Live attenuated chimeric yellow fever dengue type 2 (ChimeriVax™-DEN2) vaccine:: Phase I clinical trial for safety and immunogenicity

A randomized double-blind Phase I Trial was conducted to evaluate safety, tolerability, and immunogenicity of a yellow fever (YF)-dengue 2 (DEN2) chimera (ChimeriVax(TM)DEN2) in comparison to that of YF vaccine (YF-VAX(R)). Forty-two healthy YF naive adults randomly received a single dose of either ChimeriVax(TM)-DEN2 (high dose, 5 log plaque forming units [PFU] or low dose, 3 log PFU) or YF-VAX(R) by the subcutaneous route (SC). To determine the effect of YF preimmunity on the ChimeriVax(TM)-DEN2 vaccine, 14 subjects previously vaccinated against YF received a high dose of ChimeriVax(TM)-DEN2 as an open-label vaccine. Most adverse events were similar to YF-VAX(R) and of mild to moderate intensity, with no serious side-effects. One hundred percent and 92.3% of YF naive subjects inoculated with 5.0 and 3.0 log(10) PFU of ChimeriVax(TM)-DEN2, respectively, seroconverted to wt DEN2 (strain 1668 1); 92% of subjects inoculated with YF-VAX(R) seroconverted to YF 17D virus but none of YF naive subjects inoculated with ChimeriVax-DEN2 seroconverted to YF 17D virus. Low seroconversion rates to heterologous DEN serotypes 1, 3 and 4 were observed in YF naive subjects inoculated with either ChimeriVax(TM)-DEN2 or YF-VAX(R). In contrast, 100% of YF immune subjects inoculated with ChimeriVax(TM)-DEN2 seroconverted to all 4 DEN serotypes. Surprisingly, levels of neutralizing antibodies to DEN 1, 2 and 3 viruses in YF immune subjects persisted after 1 year. These data demonstrated that (1) the safety and immunogenicity profile of the ChimeriVax(TM)-DEN2 vaccine is consistent with that of YF-VAX(R), and (2) preimmunity to YF virus does not interfere with ChimeriVax(TM)-DEN2 immunization, but induces a long lasting and cross neutralizing antibody response to all 4 DEN serotypes. The latter observation can have practical implications toward development of a dengue vaccine.