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The Current Status of Malaria Vaccines

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The Current Status of Malaria Vaccines BioDrugs 1998 Aug; 10 (2): 123-136 IMMUNOLOGY-BASED AGENTS 1173-8804/98/0008-0123/$07.00/0 © Adis International Limited. All rights reserved. The Current Status of Malaria Vaccines José A. Stoute and W. Ripley Ballou Department of Immunology, Division of Communicable Diseases and Immunology, Walter Reed Army Institute of Research, Washington DC, USA Contents Abstract . 123 1. Vaccines Targeting the Pre-Erythrocytic Stage . 124 1.1 Vaccines That Target the Sporozoite . 124 1.2 Other Pre-Erythrocytic Stage Vaccines . 127 2. Vaccines Targeting the Asexual Erythrocytic Stage . 127 3. Transmission-Blocking Vaccines . 129 4. Major Roadblocks to a Successful Malaria Vaccine . 130 5. New Approaches to Malaria Vaccine Development . 131 5.1 Multistage, Multicomponent Vaccines . 131 5.2 DNA Vaccines . 132 Abstract A vaccine against Plasmodium falciparum malaria is needed now more than ever due the resurgence of the parasite and the increase in drug resistance. How- ever, success in developing an effective malaria vaccine has been elusive. Among pre-erythrocytic antigens, the major antigen coating the surface of the sporozoite, the circumsporozoite protein (CS), has been, and continues to be, the major target for vaccine development. Despite initial limited success with CS- based vaccines, the use of new adjuvant formulations has led to the development of a promising candidate (the RTS,S vaccine) which has shown significant effi- cacy in a preliminary trial. In addition to CS, many other malaria antigens have been identified that play an important role in the parasite life cycle which are being considered for, or are currently undergoing, clinical trials. Among the blood stage antigens, the mero- zoite surface protein 1 (MSP-1) is the most promising vaccine candidate. New approaches to immunisation against malaria being considered include the use of multistage, multicomponent vaccines in attenuated viral vectors (NYVAC-Pf7), or in a combination DNA vaccine. While there is reason to be optimistic about the prospects for an effective vaccine, many challenges lie ahead that still have to be overcome. Among these are the antigenic polymorphism exhibited by wild parasite strains and the genetic restriction of immune responses. Malaria is one of the world’s deadliest infec- parasite, a vaccine seems now more than ever the tious diseases responsible for 1.5 to 2.7 million only hope for controlling this disease. However, deaths per year, mostly in children. Due the contin- success in achieving a malaria vaccine has been ued development of drug-resistant strains of this elusive. The objective of this article is to summa- 124 Stoute & Ballou rise the most important developments in the field will induce immune responses capable of eliminat- of malaria vaccine research. For this purpose, we ing sporozoites from the circulation and/or capable will review the most promising vaccine candidate of eliminating infected hepatocytes leading to ster- antigens within the context of the portion of the life ile immunity. This is especially important if it is to cycle they are intended to disrupt. This review is be used in nonimmune populations that have no limited to Plasmodium falciparum, the deadliest of pre-existing immunity against blood stage para- all human malarias. sites. In order to better understand the approaches to malaria vaccine development it is necessary to 1.1 Vaccines That Target the Sporozoite have some familiarity with the life cycle of the par- asite (fig. 1). The malaria life cycle is complex. The One of the first malaria genes to be fully char- sporozoite form of the parasite is transmitted to acterised was the major surface protein of the ma- man by the bite of the female Anopheles mosquito. laria sporozoite, referred to as the circumsporozo- Sporozoites travel through the bloodstream and in- ite protein (CS).[1,2] The CS of all the malaria vade liver cells where they multiply asexually as species share a number of features. They all contain pre-erythrocytic stage parasites. P. falciparum pre- a central segment of amino acid repeats flanked by erythrocytic forms mature in 5 to 7 days, releasing two nonrepeat regions. In the case of P. falciparum thousands of tissue merozoites which invade eryth- malaria, the central portion contains 36 to 43 repeats rocytes and initiate the erythrocytic or blood stage of the amino acids asparagine-alanine-asparagine- phase of the infection. During the erythrocytic proline, or NANP, and 3 to 4 asparagine-valine- phase, free merozoites invade erythrocytes, un- aspartic acid-proline (NVDP) repeats.[3] The cen- dergo asexual maturation into trophozoites and tral repeating unit is the immunodominant portion schizonts, and ultimately rupture the erythrocyte of the molecule, since most of the humoral immune releasing new merozoites. It is this phase of the life responses of animals and humans against sporozo- cycle, with the cyclic destruction of erythrocytes, ites seem to be directed against this central re- that leads to the clinical disease known as malaria. peat.[4] Because antibodies against P. falciparum A small portion of merozoites that invade erythro- and P. berghei repeats were shown to inhibit spo- cytes do not multiply, but instead differentiate into rozoite invasion in vitro and protected rodents sexual forms, gametocytes. When ingested by an- against sporozoite challenge respectively,[5,6] the other female Anopheles, female and male gametes first malaria vaccines tested were based solely on unite in the mosquito midgut to form a zygote some version of this repeating amino acid unit. which subsequently develops into a motile ookinete. Since its initial identification, CS has been a ma- After invading the basal lamina of the mosquito jor focus of malaria vaccine development. This em- midgut epithelium, the ookinete develops into phasis on CS is justified by numerous studies in an oocyst containing hundreds of sporozoites. animal and human models as well as in several clin- Oocysts then mature and release sporozoites which ical trials, some of which are summarised below, migrate to the mosquito salivary glands, thus com- that have identified CS as the target of protective pleting the life cycle. immune responses. Soon after the discovery of the CS gene 2 1. Vaccines Targeting the NANP-based vaccines were tested in humans. One Pre-Erythrocytic Stage of these early vaccines consisted of a recombinant protein expressed in Escherichia coli containing 30 The pre-erythrocytic portion of the malaria life NANP repeats and 2 NVDP repeats in fusion with cycle includes events from the entry of sporozoites 32 amino acids of the out-of-frame tetracycline-re- [7] in the blood circulation to the release of merozoites sistant gene (R32tet32). The other vaccine con- from the liver. The ideal pre-erythrocytic vaccine sisted of the synthetic peptide (NANP)3 conjugated © Adis International Limited. All rights reserved. BioDrugs 1998 Aug; 10 (2) Malaria Vaccines 125 Sporozoite antigens CS TRAP Liver stage antigens LSA-1 Exp-1 Pre-erythrocytic stage ▼ Blood stage Merozoite Merozoite antigens MSP-1 RESA AMA-1 EBA-175 Schizont Trophozoite Exp-1 SERA Gametocyte Pfs230 Pfs48/45 Oocysts Gametes Mosquito midgut Ookinete Pfs25 Pfs28 Fig. 1. Life cycle of malaria. AMA-1 = apical membrane antigen 1; CS = circumsporozoite protein; EBA-175 = erythrocyte-binding antigen 175; Exp-1 = Exported Protein 1; LSA-1 = liver stage antigen 1; MSP-1 = merozoite surface protein 1; Pfs = surface antigen; RESA = ring-infected erythrocyte surface antigen; SERA = serine repeat antigen. to tetanus toxoid.[8] The results of both studies meagre and one volunteer from each group with were surprisingly similar despite the use of very relatively high anti-repeat antibody levels was pro- different antigenic constructs. In both studies, hu- tected against sporozoite challenge. Although the moral responses against the NANP repeat were demonstrated efficacy was poor, these studies © Adis International Limited. All rights reserved. BioDrugs 1998 Aug; 10 (2) 126 Stoute & Ballou served to reaffirm that sterile immunity against ma- to a portion of the hepatitis B surface antigen.[25] laria can be induced by immunisation with a syn- The development of a dual malaria/hepatitis B vac- thetic subunit vaccine. Since protection seemed to cine made sense from the standpoint that these 2 correlate with high antibody levels, it was felt that diseases are frequently endemic in the same geo- the development of more immunogenic versions of graphic areas of the world and are the cause of these vaccines would lead to better efficacy. Sub- much morbidity and mortality. In addition, it was sequent sporozoite vaccines, based on the NANP hoped that the use of the hepatitis B virus surface repeat, contained modifications conducive to the antigen as a carrier would improve the immunoge- enhancement of immune responses. Modifications nicity of the malaria CS protein. In a preliminary such as the addition of Pseudomonas aeruginosa trial, this vaccine was shown to be safe and immu- toxin A,[9] encapsulation in liposomes containing nogenic.[25] monophosphoryl lipid A (MPL),[10,11] and inclu- A subsequent generation of this vaccine in- sion of a mixture of MPL, mycobacterial cell wall cluded the nonrepeat C-terminal portions of CS in skeleton and squalene,[12] generally resulted in addition to 19 NANP repeats (RTS,S).[23] The higher antibody levels, but contrary to expectations RTS,S antigen was initially tested as two formula- did not significantly improve efficacy. tions adsorbed onto alum with or without the lipid Studies in rodents and humans immunised A derivative 3-deacyl-monophosphoryl lipid A.[23] against malaria with irradiation-attenuated sporo- Although the anti-repeat antibody levels were zoites suggested that CD4+ T helper and CD8+ T modest, 2 of 8 volunteers in the MPL plus alum cytotoxic (CTL) T cell responses were important group were protected and had CTL responses to components of the protective immune responses peptides from the C-terminus of CS.
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