Stephen S. Whitehead

Heterotypic Dengue Infection with Live Attenuated Monotypic Dengue Virus Vaccines: Implications for Vaccination of Populations in Areas Where Dengue Is Endemic

BACKGROUNDnBecause infection with any of the 4 Dengue virus serotypes may elicit both protective neutralizing antibodies and nonneutralizing antibodies capable of enhancing subsequent heterotypic Dengue virus infections, the greatest risk for severe dengue occurs during a second, heterotypic Dengue virus infection. It remains unclear whether the replication of live attenuated vaccine viruses will be similarly enhanced when administered to Dengue-immune individuals.nnnMETHODSnWe recruited 36 healthy adults who had previously received a monovalent live Dengue virus vaccine 0.6-7.4 years earlier. Participants were assigned to 1 of 4 cohorts and were randomly chosen to receive placebo or a heterotypic vaccine. The level of replication, safety, and immunogenicity of the heterotypic vaccine virus was compared with that of Dengue virus immunologically naive vaccinees.nnnRESULTSnVaccine virus replication and reactogenicity after monovalent Dengue virus vaccination in naive and heterotypically immune vaccinees was similar. In contrast to naive vaccinees, the antibody response in heterotypically immune vaccinees was broadly neutralizing and mimicked the response observed by natural secondary Dengue virus infection.nnnCONCLUSIONSnEnhanced replication of these live attenuated Dengue virus vaccines was minimal in heterotypically immune vaccinees and suggests that the further evaluation of these candidate vaccines in populations with preexisting DENV immunity can proceed safely.

Response to Ruiz-Alejo et al

TO THE EDITOR—We are pleased to respond to the comments by Ruiz-Alejo et al [1], regarding the need to conduct future studies of the live attenuated tetravalent dengue vaccine in areas endemic for dengue. We could not agree more that candidate dengue vaccines will need to be studied in the populations identified as targeted for eventual vaccination. Our study was a phase I clinical trial and was thus focused primarily on safety. Because preexisting immunity to ≥1 flavivirus can affect the antibody response to vaccination with live attenuated dengue vaccine candidates [2–4], we thought it would be most appropriate to conduct the first evaluation of this promising candidate vaccine in flavivirus-naive adults. We have 2 phase 2 trials planned for dengue-endemic areas (Brazil and Thailand), and these trials will enroll flavivirus-experienced individuals. Enrollment in dengue-endemic areas will proceed in an age deescalated manner to ensure that the safety profile of the vaccine is acceptable in adults and older children before enrolling younger children. The overall aim of these trials is to better assess the safety and immunogenicity of the candidate vaccine. Because of the surprising lack of protection against dengue virus 2 infection despite the presence of dengue virus 2 neutralizing antibody reported by Sabchareon et al [5], we have designed the trials to include immunologic assessments in all enrolled subjects, with the goal of elucidating the immune response induced by the live attenuated tetravalent vaccine. Should these phase 2 trials further establish the safety and immunogenicity profile of the vaccine, our eventual goal is to determine its efficacy in a dengue-endemic area.