Demonstration of the Blood-StagePlasmodium falciparumControlled Human Malaria Infection Model to Assess Efficacy of theP. falciparumApical Membrane Antigen 1 Vaccine, FMP2.1/AS01

Abstract

NCT02044198.

Human vaccination against RH5 induces neutralizing antimalarial antibodies that inhibit RH5 invasion complex interactions

“…A previous study affinity-purified RH5-specific human IgG from plasma of naturally exposed individuals in Mali and tested for GIA, reporting an EC 50 concentration of 55 μg/ ml (23), which suggests the vaccine-induced IgG here may be qualitatively superior to the responses induced against RH5 following natural parasite exposure. Moreover, this level is substantially lower than previous results with vaccines tested in humans against the AMA1 and MSP1 antigens, where GIA EC 50 concentrations were reported from 70-100 μg/ml (9,52,53) and > 600 μg/ml (9) for AMA1-and MSP1-specific human IgG, respectively. Consequently, the levels of GIA observed here with ChAd63-MVA RH5 outperformed those previously observed in humans with the same vectors encoding MSP1 or AMA1 (54), given that these vaccines all induce quantitatively similar levels of IgG.…”

“…Two volunteers also consistently showed a better quality of response, with a 2.5-fold improvement in the EC 50 (3.3 μg/ml RH5_FL-specific IgG) against the 3D7 clone parasite, although no other obvious differences were apparent in their antibody profile, as measured by the various ELISA assays. This EC 50 concentration is substantially lower than previous results with vaccines against the AMA1 and MSP1 antigens (9,52,53). In line with this result, the overall levels of GIA using 10 mg/ ml purified IgG from these RH5 vaccinees against 3D7 clone parasites were higher than those achieved with the same ChAd63-MVA platform used previously to deliver AMA1 or MSP1 (54), reaching significance for MSP1 (P = 0.02, Kruskal-Wallis test with Dunn's multiple comparison test comparing RH5 with AMA1 and MSP1) (Supplemental Figure 7A).…”

“…The GIA (as routinely assessed, without complement) was related to RH5_FL-specific IgG concentration ( Figure 6C), as seen for the merozoite surface protein 1 (MSP1) and apical membrane antigen 1 (AMA1) antigens following human immunization (9,52,53). Notably, the concentration of anti-RH5_FL polyclonal IgG that gives 50% GIA (EC 50 ) was only 8.2 μg/ml.…”

“…tem AS01B from GSK (P = 0.16 and P = 0.78, respectively, Mann-Whitney test) (ref. 53 and Supplemental Figure 7, A and B). This relates to the fact that the AMA1/AS01B formulation was quantitatively 10 times more immunogenic, achieving approximately 100 μg/ml AMA1-specific IgG on average in these vaccinees (53), unlike the 9.3 μg/ml RH5_FL-specific IgG measured on average in Group 2C.…”

Vaccines to Accelerate Malaria Elimination and Eventual Eradication

“…1): the perception that large numbers of circulating parasites, and genetic diversity of many, but not all potential asexual blood-stage target antigens, present an insurmountable hurdle to the vaccine-induced immunity. The disappointing clinical efficacy of AMA1-and MSP1-based vaccines have no doubt contributed to the idea that blood-stage parasitemia is intractable to control by vaccination (Spring et al 2009;Sheehy et al 2012;Payne et al 2016). These unsuccessful clinical trials have highlighted the importance of judicious antigen choice, with conserved antigens preferable to polymorphic ones and prioritization of antigens capable of evoking protective responses at relatively low antibody concentrations.…”