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™-DEN2) in comparison to that of YF vaccine (YF-VAX ® ). Forty-two healthy YF naïve adults randomly received a single dose of either ChimeriVax™-DEN2 (high dose, 5 log plaque forming units [PFU] or low dose, 3 log PFU) or YF-VAX ® 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™-DEN2 as an open-label vaccine. Most adverse events were similar to YF-VAX ® and of mild to moderate intensity, with no serious side-effects. One hundred percent and 92.3% of YF naïve subjects inoculated with 5.0 and 3.0 log 10 PFU of ChimeriVax TM -DEN2, respectively, seroconverted to wt DEN2 (strain 16681); 92% of subjects inoculated with YF-VAX ® seroconverted to YF 17D virus but none of YF naïve 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 naïve subjects inoculated with either ChimeriVax™-DEN2 or YF-VAX ® . In contrast, 100% of YF immune subjects inoculated with ChimeriVax™-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™-DEN2 vaccine is consistent with that of YF-VAX ® , 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.

This study represents the first phase III trial of the safety, tolerability, and effectiveness of tafenoquine for malaria prophylaxis. In a randomized (3:1), double-blinded study, Australian soldiers received weekly malaria prophylaxis with 200 mg tafenoquine (492 subjects) or 250 mg mefloquine (162 subjects) for 6 months on a peacekeeping deployment to East Timor. After returning to Australia, tafenoquine-receiving subjects received a placebo and mefloquine-receiving subjects received 30 mg primaquine daily for 14 days. There were no clinically significant differences between hematological and biochemical parameters of the treatment groups. Treatment-related adverse events for the two groups were similar (tafenoquine, 13.4%; mefloquine, 11.7%). Three subjects on tafenoquine (0.6%) and none on mefloquine discontinued prophylaxis because of possible drug-related adverse events. No diagnoses of malaria occurred for either group during deployment, but 4 cases (0.9%) and 1 case (0.7%) of Plasmodium vivax infection occurred among the tafenoquine and mefloquine groups, respectively, up to 20 weeks after discontinuation of medication. In a subset of subjects recruited for detailed safety assessments, treatment-related mild vortex keratopathy was detected in 93% (69 of 74) of tafenoquine subjects but none of the 21 mefloquine subjects. The vortex keratopathy was not associated with any effect on visual acuity and was fully resolved in all subjects by 1 year. Tafenoquine appears to be safe and well tolerated as malaria prophylaxis. Although the volunteers' precise exposure to malaria could not be proven in this study, tafenoquine appears to be a highly efficacious drug for malaria prophylaxis.

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We conducted a randomized, double-blind, phase III yellow fever (YF) vaccine trial among 1,107 healthy children in Sullana in northern Peru. The safety and efficacy (by measurement of geometric mean neutralizing antibody titer responses) were determined for two YF vaccines, ARILVAX (n = 738) and YF-VAX(R) (n = 369). Serocon-version rates were higher (94.9%) in ARILVAX than in YF-VAX (90.6%) recipients. The two-sided 95% confidence interval (YF-VAX-ARILVAX) was (-12.8% to -2.5%), indicating that the higher seroconversion rate for Arilvax was significant. Post-vaccination (30-day) mean log(10) neutralization indices were found to be similar for both products: 1.32 for ARILVAX and 1.26 for YF-VAX (P = 0.1404, by analysis of variance). A similar number of subjects in each group reported at least one adverse event (AE); 441 (59.8%) for ARILVAX versus 211 (59.9%) for YF-VAX. Most (591; 96.7%) of these were of a mild nature and resolved without treatment. There were no treatment-related serious AEs. This is the first randomized, double-blind comparison of two YF vaccines in a pediatric population; both vaccines were shown to be highly immunogenic and well-tolerated.