Abstract
BackgroundIn Plasmodium falciparum malaria endemic areas placental malaria (PM) is an important complication of malaria. The recurrence of malaria in primigravidae women irrespective of acquired protection during childhood is caused by the interaction between the parasite-expressed VAR2CSA antigen and chondroitin sulfate A (CSA) in the placental intervillous space and lack of protective antibodies. PM impairs fetal development mainly by excessive inflammation processes. After infections during pregnancy women acquire immunity to PM conferred by antibodies against VAR2CSA. Ideally, a vaccine against PM will induce antibody-mediated immune responses that block the adhesion of infected erythrocytes (IE) in the placenta.Principal FindingsWe have previously shown that antibodies raised in rat against individual domains of VAR2CSA can block IE binding to CSA. In this study we have immunized mice, rats and rabbits with each individual domain and the full-length protein corresponding to the FCR3 VAR2CSA variant. We found there is an inherently higher immunogenicity of C-terminal domains compared to N-terminally located domains. This was irrespective of whether antibodies were induced against single domains or the full-length protein. Species-specific antibody responses were also found, these were mainly directed against single domains and not the full-length VAR2CSA protein.Conclusions/SignificanceBinding inhibitory antibodies appeared to be against conformational B-cell epitopes. Non-binding inhibitory antibodies reacted highly against the C-terminal end of the VAR2CSA molecule especially the highly polymorphic DBL6ε domain. Differential species-specific induction of antibody responses may allow for more direct analysis of functional versus non-functional B-cell epitopes.
Highlights
Animal models are required for preclinical development of new generation vaccines against infectious diseases [1,2,3]
In line with the ELISA results measuring the reactivity against the recombinant proteins, we found that the antibody reactivity against native VAR2CSA on the surface of the infected erythrocytes (IE) differed both with respect to animal species, and with antigen type
The fulllength protein can be produced, a vaccine based on a single domain is more likely to be feasible, due to the complexity and size of the antigen
Summary
Animal models are required for preclinical development of new generation vaccines against infectious diseases [1,2,3]. The ideal animal model mimics the human immunological response, the pathogen infection pathway, and allows analysis of the mechanism of the vaccine-induced protective immune response. The development of a recombinant vaccine is initiated with identification and selection of an antigen that induces a desired immune response. At this step, multiple antigens are tested, which requires an inexpensive and easy to handle animal model. A vaccine against PM will induce antibody-mediated immune responses that block the adhesion of infected erythrocytes (IE) in the placenta
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