Development and clinical evaluation of multiple investigational monovalent DENV vaccines to identify components for inclusion in a live attenuated tetravalent DENV vaccine

The Laboratory of Infectious Diseases at the National Institute of Allergy and Infectious Diseases, National Institutes of Health has been engaged in an effort to develop a safe, efficacious, and affordable live attenuated tetravalent dengue vaccine (LATV) for more than ten years. Numerous recombinant monovalent DENV vaccine candidates have been evaluated in the SCID-HuH-7 mouse and in rhesus macaques to identify those candidates with a suitable attenuation phenotype. In addition, the ability of these candidates to infect and disseminate in Aedes mosquitoes had also been determined. Those candidates that were suitably attenuated in SCID-HuH-7 mice, rhesus macaques, and mosquitoes were selected for further evaluation in humans. This review will describe the generation of multiple candidate vaccines directed against each DENV serotype, the preclinical and clinical evaluation of these candidates, and the process of selecting suitable candidates for inclusion in a LATV dengue vaccine.

► Multiple monovalent dengue vaccine candidates were evaluated for safety, immunogenicity, and infectivity.
► The replication kinetics of multiple monovalent dengue vaccine candidates was characterized.
► Although the safety profile of all of the monovalent dengue vaccine candidates was acceptable, some candidates were not further evaluated as part of a tetravalent admixture due to poor infectivity/immunogenicity.
► Candidates with the most favorable safety and immunogenicity profiles will be further evaluated as part of a tetravalent admixture.