Stanford BIOC 230 - A Malaria vaccine that elicits in Human Antibodies

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A Malaria Vaccine That Elicits in HumansAntibodies Able to Kill PlasmodiumfalciparumPierre Druilhe1*, Franc¸ois Spertini2, Daw Soesoe1, Giampietro Corradin3, Pedro Mejia1, Subhash Singh1,Regine Audran2, Ahmed Bouzidi4, Claude Oeuvray1, Christian Roussilhon11 Biomedical Parasitology Unit, Pasteur Institute, Paris, France, 2 Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland,3 Institute of Biochemistry, University of Lausanne, Epalinges, Switzerland, 4 Sedac Therapeutics, Lille, FranceCompeting Interests: PD, DS, PM,SS, CO, and CR are affiliated withthe Pasteur Institute, which holds apatent on merozoite surfaceprotein 3.Author Contributions: PD designedthe study. DS, GC, PM, SS, and RAperformed the biologicalexperiments. PD, SS, RA, and CRanalyzed the data. FS organized theclinical trial. AB and CO producedthe vaccine. PD wrote the paper.Academic Editor: Brian Greenwood,University of London, UnitedKingdomCitation: Druilhe P, Spertini F,Soesoe D, Corradin G, Mejia P, et al.(2005) A malaria vaccine that elicitsin humans antibodies able to killPlasmodium falciparum. PLoS Med2(11): e344.Received: January 6, 2005Accepted: August 18, 2005Published: November 8, 2005DOI:10.1371/journal.pmed.0020344Copyright: Ó 2005 Druilhe et al. Thisis an open-access article distributedunder the terms of the CreativeCommons Attribution License, whichpermits unrestricted use,distribution, and reproduction in anymedium, provided the originalauthor and source are credited.Abbreviations: ADCI, antibody-dependent cellular inhibition; AI,affinity index; IFN-c, interferon-gamma; IP, intraperitoneally; LSP,long synthetic peptide; MSP3,merozoite surface protein 3; SGI,specific growth inhibition; SD,standard deviation; Th, T helper cell;WB, Western blot*To whom correspondence shouldbe addressed. E-mail: [email protected] falciparum merozoite surface protein 3 is a malaria vaccine candidate that wasidentified, characterised, and developed based on a unique immuno-clinical approach. Thevaccine construct was derived from regions fully conserved among various strains andcontaining B cell epitopes targeted by human antibodies (from malaria-immune adults) that areable to mediate a monocyte-dependent parasite killing effect. The corresponding longsynthetic peptide was administered to 36 volunteers, with either alum or Montanide ISA720 asadjuvant.Methods and FindingsBoth formulations induced cellular and humoral immune responses. With alum, theresponses lasted up to 12 mo. The vaccine-induced antibodies were predominantly ofcytophilic classes, i.e., able to cooperate with effector cells. In vitro, the antibodies induced aninhibition of the P. falciparum erythrocytic growth in a monocyte-dependent manner, whichwas in most instances as high as or greater than that induced by natural antibodies fromimmune African adults. In vivo transfer of the volunteers’ sera into P. falciparum–infectedhumanized SCID mice profoundly reduced or abrogated parasitaemia. These inhibitory effectswere 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 byvaccine-induced antibodies by both in vitro and in vivo methods. The results, showing theinduction of long-lasting antibodies directed to a fully conserved polypeptide, also challengecurrent concepts about malaria vaccines, such as unavoidable polymorphism, low antigenicity,and poor induction of immune memory.PLoS Medicine | www.plosmedicine.org November 2005 | Volume 2 | Issue 11 | e3440001Open access, freely available onlinePLoSMEDICINEIntroductionThe development of a malaria vaccine holds considerablepromise, but has been limited by major conceptual andpractical difficulties [1]. In view of the imprecise relevance ofanimal models [2], we have chosen a path where all criticalobservations leading to go/no-go decisions in the develop-ment process were based, as much as possible, on observa-tions made in Plasmodium falciparum–infected individuals[3].Merozoite surface protein 3 (MSP3) is an antigen identifiedby a novel approach in which the protection, which could bepassively transferred by IgG from protected African adultsinto naı¨ve, infected individuals [4], was used to identify amechanism of defence [5,6]. The latter, called antibody-dependent cellular inhibition (ADCI), was used to screen a P.falciparum genomic expression library and, eventually, toidentify MSP3 as the target of protective antibodies inhumans [7]. This is not the way most other vaccine candidateshave been selected [1].The decision to move from preclinical investigations intoclinical trials with an MSP3-based vaccine resulted fromconvergent data from a series of studies that strengthened theassociation between protection and antibodies directed tothis particular antigen, namely, (a) that anti-MSP3 antibodies,either naturally occurring or elicited by immunisation, couldachieve parasite killing in the presence of normal monocytes,either in vitro [7,8] or (b) in vivo by passive transfer in P.falciparum–infected immunocompromised mice [8,9]; (c) sim-ilar results were obtained with a human recombinant anti-MSP3 monoclonal antibody (M. Dziegiel and PD, unpublisheddata); (d) IgG3 anti-MSP3 antibodies were associated withprotection in the two African villages of Dielmo and Ndiop[8,10], and in the village of Oo-do in Asia [11]; (e) IgG3 anti-MSP3 antibodies were associated with an improved prognosisof drug-treated cerebral malaria [10]; and (f) strong protec-tion was induced by MSP3 in Cebidae monkeys against a P.falciparum challenge [12]. Additional arguments were that (g)the C terminus of the antigen containing the epitopestargeted by ADCI is fully conserved [13,14]; and (h) all proteicand peptidic formulations tested were immunogenic, andparticularly a synthetic polypeptide covering three B cellepitopes targeted by protective antibodies (CO, et al.,unpublished data) [8].We therefore decided to initiate a phase-I clinical trialaimed at assessing safety and immunogenicity, using apreparation of the long synthetic peptide (LSP) formulationderived from the conserved region of MSP3 (MSP3-LSP)produced under Good Manufacturing Practices. The con-struct included three B cell epitopes and four T-cell epitopes,identified in lymphocytes


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Stanford BIOC 230 - A Malaria vaccine that elicits in Human Antibodies

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