Journal of Infectious Diseases
Volume 207 Issue 5   March 1, 2013
http://www.journals.uchicago.edu/toc/jid/current

EDITORIAL COMMENTARY
Anna P. Durbin and Stephen S. Whitehead
The Dengue Human Challenge Model: Has the Time Come to Accept This Challenge?
J Infect Dis. (2013) 207(5): 697-699 doi:10.1093/infdis/jis749

Extract
(See the major article by Sun et al on pages 700–8.)
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– …

MAJOR ARTICLES AND BRIEF REPORTS
Wellington Sun, Kenneth H. Eckels, J. Robert Putnak, Arthur G. Lyons, Stephen J. Thomas, David W. Vaughn, Robert V. Gibbons, Stefan Fernandez, Vicky J. Gunther, Mammen P. Mammen, Jr, John D. Statler, and Bruce L. Innis
Experimental Dengue Virus Challenge of Human Subjects Previously Vaccinated With Live Attenuated Tetravalent Dengue Vaccines
J Infect Dis. (2013) 207(5): 700-708 doi:10.1093/infdis/jis744

Abstract
Background. Protection against dengue requires immunity against all 4 serotypes of dengue virus (DENV). Experimental challenge may be  useful in evaluating vaccine-induced immunity.

Methods. Ten subjects previously vaccinated with a live attenuated tetravalent dengue vaccine (TDV) and 4 DENV-naive control subjects  were challenged by subcutaneous inoculation of either 103 plaque-forming units (PFU) of DENV-1 or 105 PFU of DENV-3. Two additional subjects who did not develop DENV-3 neutralizing antibody (NAb) from TDV were revaccinated with 104 PFU of live attenuated DENV-3 vaccine to evaluate memory response.

Results. All 5 TDV recipients were protected against DENV-1 challenge. Of the 5 TDV recipients challenged with DENV-3, 2 were protected. All DENV-3–challenge subjects who developed viremia also developed elevated liver enzyme levels, and 2 had values that were >10 times greater than normal. Of the 2 subjects revaccinated with DENV-3 vaccine, 1 showed a secondary response to DENV-2, while neither showed such response to DENV-3. All 4 control subjects developed dengue fever from challenge. Protection was associated with presence of NAb, although 1 subject was protected despite a lack of measurable NAb at the time of DENV-1 challenge.

Conclusions. Vaccination with TDV induced variable protection against subcutaneous challenge. DENV-3 experimental challenge was associated  with transient but marked elevations of transaminases.