Immunization with the Malaria Diversity-Covering Blood-Stage Vaccine Candidate Plasmodium falciparum Apical Membrane Antigen 1 DiCo in Complex with Its Natural Ligand PfRon2 Does Not Improve the In Vitro Efficacy

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.

Diversify and Conquer: The Vaccine Escapism of Plasmodium falciparum

“…A phase Ia/Ib trial was conducted with French and Burkinabe volunteers that reported the induction of antibodies reactive to parasites from different strains [98]. A combination with its natural partner in the invasion process, PfRon2, in an attempt to increase the potency of the IgG antibodies induced has also been tried [99]. However, though this combination was shown to improve the protection conferred by AMA1 alone to P. falciparum infection in Aotus monkeys [100], Ron2 did not improve cross-strain antibodies in humans, nor in vitro growth inhibition [99].…”

“…A combination with its natural partner in the invasion process, PfRon2, in an attempt to increase the potency of the IgG antibodies induced has also been tried [99]. However, though this combination was shown to improve the protection conferred by AMA1 alone to P. falciparum infection in Aotus monkeys [100], Ron2 did not improve cross-strain antibodies in humans, nor in vitro growth inhibition [99]. These data suggest it would be very difficult to cover the worldwide haplotypes in order to confer a global protection against malaria.…”

Structure-based design of a strain transcending AMA1-RON2L malaria vaccine

“…AMA1-based vaccines induce strong antibody responses but do not provide significant protection against clinical malaria in controlled infection studies, and their efficacy in field studies is lower than expected 43 , 46 , 57 , 58 . Variations in the dose, adjuvant, and formulation of AMA1-based vaccines showed only moderate improvements 48 , 59 – 61 . In contrast, rats immunized with the two-component AMA1-RON2L complex elicited higher levels of anti-AMA1 neutralizing antibodies than those immunized with AMA1 alone, likely because the AMA1-RON2L complex better mimics the true AMA1 structure on invading merozoites 62 .…”

“…Antibody responses elicited by single AMA1 alleles show significantly lower efficacy against heterologous strains 47 . To address this problem and achieve strain-transcending protection, combinations of up to seven AMA1 alleles or the design of three diversity covering (DiCo) variants to elicit strain-transcending antibody responses were evaluated with limited success 33 , 48 , 51 – 55 . Malaria antigens also display the immune evasion phenomenon of antigenic diversion, where the action of neutralizing antibodies is prevented by interfering non-neutralizing antibodies that enable parasite survival 56 .…”