Abstract
BackgroundThe high incidence and mortality rate of malaria remains a serious burden for many developing countries, and a vaccine that induces durable and highly effective immune responses is, therefore, desirable. An earlier analysis of the stage-specific in vitro efficacy of a malaria vaccine candidate cocktail (VAMAX) considered the general properties of complex multi-component, multi-stage combination vaccines in rabbit immunization experiments using a hyper-immunization protocol featuring six consecutive boosts and a strong, lipopolysaccharide-based adjuvant. This follow-up study investigates the effect of antigen dose on the in vitro efficacy of the malaria vaccine cocktail using a conventional vaccination scheme (one prime and two boosts) and a human-compatible adjuvant (Alhydrogel®).ResultsIgG purified from rabbits immunized with 0.1, 1, 10 or 50 µg doses of the VAMAX vaccine candidate cocktail was analysed for total IgG and antigen-cocktail-specific titers. An increase in cocktail-specific titers was observed between 0.1 and 1 µg and between 10 and 50 µg, whereas no significant difference in titers was observed between 1 and 10 µg. Antigen component-specific antibody titers and stage-specific in vitro efficacy assays were performed with pooled IgG from animals immunized with 1 and 50 µg of the VAMAX cocktail. Here, the component-specific antibody levels showed clear dose dependency whereas the determined stage-specific in vitro IC50 values (as a correlate of efficacy) were only dependent on the titer amounts of stage-specific antibodies.ConclusionsThe stage-specific in vitro efficacy of the VAMAX cocktail strongly correlates with the corresponding antigen-specific titers, which for their part depend on the antigen dose, but there is no indication that the dose has an effect on the in vitro efficacy of the induced antibodies. A comparison of these results with those obtained in the previous hyper-immunization study (where higher levels of antigen-specific IgG were observed) suggests that there is a significant need to induce an immune response matching efficacy requirements, especially for a PfAMA1-based blood stage vaccine, by using higher doses, better adjuvants and/or better formulations.
Highlights
The high incidence and mortality rate of malaria remains a serious burden for many developing countries, and a vaccine that induces durable and highly effective immune responses is, desirable
While the GSK vaccine Mosquirix®, based on circumsporozoite protein (PfCSP) [3,4,5], exclusively targets the pre-erythrocytic stage of P. falciparum to prevent the establishment of the parasite within the liver, other approaches focus on blood-stage antigens that can be found on the surface of merozoites, to induce immune responses that block the invasion of red blood cells and thereby prevent or reduce clinical episodes
The proteins were obtained at high purity (>95 % determined by analytical size exclusion chromatography (SEC)) the apparent molecular masses agreed with the calculated values of 87,592 Da for VAMAX 1, 89,906 Da for VAMAX 2 and 80,864 Da for VAMAX 6 (Table 1), there was no indication of relevant amounts of degradation products, and the specific monoclonal antibodies detected the corresponding antigen domains (Fig. 1b–e)
Summary
The high incidence and mortality rate of malaria remains a serious burden for many developing countries, and a vaccine that induces durable and highly effective immune responses is, desirable. An earlier analysis of the stage-specific in vitro efficacy of a malaria vaccine candidate cocktail (VAMAX) considered the general properties of complex multi-component, multi-stage combination vaccines in rabbit immunization experiments using a hyper-immunization protocol featuring six consecutive boosts and a strong, lipopolysaccharide-based adjuvant. In addition to PfMSP1 and fragments thereof [6, 7], PfMSP2 [8] and PfMSP3 [9, 10], the apical membrane antigen PfAMA1 [11, 12] has been proposed as a promising blood-stage vaccine candidate This molecule is highly polymorphic, so allele-specific immune responses show moderate or even low efficacy against heterologous strains of P. falciparum. The authors sought to confirm the observed correlation between antigen abundance within the improved VAMAX cocktail and the proportions of the corresponding antigen-specific antibodies found in the rabbit immune IgG fraction
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