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

Abstract

The goal of the Malaria Vaccine Program at the Walter Reed Army Institute of Research (WRAIR) is to develop a licensed multi-antigen, multi-stage vaccine against Plasmodium falciparum able to prevent all symptomatic manifestations of malaria by preventing parasitemia. A secondary goal is to limit disease in vaccinees that do develop malaria. Malaria prevention will be achieved by inducing humoral and cellular immunity against the pre-erythrocytic circumsporozoite protein (CSP) and the liver stage antigen-1 (LSA-1). The strategy to limit disease will target immune responses against one or more blood stage antigens, merozoite surface protein-1 (MSP-1) and apical merozoite antigen-1 (AMA-1). The induction of T-and B-cell memory to achieve a sustained vaccine response may additionally require immunization with an adenovirus vector such as adenovirus serotype 35. RTS,S, a CSP-derived antigen developed by GlaxoSmithKline Biologicals in collaboration with the Walter Reed Army Institute of Research over the past 17 years, is the cornerstone of our program. RTS,S formulated in AS02A (a GSK proprietary formulation) is the only vaccine candidate shown in field trials to prevent malaria and, in one instance, to limit disease severity. Our vaccine development plan requires proof of an individual antigen's efficacy in a Phase 2 laboratory challenge or field trial prior to its integration into an RTS,S-based, multi-antigen vaccine. Progress has been accelerated through extensive partnerships with industrial, D.G. Heppner Jr. et al. / Vaccine 23 (2005) [2243][2244][2245][2246][2247][2248][2249][2250] academic, governmental, and non-governmental organizations. Recent safety, immunogenicity, and efficacy trials in the US and Africa are presented, as well as plans for the development of a multi-antigen vaccine.

Evaluation of Immunoglobulin G Responses to Plasmodium falciparum and Plasmodium vivax in Malian School Children Using Multiplex Bead Assay

“…The external domain of AMA-1 and MSP-1 42 antigens were produced at Walter Reed Army Institute of Research under previously published conditions. 16 To couple antigens to polystyrene beads, the 1-ethyl-3-(3-dimethylaminopropyl) (Calbiochem, Woburn, MA) carbodiimide method was used to convert carboxyl groups on the surface of specifically classified spectral magnetic polystyrene microspheres (MagPlex Beads; Luminex Corporation, Austin, TX) to reactive esters. The esters readily react with available primary amino groups on the antigens to form covalent amide bonds between antigen and microspheres.…”

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

“…One strategy to augment the partial protective efficacy of the RTS,S/AS02A vaccine is to combine it with one or more antigens independently proven to limit or prevent parasitemia such as FMP2.1 [31]. Accordingly, we conducted the present Phase 1 dose-escalation trial at the WRAIR Clinical Trials Center in malaria-naïve adults to establish a preliminary safety and immunogenicity profile before proceeding to clinical trials of FMP2.1/AS02A in endemic populations in the Republic of Mali.…”

Malaria Vaccine Development: A Challenge for Africa

“…It is being developed by a partnership between the PATH Malaria Vaccine Initiative (a grantee of the Gates Foundation), the pharmaceutical company, GlaxoSmithKline, and the Walter Reed Army Institute of Research (26). In the vaccine, a portion of CSP has been fused to the immunogenic "S antigen" of the hepatitis B virus; this recombinant protein is injected alongside the potent AS02A adjuvant (33).…”