Vaccination of Monkeys with RecombinantPlasmodium falciparumApical Membrane Antigen 1 Confers Protection against Blood-Stage Malaria

Abstract

A major challenge facing malaria vaccine development programs is identifying efficacious combinations of antigens. To date, merozoite surface protein 1 (MSP1) is regarded as the leading asexual vaccine candidate. Apical membrane antigen 1 (AMA1) has been identified as another leading candidate for an asexual malaria vaccine, but without any direct in vivo evidence that a recombinant form of Plasmodium falciparum AMA1 would have efficacy. We evaluated the efficacy of a form of P. falciparum AMA1, produced in Pichia pastoris, by vaccinating Aotus vociferans monkeys and then challenging them with P. falciparum parasites. Significant protection from this otherwise lethal challenge with P. falciparum was observed. Five of six animals had delayed patency; two of these remained subpatent for the course of the infection, and two controlled parasite growth at <0.75% of red blood cells parasitized. The protection induced by AMA1 was superior to that obtained with a form of MSP1 used in the same trial. The protection induced by a combination vaccine of AMA1 and MSP1 was not superior to the protection obtained with AMA1 alone, although the immunity generated appeared to operate against both vaccine components.Many malaria vaccine strategies, including our own, depend on including multiple asexual antigens in order (i) to improve coverage of polymorphisms in field isolates, (ii) to overcome individual nonresponsiveness to some antigens, (iii) to improve vaccine efficacy by eliciting immunity to multiple targets, and (iv) to prevent or delay the evolution of escape mutants. If we include two different antigens in a vaccine combination, ideally, synergy in protection will be induced.The most extensive experience in vaccine trials with New World monkeys has been obtained with the C-terminal 42-kDa portion of merozoite surface protein 1 (MSP1 42 ) (3,10,17,18). Recombinant forms of MSP1 42 have been efficacious against homologous parasite challenges, and MSP1 42 is regarded as a leading asexual vaccine candidate.We have now produced a second antigen, Plasmodium falciparum apical membrane antigen 1 (AMA1) (see reference 13a), and in the present study we test the efficacy of this antigen, both alone and in combination with MSP1 42 , in a vaccine trial with Aotus vociferans monkeys.AMA1 is the subject of intensive vaccine research; at least six of the major malaria vaccine research centers have AMA1 programs. This is based on protection against rodent malaria (Plasmodium chabaudi [1,2,6,20] and Plasmodium yoelii [16]) and nonhuman primate malarias (Plasmodium knowlesi [7] and Plasmodium fragile [5]) by use of purified parasite and recombinant antigens and on the generation in rabbits of an in vitro growth-inhibitory antiserum to an Escherichia coli-expressed recombinant P. falciparum AMA1 (12).However, no evidence exists that vaccine-elicited immunity to a recombinant form of P. falciparum AMA1 will be effective against a P. falciparum challenge in vivo, and establishing this prior to human trials is seen by us as essential, especi...

Towards an RTS,S-based, multi-stage, multi-antigen vaccine against falciparum malaria: progress at the Walter Reed Army Institute of Research

“…AMA-1, like MSP-1, is the target of protective immunity, as supported by epidemiological observations [58], in vitro demonstrations [55], and by protection studies in which mice [59] or monkeys [60] immunized with recombinant forms of AMA-1 were protected from lethal challenge with homologous parasites. Scientists at the WRAIR have produced a correctly folded GMP recombinant protein in E. coli based upon the P. falciparum 3D7 strain AMA-1 ectodomain [61].…”

Phase I dose escalation safety and immunogenicity trial of Plasmodium falciparum apical membrane protein (AMA-1) FMP2.1, adjuvanted with AS02A, in malaria-naïve adults at the Walter Reed Army Institute of Research

“…Naturally acquired antibody to PfAMA-1 in endemic populations is associated with protection from falciparum malaria [10,11]. Immunization of New World monkeys with recombinant PfAMA-1 formulated with Freund's adjuvant has conferred significant protection against homologous P. falciparum challenge [12,13], but limited protection when formulated with adjuvants intended for human use such as Montanide or AS02A [Barnwell, unpublished]. Several PfAMA-1 vaccines are in development, but none have been tested for clinical efficacy [14][15][16][17][18][19][20].…”

Conditional Expression ofToxoplasma gondiiApical Membrane Antigen-1 (TgAMA1) Demonstrates That TgAMA1 Plays a Critical Role in Host Cell Invasion

“…Since its initial discovery Ͼ15 years ago, AMA1 has received considerable attention as a malaria vaccine candidate (Deans et al, 1988;Collins et al, 1994;Anders et al, 1998;Kennedy et al, 2002;Stowers et al, 2002). AMA1 proteins are type I transmembrane proteins, with a short C-terminal cytoplasmic tail and a large N-terminal extracellular domain (ectodomain) containing 12-16 conserved cysteine residues (Waters et al, 1990;Hodder et al, 1996;Donahue et al, 2000;Hehl et al, 2000;Gaffar et al, 2004).…”