Dengue virus (DENV) has become the most important arbovirus worldwide with estimates of as many as 400 dengue infections occurring annually. These infections result in approximately 100 million symptomatic cases of which more than 2 million are classified as severe disease and approximately 21,000 result in death. Neutralizing antibody, the accepted immunologic endpoint chosen to move candidate DENV vaccines forward, was not predictive of protection against DENV illness in two efficacy trials of the recently licensed live attenuated dengue vaccine Dengvaxia. The vaccine was found to have significantly lower protection in those subjects who were dengue-naïve at the time of first vaccination. In addition, the vaccine induced an excess number of hospitalized and severe cases of dengue in the third year of the study in children younger than 9. These results have made it more difficult for vaccine manufacturers to determine which candidates should be further evaluated in large efficacy trials in endemic areas where vaccine failure could predispose subjects to more severe disease should they subsequently become infected with DENV and have heightened the need to define correlates of protection for dengue. A dengue human infection model (DHIM) would be useful in down-selecting candidate vaccines prior to testing in endemic areas as well as identifying putative correlates of protection. We have developed a DHIM for both DENV-2 and DENV-3. The live attenuated tetravalent dengue vaccine TV003 induced protection against challenge with DENV-2 in 100% of vaccinated subjects. In contrast, 100% of controls were viremic (mean peak titer 2.3 log10 PFU/mL) for multiple days and 80% developed a rash. To evaluate the role of heterotypic immunity in protection against dengue, we administered a trivalent vaccine formulation consisting of the DENV-1, DENV-3, and DENV-4 vaccine candidate viruses and challenge subjects 6 months later with DENV-2. We are also evaluated the evolution of the immune response to sequential DENV infection by infecting subjects with the DENV-1 vaccine candidate virus and then administering the DENV-2 challenge virus 9 months later. The clinical, virologic, and immunologic results from these studies will be discussed.