A Malaria Vaccine That Elicits in Humans Antibodies Able to Kill Plasmodium falciparum

Abstract

Background Plasmodium falciparum merozoite surface protein 3 is a malaria vaccine candidate that was identified, characterised, and developed based on a unique immuno-clinical approach. The vaccine construct was derived from regions fully conserved among various strains and containing B cell epitopes targeted by human antibodies (from malaria-immune adults) that are able to mediate a monocyte-dependent parasite killing effect. The corresponding long synthetic peptide was administered to 36 volunteers, with either alum or Montanide ISA720 as adjuvant.Methods and FindingsBoth formulations induced cellular and humoral immune responses. With alum, the responses lasted up to 12 mo. The vaccine-induced antibodies were predominantly of cytophilic classes, i.e., able to cooperate with effector cells. In vitro, the antibodies induced an inhibition of the P. falciparum erythrocytic growth in a monocyte-dependent manner, which was in most instances as high as or greater than that induced by natural antibodies from immune African adults. In vivo transfer of the volunteers' sera into P. falciparum–infected humanized SCID mice profoundly reduced or abrogated parasitaemia. These inhibitory effects were related to the antibody reactivity with the parasite native protein, which was seen in 60% of the volunteers, and remained in samples taken 12 mo postimmunisation.ConclusionThis is the first malaria vaccine clinical trial to clearly demonstrate antiparasitic activity by vaccine-induced antibodies by both in vitro and in vivo methods. The results, showing the induction of long-lasting antibodies directed to a fully conserved polypeptide, also challenge current concepts about malaria vaccines, such as unavoidable polymorphism, low antigenicity, and poor induction of immune memory.

A Novel Antibody-Dependent Cellular Cytotoxicity Mechanism Involved in Defense against Malaria Requires Costimulation of Monocytes FcγRII and FcγRIII

“…Moreover, IgG1 may also down-regulate MN activation by triggering the regulatory Fc␥RIIb (51). Though IgG3 is clearly more potent, IgG1 still plays a substantial role in ADCI as shown by our results and by the effect in ADCI of Abs induced in human volunteers by the MSP-3 vaccine, which were mostly of IgG1 subclass (14). Finally, IgG1 is also far more stable and has a longer half-life than IgG3.…”

“…As ADCI is an indirect mechanism of defense, we have argued that there is no direct immune pressure generating antigenic polymorphism (52). Conserved antigenic determinants offer substantial advantages for vaccine development and this is indeed the case for the MSP-3-LSP vaccine candidate recently undergoing clinical trials (14,58). Investigations into genomic and proteomic data for molecules released by erythrocytic schizonts, presenting conserved regions, and targeted by cytophilic human Abs, shall lead to the discovery of novel vaccine candidates that have not been searched for, up to now.…”

“…We identified by this means merozoite surface protein-3 (MSP-3) (11) and subsequently the involvement of glutamate-rich protein (GLURP) and serine repeat protein (SERP) in this mechanism (12,13); all three are now undergoing vaccine trials (14).…”

The Impact of Immune Responses on the Asexual Erythrocytic Stages of Plasmodium and the Implication for Vaccine Development

“…MSP-3 specific antibodies found in sera from malaria-endemic areas are associated with protective immunity (Soe et al, 2004). MSP-3 based vaccines have been designed as long peptides representing the conserved C-terminus of the antigen (Druilhe et al, 2005;Sirima et al, 2007). Anti-parasite activity of MSP-3 specific antibodies was not evident unless monocytic cells were used in the assay (ADCI).…”

Synthetic Peptide Vaccines

“…These peptide immunogens were highly conservative for all plasmodium isolates; they induced formation of cytophilic antibodies of IgG1 and IgG3 subclasses; via opsonizing shizonts they attracted monocytes that caused shizont lysis (Theisen et al, 2001;Soe et al, 2004). Phase I clinical trials (Druilhe et al, 2005;Sirima et al, 2009) demonstrated formation of long (at least 1 year) immune response to these vaccines. At the moment Phase IIb clinical trial of the MSP3-LSP vaccine continues (http://www.amanet-trust.org/ext/reports /newsletters/issue23June08.pdf).…”