ChimeriVax-JE is a live, attenuated vaccine against Japanese encephalitis, using yellow fever (YF) 17D vaccine as a vector. In a double-blind phase 2 trial, 99 adults received vaccine, placebo, or YF 17D vaccine (YF-VAX). ChimeriVax-JE was well tolerated, with no differences in adverse events between treatment groups. Viremias resulting from administration of ChimeriVax-JE and YF-VAX were of short duration and low titer; 82 (94%) of 87 subjects administered graded doses (1.8-5.8 log(10)) of ChimeriVax-JE developed neutralizing antibodies. A second dose, administered 30 days later, had no booster effect. Previous inoculation with YF did not interfere with ChimeriVax-JE, but there was a suggestion (not statistically significant) that ChimeriVax-JE interfered with YF-VAX administered 30 days later. A separate study explored immunological memory both in subjects who had received ChimeriVax-JE 9 months before and in ChimeriVax-JE-naive subjects challenged with inactivated mouse-brain vaccine (JE-VAX). Anamnestic responses were observed in preimmune individuals. ChimeriVax-JE appears to be a safe vaccine that provides protective levels of neutralizing antibody after a single dose.

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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.

Salmonella enterica serovar Typhi strain CVD 908-htrA is a live attenuated strain which may be useful as an improved oral typhoid vaccine and as a vector for cloned genes of other pathogens. We conducted a phase 2 trial in which 80 healthy adults received one of two dosage levels of CVD 908-htrA in a double-blind, placebocontrolled, crossover study. There were no differences in the rates of side effects among volunteers who received high-dose vaccine (4.5 ؋ 10 8 CFU), lower-dose vaccine (5 ؋ 10 7 CFU), or placebo in the 21 days after vaccination, although recipients of high-dose vaccine (8%) had more frequent diarrhea than placebo recipients (0%) in the first 7 days. Seventy-seven percent and 46% of recipients of high-and lower-dose vaccines, respectively, briefly excreted vaccine organisms in their stools. All blood cultures were negative. Antibody-secreting cells producing antilipopolysaccharide (LPS) immunoglobulin A (IgA) were detected in 100 and 92% of recipients of high-and lower-dose vaccines, respectively. Almost half the volunteers developed serum anti-LPS IgG. Lymphocyte proliferation and gamma interferon production against serovar Typhi antigens occurred in a significant proportion of vaccinees. This phase 2 study supports the further development of CVD 908-htrA as a single-dose vaccine against typhoid fever and as a possible live vector for oral delivery of other vaccine antigens.Attenuated Salmonella enterica serovar Typhi oral vaccine Ty21a (7) and parenteral purified Vi polysaccharide vaccine (1, 13) have replaced parenteral killed whole-cell vaccine as the recommended prophylaxis against typhoid fever. However, both of these vaccines have disadvantages. The Vi vaccine is T-cell independent and so does not stimulate helper T cells that could enhance and broaden the immune response and elicit immunologic memory. Ty21a requires three or four doses for optimal immunogenicity.A single-dose, oral serovar Typhi vaccine strain is highly desirable. Moreover, such a strain would also be a promising vector for the delivery of heterologous cloned antigens (2,6,8,9,22,25). One strategy for attenuating salmonellae has been to introduce defined deletions into the genes encoding enzymes of the aromatic amino acid biosynthesis pathway, thereby rendering the bacteria auxotrophic for para-aminobenzoic acid (PABA) and dihydroxybenzoate (DHB) (10). These are substrates that the organism cannot scavenge in sufficient quantities in mammalian tissues to sustain growth. Such aro deletion mutants of S. enterica serovar Typhimurium are safe and immunogenic as live oral vaccines in mice and cattle (4,10,12,19). Analogous auxotrophic mutants of serovar Typhi have been prepared as typhoid vaccines and vaccine vectors for humans.In recent studies, vaccine strain CVD 908, a derivative of wild-type strain Ty2 harboring deletion mutations in aroC and in aroD, has been evaluated with adult volunteers. CVD 908 was well tolerated and highly immunogenic when given to volunteers in phase 1 studies after having been freshly harvested f...

authors note that Fig. 5 did not include all vaccine study groups. The corrected figure and legend appear below. This error does not affect the conclusions of the article. Confidence intervals for Spearman's rank correlation of log 10 IFN-␥ producing PBMC per million and log10 stimulation index were based on Fisher's transformation. On day 14, the correlation was 0.491 (95% CI, 0.231-0.686); on day 28, the correlation was 0.188 (95% CI: Ϫ0.112 to 0.456).