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    • The development of a malaria vaccine is considered as one

    2018-11-13

    The development of a malaria vaccine is considered as one of the most cost-effective measures to counter the disease. Valuable progress has been achieved in the last 30years in the development of subunit vaccines () that could be included in the Expanded Program of Immunization (EPI), whereas the counterpart lags very much behind. Currently, the most advanced malaria vaccine candidate, the RTS,S vaccine based on the circumsporozoite (CS) protein, has gone through extensive testing in Africa where a recent phase 3 trial showed a 27 and 46% protection against clinical malaria in African infant and children respectively but unfortunately its efficacy wanes down in a relatively short time (). The goal of the RTS,S Clinical Trial Partnership is now to seek a license for the first-generation malaria vaccine. Due to the fact that efficacy was different depending on the location and transmission rate, this intervention may be approved only for those regions where the efficacy was highest. In situations where the RTS,S efficacy is low, the limited available resources may be better used for other efficacious interventions such as artemisinin-based combination therapies (ACTs), insecticide-treated mosquito net (ITN) and indoor residual spraying (IRS). In addition, prevision for a booster immunization may be considered, and clinical trials to determine its benefit must also be performed. This would further reduce resources needed for the interventions mentioned above. The homologation of the RTS,S vaccine may also pose a challenge to the development of alternative vaccines to increase the efficacy of RTS,S either as combination of RTS,S with new opioid receptor antagonist or totally new formulations as discussed recently by Fowkes et al. (), since any new formulation would need to be compared side-by-side with RTS,S vaccine. It is possible that the most effective combinations might derive from mixing vaccines that are found efficacious when tested alone, that target different stages of parasite life and/or are based on different mechanisms. In particular, one might speculate adding to RTS,S the RH5 antigen (whose antibodies are active in the in vitro inhibition of RBC infection by merozoites of heterologous strains), or antigens acting in the ADCI and/or opsonization as fragments from MSP2, MSP3, GLURP and PFF0165. Even though single antigens might be only weakly effective, their combination together with RTS,S is expected to be more effective in controlling the disease and, as a result, reducing transmission by mosquitoes (). To this end, efforts should also be made to develop a transmission-blocking vaccine (). Known as “altruistic vaccination”, vaccinating in low-prevalence areas would have no direct benefit at the individual level but would protect their neighbors from becoming infected. This could be a stand-alone mosquito-stage vaccine or, more likely, a multi-component vaccine adding a mosquito-stage component to the partial transmission-blocking activity of a pre-erythrocytic vaccine. In parallel, more resources should be allocated for testing new vaccines and to determine the mechanisms of protection for this species.
    In 2012, an estimated 207 million malaria cases and 627,000 malaria deaths were reported worldwide (). For millennia, malaria has exerted significant evolutionary pressure on the human genome, selecting for balanced polymorphisms that confer disease protection. This possibility was first proposed in 1949 by J. B. S. Haldane, who suggested that reduced fitness in -thalassemia homozygotes due to severe anemia was offset by increased fitness in heterozygotes due to malaria protection (). In 1954, A. S. Allison demonstrated in Kenya that hemoglobin S (HbS) heterozygosity (HbAS, sickle-cell trait) conferred protection from malaria, and proposed that this protection balanced the severe anemia morbidity and premature fatality associated with HbS homozygosity (HbSS, sickle-cell disease) (). Clinical studies have since associated HbC and αthalassemia with malaria protection (), and shown that αthalassemia antagonizes HbAS; that is, HbAS children who co-inherit αthalassemia are not protected from malaria ().