Abstract
The blood-stage malaria vaccine candidate Plasmodium falciparum apical membrane antigen 1 (PfAMA1) can induce strong parasite growth-inhibitory antibody responses in animals but has not achieved the anticipated efficacy in clinical trials. Possible explanations in humans are the insufficient potency of the elicited antibody responses, as well as the high degree of sequence polymorphisms found in the field. Several strategies have been developed to improve the cross-strain coverage of PfAMA1-based vaccines, whereas innovative concepts to increase the potency of PfAMA1-specific IgG responses have received little attention even though this may be an essential requirement for protective efficacy. A previous study has demonstrated that immunization with a complex of PyAMA1 and PyRON2, a ligand with an essential functional role in erythrocyte invasion, leads to protection from lethal Plasmodium yoelli challenge in an animal model and suggested to extend this strategy toward improved strain coverage by using multiple PfAMA1 alleles in combination with PfRon2L. As an alternative approach along this line, we decided to use PfRon2L in combination with three PfAMA1 diversity covering variants (DiCo) to investigate the potential of this complex to induce more potent parasite growth inhibitory immune response in combination with better cross-strain-specific efficacy. Within the limits of the study design, the ability of the PfAMA1 DiCo-Mix to induce cross-strain-specific antibodies was not affected in all immunization groups, but the DiCo–PfRon2L complexes did not improve the potency of PfAMA1-specific IgG responses.
Highlights
Malaria remains a major global health problem affecting >200 million people and killing more than 500,000 per year [1]
A complex of AMA1 and Ron2L as the immunogen achieved higher efficacy than AMA1 alone in an in vitro parasite growth inhibition assay (GIA) using P. falciparum and protected mice against a lethal challenge with P. yoelii [35]. Even though this strategy improves the potency of AMA1-based vaccines, it does not address the need for cross-strain protection, leading the authors of the abovementioned study to suggest the use of multiple Plasmodium falciparum apical membrane antigen 1 (PfAMA1)– Pf Ron2 complexes representing different PfAMA1 alleles [35]
After generating the expression constructs and the corresponding recombinant A. tumefaciens cultures, small-scale transient expression was carried out in N. benthamiana allowing the provision of recombinant proteins within a few days [38]
Summary
Malaria remains a major global health problem affecting >200 million people and killing more than 500,000 per year [1]. Several epidemiological studies in different countries have revealed large numbers of different PfAMA1 haplotypes even in defined endemic areas [12, 13] This high degree of polymorphism in the field is likely to be a parasite strategy to evade the immune system [11], presenting a serious challenge for the development of effective PfAMA1-based vaccine candidates. A complex of AMA1 and Ron2L (a synthetic peptide, representing the PfAMA1-binding domain of Pf Ron2) as the immunogen achieved higher efficacy than AMA1 alone in an in vitro parasite growth inhibition assay (GIA) using P. falciparum and protected mice against a lethal challenge with P. yoelii [35] Even though this strategy improves the potency of AMA1-based vaccines, it does not address the need for cross-strain protection, leading the authors of the abovementioned study to suggest the use of multiple PfAMA1– Pf Ron complexes representing different PfAMA1 alleles [35]. We chose to investigate a scenario involving the minimum number of different recombinant molecules by using the three DiCo PfAMA1 variants [19] in a complex with Pf Ron2L
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