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Background Plasmodium vivax and its mosquito vectors have several distinctive characteristics that allow the transmission of this parasite in both temperate and tropical climates [1,2]. None, however, are as unique as its ability to form hypnozoites—dormant forms that reactivate periodically to cause multiple bouts of clinical malaria—that may be responsible for up to 80% of clinical episodes [1]. Unlike P. falciparum, which can be cured with blood schizonticidal drugs to eliminate the parasite reservoir, P. vivax needs to be treated with a combination of drugs that act on blood-stage as well as the dormant liver–stage parasites. Treatment of hypnozoites relies on a single line of 8-aminoquinoline drugs. Primaquine (PQ), the only approved drug for treating hypnozoites, causes severe hemolysis in individuals with glucose 6-phosphate dehydrogenase (G6PD) deficiency. In addition to G6PD-deficient individuals, the drug is contraindicated for the treatment of pregnant or breastfeeding women as well as infants. More recently, a deficiency in PQ metabolism that results in inadequate therapeutic levels of the active metabolite was identified in individuals that are poor or intermediate metabolizers of the drug, thus expanding the pool of subjects that cannot undergo radical cure needed for the treatment of P. vivax [3]. Thus, even if mass drug administration campaigns were a feasible option, because of the large groups of subjects that are not amenable to radical cure, vaccines will be an important component in the toolkit to prevent P. vivax malaria. The circumsporozoite (CS) protein of Plasmodia has been the lead vaccine candidate for malaria. RTS,S, the most advanced vaccine for malaria, which is based on the CS protein of P. falciparum, underwent its first efficacy evaluation in humans adjuvanted with monophosphoryl lipid A and alum. Following promising immunogenicity (though low efficacy) in this first-in-human study [4], the vaccine was deemed suitable for further clinical testing. In 1997, Stoute and colleagues published the results of the second efficacy study conducted using a panel of more potent adjuvants [5]. A vaccine efficacy of 86% was observed using one of the adjuvants tested in this study. Almost 20 years later, in 2016, Regules and colleagues [6] published an article in which they revisited the immunization and dosing schedule used in the first study and demonstrated high levels of protection similar to those achieved in the 1997 Stoute study. In the interim, RTS,S has been tested in thousands of individuals—ranging from malaria-naïve adults in nonendemic areas to infants 6–12 weeks old in endemic areas [7]. Knowledge gained on the duration and quality of immune responses and vaccine efficacy in Phase II and III studies resulted in the design and execution of the Regules study, which led to an improvement in vaccine efficacy.

Rationale for Further Development of a Vaccine Based on the Circumsporozoite Protein of Plasmodium vivax