Recombinant Liver Stage Antigen-1 (LSA-1) formulated with AS01 or AS02 is safe, elicits high titer antibody and induces IFN-gamma/IL-2 CD4+ T cells but does not protect against experimental Plasmodium falciparum infection.

Plasmodium falciparum Liver Stage Antigen 1 (LSA-1) is a pre-erythrocytic stage antigen. Our LSA-1 vaccine candidate is a recombinant protein with full-length C- and N-terminal flanking domains and two of the 17 amino acid repeats from the central repeat region termed "LSA-NRC." We describe the first Phase I/II study of this recombinant LSA-NRC protein formulated with either the AS01 or AS02 adjuvant system. We conducted an open-label Phase I/II study. Thirty-six healthy malaria-naïve adults received one of four formulations by intra-deltoid injection on a 0 and 1 month schedule; low dose (LD) LSA-NRC/AS01:10microg LSA-NRC/0.5ml AS01 (n=5), high dose (HD) LSA-NRC/AS01: 50microg LSA-NRC/0.5ml AS01 (n=13); LD LSA-NRC/AS02: 10microg LSA-NRC/0.5ml AS02 (n=5) and HD LSA-NRC/AS02: 50microg LSA-NRC/0.5ml AS02 (n=13). Two weeks post-second immunization, the high dose vaccinees and 6 non-immunized infectivity controls underwent experimental malaria sporozoite challenge. The vaccines showed a reassuring safety profile but were moderately reactogenic. There were no serious adverse events. All subjects seroconverted after the first immunization. Following the second immunization, LSA-1-specific CD4+ T cells producing two cytokines (IL-2 and IFN-gamma) were found by intra-cellular staining in all subjects in the LD LSA-NRC/AS01B group and in 3 of 5 subjects in the LD LSA-NRC/AS02 group. In contrast, the HD LSA-NRC/AS01 and HD LSA-NRC/AS02 group subjects had fewer LSA-1-specific CD4+ T cells, and minimal to no IFN-gamma responses. There was no increase in LSA-1-specific CD8+ T cells found in any group. Per protocol, 22 high dose vaccinees, but no low dose vaccinees, underwent P. falciparum homologous malaria challenge (3D7 clone). All vaccinees became parasitemic and there was no delay in their pre-patent period versus controls (p=0.95). LSA-NRC/AS01 and LSA-NRC/AS02 elicited antigen-specific antibody and CD4+ T cell responses, but elicited no protective immunity. Although the optimal antigen dose of LSA-NRC may not have been selected for the challenge portion of the protocol, further vaccine development based upon LSA-1 should not be excluded and should include alternative vaccine platforms able to elicit additional effector mechanisms such as CD8+ T cells.

Cummings JF ，Spring MD ，Schwenk RJ ，Ockenhouse CF ，Kester KE ，Polhemus ME ，Walsh DS ，Yoon IK ，Prosperi C ，Juompan LY ，Lanar DE ，Krzych U ，Hall BT ，Ware LA ，Stewart VA ，Williams J ，Dowler M ，Nielsen RK ，Hillier CJ ，Giersing BK ，Dubovsky F ，Malkin E ，Tucker K ，Dubois MC ，Cohen JD ，Ballou WR ，Heppner DG Jr ... -  《-》

Phase I dose escalation safety and immunogenicity trial of Plasmodium falciparum apical membrane protein (AMA-1) FMP2.1, adjuvanted with AS02A, in malaria-naïve adults at the Walter Reed Army Institute of Research.

Polhemus ME ，Magill AJ ，Cummings JF ，Kester KE ，Ockenhouse CF ，Lanar DE ，Dutta S ，Barbosa A ，Soisson L ，Diggs CL ，Robinson SA ，Haynes JD ，Stewart VA ，Ware LA ，Brando C ，Krzych U ，Bowden RA ，Cohen JD ，Dubois MC ，Ofori-Anyinam O ，De-Kock E ，Ballou WR ，Heppner DG Jr ... -  《VACCINE》

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-naïve adults at the Walter Reed Army Institute of Research.

Kester KE ，Cummings JF ，Ockenhouse CF ，Nielsen R ，Hall BT ，Gordon DM ，Schwenk RJ ，Krzych U ，Holland CA ，Richmond G ，Dowler MG ，Williams J ，Wirtz RA ，Tornieporth N ，Vigneron L ，Delchambre M ，Demoitie MA ，Ballou WR ，Cohen J ，Heppner DG Jr ，RTS,S Malaria Vaccine Evaluation Group ... -  《VACCINE》

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.

In 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.

Kester KE ，Gray Heppner D Jr ，Moris P ，Ofori-Anyinam O ，Krzych U ，Tornieporth N ，McKinney D ，Delchambre M ，Ockenhouse CF ，Voss G ，Holland C ，Beckey JP ，Ballou WR ，Cohen J ，RTS,S/TRAP Group ... -  《-》

Evaluation of a prime-boost vaccine schedule with distinct adenovirus vectors against malaria in rhesus monkeys.

Rodríguez A ，Mintardjo R ，Tax D ，Gillissen G ，Custers J ，Pau MG ，Klap J ，Santra S ，Balachandran H ，Letvin NL ，Goudsmit J ，Radosević K ... -  《-》