A phase IIa, randomized, double-blind, safety, immunogenicity and efficacy trial of Plasmodium falciparum vaccine antigens merozoite surface protein 1 and RTS,S formulated with AS02 adjuvant in healthy, malaria-naïve adults.

BACKGROUND: To improve the efficacy of Plasmodium falciparum malaria vaccine RTS,S/AS02, we conducted a study in 2001 in healthy, malaria-naïve adults administered RTS,S/AS02 in combination with FMP1, a recombinant merozoite surface-protein-1, C-terminal 42kD fragment. METHODS: A double-blind Phase I/IIa study randomized N = 60 subjects 1:1:1:1 to one of four groups, N = 15/group, to evaluate safety, immunogenicity, and efficacy of intra-deltoid half-doses of RTS,S/AS02 and FMP1/AS02 administered in the contralateral (RTS,S + FMP1-separate) or same (RTS,S + FMP1-same) sites, or FMP1/AS02 alone (FMP1-alone), or RTS,S/AS02 alone (RTS,S-alone) on a 0-, 1-, 3-month schedule. Subjects receiving three doses of vaccine and non-immunized controls (N = 11) were infected with homologous P. falciparum 3D7 sporozoites by Controlled Human Malaria Infection (CHMI). RESULTS: Subjects in all vaccination groups experienced mostly mild or moderate local and general adverse events that resolved within eight days. Anti-circumsporozoite antibody levels were lower when FMP1 and RTS,S were co-administered at the same site (35.0 µg/mL: 95 % CI 20.3-63), versus separate arms (57.4 µg/mL: 95 % CI 32.3-102) or RTS,S alone (62.0 µg/mL: 95 % CI: 37.8-101.8). RTS,S-specific lymphoproliferative responses and ex vivo ELISpot CSP-specific interferon-gamma (IFN-γ) responses were indistinguishable among groups receiving RTS,S/AS02. There was no difference in antibody to FMP1 among groups receiving FMP1/AS02. After CHMI, groups immunized with a RTS,S-containing regimen had âˆ¼ 30 % sterile protection against parasitemia, and equivalent delays in time-to-parasitemia. The FMP1/AS02 alone group showed no sterile immunity or delay in parasitemia. CONCLUSION: Co-administration of RTS,S and FMP1/AS02 reduced anti-RTS,S antibody, but did not affect tolerability, cellular immunity, or efficacy in a stringent CHMI model. Absence of efficacy or delay of patency in the sporozoite challenge model in the FMP1/AS02 group did not rule out efficacy of FMP1/AS02 in an endemic population. However, a Phase IIb trial of FMP1/AS02 in children in malaria-endemic Kenya did not demonstrate efficacy against natural infection. CLINICALTRIALS: gov identifier: NCT01556945.

Protective immunity in baboons vaccinated with a recombinant antigen or radiation-attenuated cercariae of Schistosoma mansoni is antibody-dependent.

Mice vaccinated with radiation-attenuated cercariae of Schistosoma mansoni exhibit high levels of resistance to challenge infection. We have previously shown that sera from these mice recognize polypeptides that are expressed on the surface of newly transformed schistosomula. We have cloned and sequenced a cDNA that encodes a 62-kDa portion of one of these polypeptides. Vaccination of mice with this 62-kDa polypeptide (designated rlrV-5) elicits high antibody titers and significant resistance to challenge infection. We report here the results of a vaccination trial in baboons with the rlrV-5 or radiation-attenuated cercariae. rlrV-5 was presented either in the form of protein micelles or complexed with the outer membrane protein of meningococcus to form proteosomes. The level of protection achieved in these groups ranged from 0 to 54%, with a mean of 27.7%. In baboons exposed to radiation-attenuated cercariae the level of protection was very high, with a mean of 84%. The resistance observed after vaccination with rlrV-5 or radiation-attenuated cercariae was reflected in the overall histopathology. Vaccination of baboons with rlrV-5 or radiation-attenuated cercariae elicited an antibody response against epitopes exposed on the surface of newly transformed schistosomula. In the case of baboons vaccinated with radiation-attenuated cercariae, this response was not limited to epitopes encompassed by rlrV-5. Analysis of individual baboon sera by ELISA demonstrated that there was a direct correlation between the anti-rlrV-5 titer and resistance to challenge worm burden, suggesting that the immunoprotective mechanism is antibody-dependent.