Safety and Immunogenicity of a Malaria Vaccine, Plasmodium falciparum AMA-1/MSP-1 Chimeric Protein Formulated in Montanide ISA 720 in Healthy Adults

Abstract

BackgroundThe P. falciparum chimeric protein 2.9 (PfCP-2.9) consisting of the sequences of MSP1-19 and AMA-1 (III) is a malaria vaccine candidate that was found to induce inhibitory antibodies in rabbits and monkeys. This was a phase I randomized, single-blind, placebo-controlled, dose-escalation study to evaluate the safety and immunogenicity of the PfCP-2.9 formulated with a novel adjuvant Montanide ISA720. Fifty-two subjects were randomly assigned to 4 dose groups of 10 participants, each receiving the test vaccine of 20, 50, 100, or 200 µg respectively, and 1 placebo group of 12 participants receiving the adjuvant only.Methods and FindingsThe vaccine formulation was shown to be safe and well-tolerated, and none of the participants withdrew. The total incidence of local adverse events (AEs) was 75%, distributed among 58% of the placebo group and 80% of those vaccinated. Among the vaccinated, 65% had events that were mild and 15% experienced moderate AEs. Almost all systemic adverse reactions observed in this study were graded as mild and required no therapy. The participants receiving the test vaccine developed detectable antibody responses which were boosted by the repeated vaccinations. Sixty percent of the vaccinated participants had high ELISA titers (>1∶10,000) of antigen-specific antibodies which could also recognize native parasite proteins in an immunofluorescence assay (IFA).ConclusionThis study is the first clinical trial for this candidate and builds on previous investigations supporting PfCP-2.9/ISA720 as a promising blood-stage malaria vaccine. Results demonstrate safety, tolerability (particularly at the lower doses tested) and immunogenicity of the formulation. Further clinical development is ongoing to explore optimizing the dose and schedule of the formulation to decrease reactogenicity without compromising immunogenicity.Trial RegistrationChinese State Food and Drug Administration (SFDA) 2002SL0046; Controlled-Trials.com ISRCTN66850051 [66850051]

Anti-Apical-Membrane-Antigen-1 Antibody Is More Effective than Anti-42-Kilodalton-Merozoite-Surface-Protein-1 Antibody in Inhibiting Plasmodium falciparum Growth, as Determined by the In Vitro Growth Inhibition Assay

“…However, while it is unknown whether growthinhibitory activity in vitro can be a marker of clinical protection induced by a blood-stage vaccine, the GIA is one of only a few assays to measure functional activity of anti-AMA1/MSP1 antibodies against parasites at this time. Indeed, to demonstrate biologic activity of induced antibodies, the GIA has been used not only for preclinical development but also for clinical phase 1 trials of AMA1-and/or MSP1-based vaccines (6,12,15,16,22,23,24,26).…”

Toward the Rational Design of a Malaria Vaccine Construct Using the MSP3 Family as an Example: Contribution of Antigenicity Studies in Humans

“…Indeed, they pave the way toward the rational design of a multisubunit vaccine construct based on a family of proteins with both homologous and divergent sequences that are highly conserved. This combination strategy differs from constructs combining different polymorphic antigens (13,17,19,23,24,27,38). The C-terminal sequences being conserved, a polyantigenic MSP3 vaccine avoids antigen polymorphism, a recognized bottleneck for vaccine development (18,22,26,37).…”

Phase I Safety and Immunogenicity Trial of Plasmodium vivax CS Derived Long Synthetic Peptides Adjuvanted with Montanide ISA 720 or Montanide ISA 51

“…33 Several phase I clinical trials have been conducted using different malaria vaccine antigens in which these two adjuvants have been able to stimulate both humoral and cellular immune responses. [34][35][36][37] We present here a phase I clinical trial conducted with the same P. vivax CS derived peptides formulated in two different adjuvants, and provide further safety and immunogenicity data as part of a clinical development plan that aims at developing vaccines to prevent malaria.…”