Unsuccessful clinical trials in humans have ruled out the once-promising malaria vaccine candidate antigen Plasmodium falciparum Merozoite Surface Protein 1 (MSP1). However, successful non-human primates immunization studies with parasites cultures-derived full-length MSP1 had rendered protection and clearance of blood infections from the monkeys. Difficulties at the time to recombinantly produce the whole full-length MSP1 protein as a vaccine construct, together with the high immunogenicity demonstrated against the C-terminal p42 fragment of MSP1 in immune-epidemiological studies, directed the interest of MSP1-based vaccines towards the design of subunit vaccines. The focus was quickly set on the GPI-anchored p19 subunit, the only remaining fragment of MSP1 attached to the merozoite surface at the onset of erythrocyte’s invasion and believed to play a crucial role in this important process.
Neutralizing antibodies inhibiting merozoite invasion have been considered key for immune protection. However, there is an increasing body of evidence suggesting a role of the innate immunity, via Fc-mediated effector mechanisms, in parasite clearance. These antibody functions have shown to highly correlate with protection in individuals from malaria endemic regions.
A previous publication by Blank & Fürle et al. demonstrated that SumayaVac-1, the first entire full-length MSP1-based malaria vaccine candidate expressed in E. coli, was safe, well-tolerated, and immunogenic in a first in human trial conducted in Heidelberg (Germany). SumayaVac-1 elicited high antibody titers in naïve volunteers that remained for more than six months after the last immunization over the level of semi-immune individuals from Africa.
In our recently published paper in npj Vaccines we describe that both, IgG and IgM antibodies elicited by SumayaVac-1 can activate, in a strain transcending manner, potent Fc-mediated effector mechanisms involved in the interaction with complement as well as with various immune cells, including monocytes, neutrophils, and NK cells, known to combat parasites. Notably, the N-terminal fragment p83, which contains highly conserved regions, emerged as a key target of functional immunoglobulins. Additionally, SumayaVac-1 elicited a recallable cellular cytotoxicity by IFN-γ producing CD8+ T cells, although at a low scale.
An ongoing clinical trial in Bagamoyo (Tanzania) will preliminarily evaluate the vaccine's proof of concept of efficacy through a control human malaria infection (CHMI). We will further determine if the quality feature of the SumayaVac-1 to elicit broadly functional antibodies at titers sufficient to stimulate several immune mechanisms can lead to a control in blood stage development of P. falciparum.
In the pursuit of malaria eradication, SumayaVac-1 may arise as a key contributor to other available tools to fight malaria by itself and/or by complementing other effective vaccines readily available, or soon in the market, targeting the liver stage, thereby extending protection against any potential parasite escaping the pre-erythrocytic immunological coverage.
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