Phase I/IIa safety, immunogenicity, and efficacy trial of NYVAC-Pf7, a pox-vectored, multiantigen, multistage vaccine candidate for Plasmodium falciparum malaria.

Candidate malaria vaccines have failed to elicit consistently protective immune responses against challenge with Plasmodium falciparum. NYVAC-Pf7, a highly attenuated vaccinia virus with 7 P. falciparum genes inserted into its genome, was tested in a phase I/IIa safety, immunogenicity, and efficacy vaccine trial in human volunteers. Malaria genes inserted into the NYVAC genome encoded proteins from all stages of the parasite's life cycle. Volunteers received three immunizations of two different dosages of NYVAC-Pf7. The vaccine was safe and well tolerated but variably immunogenic. While antibody responses were generally poor, cellular immune responses were detected in >90% of the volunteers. Of the 35 volunteers challenged with the bite of 5 P. falciparum-infected Anopheles mosquitoes, 1 was completely protected, and there was a significant delay in time to parasite patency in the groups of volunteers who received either the low or high dose of vaccine compared with control volunteers.

NYVAC-Pf7: a poxvirus-vectored, multiantigen, multistage vaccine candidate for Plasmodium falciparum malaria.

The highly attenuated NYVAC vaccinia virus strain has been utilized to develop a multiantigen, multistage vaccine candidate for malaria, a disease that remains a serious global health problem and for which no highly effective vaccine exists. Genes encoding seven Plasmodium falciparum antigens derived from the sporozoite (circumsporozoite protein and sporozoite surface protein 2), liver (liver stage antigen 1), blood (merozoite surface protein 1, serine repeat antigen, and apical membrane antigen 1), and sexual (25-kDa sexual-stage antigen) stages of the parasite life cycle were inserted into a single NYVAC genome to generate NYVAC-Pf7. Each of the seven antigens was expressed in NYVAC-Pf7-infected culture cells, and the genotypic and phenotypic stability of the recombinant virus was demonstrated. When inoculated into rhesus monkeys, NYVAC-Pf7 was safe and well tolerated. Antibodies that recognize sporozoites, liver, blood, and sexual stages of P. falciparum were elicited. Specific antibody responses against four of the P.falciparum antigens (circumsporozoite protein, sporozoite surface protein 2, merozoite surface protein 1, and 25-kDa sexual-stage antigen) were characterized. The results demonstrate that NYVAC-Pf7 is an appropriate candidate vaccine for further evaluation in human clinical trials.

Decreased counts of blood neutrophils, monocytes, and platelets in human immunodeficiency virus-infected children and young adults treated with diethyldithiocarbamate.

Nineteen young human immunodeficiency virus-infected patients were randomized to receive 400 mg of oral diethyldithiocarbamate (DTC) per m2 or placebo weekly for 12 weeks. Changes in blood CD4+ lymphocytes were not significantly different between groups. However, neutrophil, monocyte, and platelet counts consistently decreased during DTC treatment, suggesting DTC-mediated myelosuppression.

Immunogenicity of Haemophilus influenzae type b polysaccharide-tetanus toxoid conjugate vaccine in infants.

OBJECTIVE: To compare the safety and immunogenicity of three investigational lots of Haemophilus influenzae type b polysaccharide-tetanus toxoid (PRP-T) conjugate vaccine in infants. DESIGN: A multicenter, randomized immunogenicity trial. Infants were vaccinated at 2, 4, and 6 months of age with one of three lots of PRP-T. A control group received H influenzae type b oligomers conjugated to CRM197 (HbOC). Serum was obtained before each injection and 1 month after the third dose, and assayed blindly for antibody in one laboratory. SUBJECTS: Four hundred eighty-four infants from private pediatric practices located in five geographic areas. MEASUREMENTS AND RESULTS: There were no significant differences in the number of adverse events reported for infants receiving PRP-T or HbOC, and the rates did not exceed those observed previously in infants given diphtheria-tetanus-pertussis vaccine alone. Total serum anti-PRP antibody responses were analyzed in 336 infants who met strict inclusion criteria. After one, two, or three doses, the respective antibody responses to each of the three lots of PRP-T and to HbOC vaccine were similar. The only exception was one lot of PRP-T, which after one or two injections elicited significantly higher geometric mean antibody responses than the other two lots or the HbOC vaccine. After a third injection, there were no significant lot differences. Combining the data from the different lots, there were no significant differences in the geometric mean antibody concentration after three doses of PRP-T or HbOC (8.3 vs 7.7 micrograms/mL), and 95% and 91%, respectively, of infants had greater than 1.0 microgram/mL of antibody. There were no significant differences in the magnitudes of the respective IgG1-, IgG2-, and IgM-specific antibody concentrations between infants given PRP-T or HbOC. CONCLUSIONS: The three investigational lots of PRP-T tested were safe and were as immunogenic as or more so than the licensed HbOC conjugate vaccine.