DENV serotype remained elusive.