Experimental dengue virus challenge of human subjects previously vaccinated with live attenuated tetravalent dengue vaccines

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.