The Dengue Human Challenge Model: Has the Time Come to Accept This Challenge?

In an important article in this issue of the Journal, Sun et al describe the first human challenge of recipients of a live attenuated tetravalent dengue vaccine (TDV) with dengue virus (DENV) known to induce symptomatic disease [1]. The challenge viruses were originally evaluated as candidate vaccines for inclusion in a TDV vaccine but were underattenuated and induced mild dengue illness in vaccinees [2, 3]. In the current study, investigators evaluated the relationship between neutralizing antibody at the time of challenge and the ability to protect against viremia and symptomatic illness. Although the number of subjects was small, the authors found that subjects with higher titers of neutralizing antibody were protected. Importantly, enhanced viremia and enhanced disease were not observed. A human challenge model for dengue could be useful in addressing the complexities of vaccine and drug development for dengue. These include the lack of an animal model that reproduces the disease observed in humans, the necessity of the vaccine to be effective against all 4 DENV serotypes, and the lack of an identified correlate of protection. Previously, experimental infection of humans was essential in identifying the individual DENV serotypes, the mode of transmission of dengue, the incubation period of DENV, the kinetics of viremia, and the role of antibody in protection [4, 5]. Human challenge models have been used effectively in early phase clinical trials to provide a preliminary estimate of vaccine efficacy prior to engaging in large field efficacy studies and have also been used for drug development [6–11]. Vaccines that may have otherwise been evaluated in thousands of volunteers in phase III efficacy trials were eliminated from further evaluation. Although a human challenge model could be very useful for dengue vaccine and drug development, experimental DENV infection presents some unique challenges, primarily related to safety. There is the well-characterized risk of more severe dengue with subsequent, heterotypic infection. As a result, infecting volunteers with wild-type DENV after vaccination could induce severe illness should the vaccine not be protective. Despite these hurdles, a dengue human challenge model (DHCM) workshop, sponsored by the Walter Reed Army Institute of Research and the National Institutes of Health, was convened in Philadelphia in 2011. Experts in dengue vaccine research, dengue immunopathology, challenge models for other diseases, and regulatory officials discussed the potential of a DHCM. The consensus from the workshop was that a DHCM could be developed safely, should appropriate challenge strains of DENV be identified and produced under current good manufacturing practices. Topics of discussion included potential areas of use for the DHCM, the clinical end points of the model, the strains of DENV that should be used, and the regulatory hurdles that must be addressed. Although the DHCM has the potential to accelerate the development of dengue vaccines and therapeutics, the greatest concern remains its safety. Unlike human challenge models involving malaria, influenza, and enteric bacterial infection, a licensed antidengue therapeutic agent does not exist that could treat a volunteer who becomes ill following challenge. Although the majority of natural DENV infections are mildly symptomatic, dengue illness can be severe and, in some cases, even life threatening. For this reason, the clinical end points of any DHCM must be carefully designed and must be reproducible. The consensus from the DHCM workshop was that the end points of a useful challenge model could be peak virus titer and duration of viremia, with or without mild clinical illness; illness resulting in a vascular leak syndrome or other clinical signs and symptoms of severe dengue would not be acceptable. Viruses chosen for use in the DHCM would have to induce reproducible levels of viremia and reproducible clinical Received and accepted 9 November 2012. Correspondence: Anna P. Durbin, MD, Johns Hopkins Bloomberg School of Public Health, 624 N Broadway, Rm 251, Baltimore, MD 21205 (adurbin@jhsph.edu). The Journal of Infectious Diseases © The Author 2012. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. permissions@oup.com. DOI: 10.1093/infdis/jis749