Abstract
The development of vaccines against complex intracellular pathogens, such as Plasmodium spp., where protection is likely mediated by cellular immune responses, has proven elusive. The availability of whole genome, proteome and transcriptome data has the potential to advance rational vaccine development but yet there are no licensed vaccines against malaria based on antigens identified from genomic data. Here, we show that the Plasmodium yoelii orthologs of four Plasmodium falciparum proteins identified by an antibody-based genome-wide screening strategy induce a high degree of sterile infection-blocking protection against sporozoite challenge in a stringent rodent malaria model. Protection increased in multi-antigen formulations. Importantly, protection was highly correlated with the induction of multifunctional triple-positive T cells expressing high amounts of IFN-γ, IL-2 and TNF. These data demonstrate that antigens identified by serological screening are targets of multifunctional cellular immune responses that correlate with protection. Our results provide experimental validation for the concept of rational vaccine design from genomic sequence data.
Highlights
With almost half of the world’s population at risk of malaria, approximately 200 million reported clinical cases and half a million deaths annually, mostly in children under the age of 5 years, malaria remains a major public health problem[1]
We evaluated four previously uncharacterized P. falciparum proteins identified from antibody-based genome-wide screening platforms as potential pre-erythrocytic malaria vaccines candidates
Three of these proteins (P. falciparum PFL1620 = P. yoelii PY03832; MALP1.22 = PY01533; PF10925w = PY01606) were identified in the signature of 16 P. falciparum antigens associated with protective immunity induced by experimental immunisation with P. falciparum radiation attenuated sporozoites (RAS) as well as in the signature of 46 P. falciparum antigens associated with naturally acquired immunity)[19,22]
Summary
With almost half of the world’s population (an estimated 3.2 billion people) at risk of malaria, approximately 200 million reported clinical cases and half a million deaths annually, mostly in children under the age of 5 years, malaria remains a major public health problem[1]. Vaccine efficacy against clinical malaria in the target group of infants aged 6–12 weeks at first vaccination was only 18% following the 3-dose primary schedule and 26% following a booster dose at 18 months, and decayed rapidly[13,14]. Of concern, this Phase 3 evaluation identified a risk of febrile seizures for RTS,S/AS01 as well as significantly more cases of both cerebral malaria and meningitis in vaccine recipients than controls and significantly higher all-cause mortality in girls[13]. Other well characterised P. falciparum sporozoite and liver antigens include sporozoite surface protein (SSP2/TRAP), liver stage antigen 1 (LSA1), cell-traversal protein for ookinetes and sporozoites (CelTOS), sporozoite threonine asparagine rich protein (STARP) and exported protein 1 (EXP1) but none of these have proved to be highly efficacious in clinical studies (reviewed in ref.[8])
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