Experimental Dengue Virus Challenge of Human Subjects Previously Vaccinated With Live Attenuated Tetravalent Dengue Vaccines
Wellington Suna b✉, Kenneth H. Eckelsc d, Joseph Robert Putnakb e, Arthur G. Lyonsb e, Stephen James Thomasb e, David W. Vaughnb e, Robert V. Gibbonsb e, Stefan Fernandezb e, V. J. Guntherb e, M. P. Mammenf g, John D. Statlerh i,
- aDepartment of Virus Diseases, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA. wellington.sun@fda.hhs.gov
- b1Department of Virus Diseases
- cPilot Bioproduction Facility, Walter Reed Army Institute of Research, Silver Spring, Maryland
- d2Pilot Bioproduction Facility, Walter Reed Army Institute of Research, Silver Spring, Maryland
- eDepartment of Virus Diseases
- fDepartment of Virology, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand
- g5Department of Virology, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand
- hDepartment of Radiology, Walter Reed Army Medical Center, Washington, D. C
- i3Department of Radiology, Walter Reed Army Medical Center, Washington, D. C
- jVaccine Discovery and Development, GlaxoSmithKline, King of Prussia, Pennsylvania
- k4Vaccine Discovery and Development, GlaxoSmithKline, King of Prussia, Pennsylvania
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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 10(3) plaque-forming units (PFU) of DENV-1 or 10(5) PFU of DENV-3. Two additional subjects who did not develop DENV-3 neutralizing antibody (NAb) from TDV were revaccinated with 10(4) 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.