Human immunodeficiency virus cell entry: New insights into the fusion mechanism

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Phase 2a Trial of 0, 1, and 3 Month and 0, 7, and 28 Day Immunization Schedules of Malaria Vaccine RTS,S/AS02 in Malaria-Naive Adults at the Walter Reed Army Institute of Research

Background: Immunization with RTS,S/AS02 consistently protects some vaccinees against malaria infection in experimental challenges and in field trials. A brief immunization schedule against falciparum malaria would be compatible with the Expanded Programme on Immunization, or in combination with other prevention measures, interrupt epidemic malaria or protect individuals upon sudden travel to an endemic area. Methods: We conducted an open label, Phase 2a trial of two different full dose schedules of RTS,S/AS02 in 40 healthy malaria-naıve adults. Cohort 1 (n = 20) was immunized on a 0, 1, and 3 month schedule and Cohort 2 (n = 20) on a 0, 7, and 28 day schedule. Three weeks later, 38 vaccinees and 12 unimmunized infectivity controls underwent malaria challenge. Results: Both regimens had a good safety and tolerability profile. Peak GMCs of antibody to the circumsporozoite protein (CSP) were similar in Cohort 1 (78 μg/mL; 95% CI: 45—134) and Cohort 2 (65 μg/mL; 95% CI: 40—104). Vaccine efficacy for Cohort 1 was 45% (95% CI: 18—62%) and for Cohort 2, 39% (95% CI: 11—56%). Protected volunteers had a higher GMC of anti-CSP antibody (114 μg/mL) than did volunteers with a 2-day delay (70 μg/mL) or no delay (30 μg/mL) in the time to onset of parasitemia (Kruskal—Wallis, p = 0.019). A trend was seen for higher CSP-specific IFN-γ responses in PBMC from protected volunteers only in Cohort 1, but not in Cohort 2, for ex vivo and for cultured ELISPOT assays. Conclusion: In malaria-naıve adults, the efficacy of three-dose RTS,S/AS02 regimens on either a 0, 1, and 3 month schedule or an abbreviated 0, 7, and 28 day schedule was not discernibly different from two previously reported trials of two-dose regimens given at 0, 1 month that conferred 47% (95% CI: −19 to 76%) protection and in another trial 42% (95% CI: 5—63%). A strong association of CSP-specific antibody with protection against malaria challenge is observed and confirms similar observations made in other studies. Subsequent trials of adjuvanted RTS,S in African children and infants on a 0, 1, and 2 month schedule have demonstrated a favorable safety and efficacy profile

Sequential Phase 1 and Phase 2 randomized, controlled trials of the safety, immunogenicity and efficacy of combined pre-erythrocytic vaccine antigens RTS,S and TRAP formulated with AS02 Adjuvant System in healthy, malaria naïve adults

AbstractIn an attempt to improve the efficacy of the candidate malaria vaccine RTS,S/AS02, two studies were conducted in 1999 in healthy volunteers of RTS,S/AS02 in combination with recombinant Plasmodium falciparum thrombospondin-related anonymous protein (TRAP). In a Phase 1 safety and immunogenicity study, volunteers were randomized to receive TRAP/AS02 (N=10), RTS,S/AS02 (N=10), or RTS,S+TRAP/AS02 (N=20) at 0, 1 and 6-months. In a Phase 2 challenge study, subjects were randomized to receive either RTS,S+TRAP/AS02 (N=25) or TRAP/AS02 (N=10) at 0 and 1-month, or to a challenge control group (N=8). In both studies, the combination vaccine had an acceptable safety profile and was acceptably tolerated. Antigen-specific antibodies, lymphoproliferative responses, and IFN-γ production by ELISPOT assay elicited with the combination vaccine were qualitatively similar to those generated by the single component vaccines. However, post-dose 2 anti-CS antibodies in the RTS,S+TRAP/AS02 vaccine recipients were lower than in the RTS,S/AS02 vaccine recipients. After challenge, 10 of 11 RTS,S+TRAP/AS02 vaccinees, 5 of 5 TRAP/AS02 vaccinees, and 8 of 8 infectivity controls developed parasitemia, with median pre-patent periods of 13.0, 11.0, and 12.0 days, respectively. The absence of any prevention or delay of parasitemia by TRAP/AS02 suggests no apparent added value of TRAP/AS02 as a candidate vaccine. The absence of significant protection or delay of parasitemia in the 11 RTS,S+TRAP/AS02 vaccine recipients contrasts with previous 2 dose studies of RTS,S/AS02. The small sample size did not permit identifying statistically significant differences between the study arms. However, we speculate, within the constraints of the challenge study, that the presence of the TRAP antigen may have interfered with the vaccine efficacy previously observed with this regimen of RTS,S/AS02, and that any future TRAP-based vaccines should consider employing alternative vaccine platforms