Analysis of a Multi-component Multi-stage Malaria Vaccine Candidate—Tackling the Cocktail Challenge

Abstract

Combining key antigens from the different stages of the P. falciparum life cycle in the context of a multi-stage-specific cocktail offers a promising approach towards the development of a malaria vaccine ideally capable of preventing initial infection, the clinical manifestation as well as the transmission of the disease. To investigate the potential of such an approach we combined proteins and domains (11 in total) from the pre-erythrocytic, blood and sexual stages of P. falciparum into a cocktail of four different components recombinantly produced in plants. After immunization of rabbits we determined the domain-specific antibody titers as well as component-specific antibody concentrations and correlated them with stage specific in vitro efficacy. Using purified rabbit immune IgG we observed strong inhibition in functional in vitro assays addressing the pre-erythrocytic (up to 80%), blood (up to 90%) and sexual parasite stages (100%). Based on the component-specific antibody concentrations we calculated the IC50 values for the pre-erythrocytic stage (17–25 μg/ml), the blood stage (40–60 μg/ml) and the sexual stage (1.75 μg/ml). While the results underline the feasibility of a multi-stage vaccine cocktail, the analysis of component-specific efficacy indicates significant differences in IC50 requirements for stage-specific antibody concentrations providing valuable insights into this complex scenario and will thereby improve future approaches towards malaria vaccine cocktail development regarding the selection of suitable antigens and the ratios of components, to fine tune overall and stage-specific efficacy.

ThePlasmodium falciparumblood stages acquire factor H family proteins to evade destruction by human complement

“…In accordance with our observations that the ACP is as a major threat for the malaria parasites in the mosquito midgut, transmission blocking antibodies against prominent sexual stage surface proteins like Pfs230 or Pfs25 require active human complement to kill the mosquito midgut stages, as was previously shown in standard membrane feeding assays (e.g. Read et al, 1994;Williamson et al, 1995;Healer et al, 1997;Beiss et al, 2015;Boes et al, 2015;reviewed in Pradel, 2007). Furthermore, in the presence of anti-Pfs230 antibodies complement factor C1q binds to the gamete surface and activates the classical complement pathway (Simon et al, 2013).…”

“…Read et al , 1994; Williamson et al , 1995; Healer et al , 1997; Beiss et al , 2015; Boes et al , 2015; reviewed in Pradel, 2007). Furthermore, in the presence of anti‐Pfs230 antibodies complement factor C1q binds to the gamete surface and activates the classical complement pathway (Simon et al , 2013).…”

Characterization of a novel inhibitory human monoclonal antibody directed against Plasmodium falciparum Apical Membrane Antigen 1

“…Very efficient murine mAbs directed at other plasmodial targets such as reticulocyte-binding protein homologue 5 (Rh5) show IC 50 values of 50–100 μg/ml44, and AMA1-specific polyclonal rabbit IgG generated by hyperimmunization protocols could achieve IC 50 values in a similar range of 34–180 μg/ml7375. A direct comparison between polyclonal and monoclonal antibodies is difficult as in vivo, an entire spectrum of antibodies contributes to the defense against plasmodial infections and a successful control is likely due to synergistic effects of these antibodies.…”

Differential T‐cell responses to a chimeric Plasmodium falciparum antigen; UB05‐09, correlates with acquired immunity to malaria

“…Identification of more potent vaccine candidates may require scavenging for other protective antigen especially those related to CSP like UB09 which is a fragment of CRA as well as evaluating the ability of the chimeric construct of UB09 and UB05 to elicit stronger protective immune response. It has been shown elsewhere that chimeric constructs enhance immune responses .…”