The Synthetic Plasmodium falciparum Circumsporozoite Peptide PfCS102 as a Malaria Vaccine Candidate: A Randomized Controlled Phase I Trial

Abstract

BackgroundFully efficient vaccines against malaria pre-erythrocytic stage are still lacking. The objective of this dose/adjuvant-finding study was to evaluate the safety, reactogenicity and immunogenicity of a vaccine candidate based on a peptide spanning the C-terminal region of Plasmodium falciparum circumsporozoite protein (PfCS102) in malaria naive adults.Methodology and Principal FindingsThirty-six healthy malaria-naive adults were randomly distributed into three dose blocks (10, 30 and 100 µg) and vaccinated with PfCS102 in combination with either Montanide ISA 720 or GSK proprietary Adjuvant System AS02A at days 0, 60, and 180. Primary end-point (safety and reactogenicity) was based on the frequency of adverse events (AE) and of abnormal biological safety tests; secondary-end point (immunogenicity) on P. falciparum specific cell-mediated immunity and antibody response before and after immunization. The two adjuvant formulations were well tolerated and their safety profile was good. Most AEs were local and, when systemic, involved mainly fatigue and headache. Half the volunteers in AS02A groups experienced severe AEs (mainly erythema). After the third injection, 34 of 35 volunteers developed anti-PfCS102 and anti-sporozoite antibodies, and 28 of 35 demonstrated T-cell proliferative responses and IFN-γ production. Five of 22 HLA-A2 and HLA-A3 volunteers displayed PfCS102 specific IFN-γ secreting CD8+ T cell responses. Responses were only marginally boosted after the 3rd vaccination and remained stable for 6 months. For both adjuvants, the dose of 10 µg was less immunogenic in comparison to 30 and 100 µg that induced similar responses. AS02A formulations with 30 µg or 100 µg PfCS102 induced about 10-folds higher antibody and IFN-γ responses than Montanide formulations.Conclusions/SignificancePfCS102 peptide was safe and highly immunogenic, allowing the design of more advanced trials to test its potential for protection. Two or three immunizations with a dose of 30 µg formulated with AS02A appeared the most appropriate choice for such studies.Trial RegistrationSwissmedic.ch 2002 DR 1227

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“…In contrast, there was no apparent effect of the CpG adjuvant dose. Consistent with these findings, several studies reported higher rates of antigenspecific T-cell responses when evaluating immunogenicity in high-dose vaccine settings (50)(51)(52). This was also shown in a large randomized placebo-controlled trial, in which higher responder rates (i.e., frequency, IFNγ secretion, and proliferation index) were recorded when using higher hepatitis C virus peptide vaccine doses or increasing numbers of vaccinations (53).…”

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“…29 Montanide ISA 720 has been used in Phase I clinical trials for malaria vaccines. [30][31][32] Montanide ISA 51 was also tested for use in a malaria vaccine, but the vaccine was quite reactogenic and the Phase I trial was halted, 33 although another malaria vaccine containing ISA 51 has been tested in nonhuman primates, and efforts are under way to begin clinical trials with this vaccine. 34 One major drawback, however, of using Montanides for large-scale vaccination is their high manufacturing cost.…”

Pre-Erythrocytic Vaccine Candidates in Malaria

“…Elevated ELIS" and IF" titers were seen with IS" 720 formulation as compared to alum. In a second clinical trial, PfCS102 formulated in IS" 720 or "S02" elicited IFN-γ secreting CD8+ T cells speciic to malaria in some individuals [120]. Tenfold higher antibody and cellular responses were obtained with the "S02 adjuvant formulation.…”