Last Updated: 27/11/2025
Microbiota control of protective immunity against malaria
Objectives
This proposal aims at demonstrating, as a proof of principle, that a novel approach might be considered towards the development of a highly protective malaria vaccine. The novel strategy to be developed under this proposal capitalizes on current understanding of the human immune response elicited by the immunogenic Galα1-3Galβ1-4GlcNAc-R (α-gal) when expressed by specific components of the gut microbiota. This natural defense mechanism will be investigated in detail so that it can be manipulated for therapeutic purposes, namely, to boost protective immunity against malaria. This will be explored in two contexts:
- to increase natural protection against Plasmodium infection and
- to boost the immunogenicity of candidate malaria vaccines.
Malaria’s death toll decreased by 20-25% over the past decade, presumably due to the introduction of global malaria control programs enabling widespread use of bed nets as well as access to efficient pharmacologic agents targeting Plasmodium, the causative agent of malaria. Nonetheless, malaria eradication is seriously threatened by the inherent capacity of Plasmodium to rapidly evolve drug resistance, giving rise to parasites refractory to anti-malarial drugs. This argues strongly that to achieve malaria eradication it will be necessary to develop a highly efficient vaccine reaching 80-90% protection threshold, including in children. In line with this notion, several malaria candidate vaccines are currently under different stages of development, but, with the exception of “attenuated” sporozoite vaccines, none has so far reached this protection threshold.
Preliminary data leading to this proposal supports strongly the notion that the strategy to be deployed should generate unparalleled protective immunity against malaria. First, it was found out that the α-gal antigen (i.e. epitope) is expressed at the surface of Plasmodium sporozoites from different species, including the highly virulent human pathogen Plasmodium falciparum. Second, it was found that natural anti-α-gal antibodies (Abs) can confer protection against malaria transmission in mice and that these Abs are also associated with protection against malaria transmission in endemic regions. This argues that the human anti-α-gal Ab response can confer protection against Plasmodium falciparum infection, and presumably therefore reduce the mortality and morbidity associated with malaria in human populations. Third, it was found that vaccination against a synthetic form of the α-gal glycan is sufficient per se to confer sterile protection against malaria transmission in mice. Fourth, others have found that once coupled to protein antigens, the α-gal glycan can enhance by up to 10-100 fold the immunogenicity of that antigen. This “boosting effect” requires the presence of circulating anti-α-gal Abs at the time of immunization and acts via a mechanism detailed elsewhere. Also relevant to this proposal is the finding that colonization by specific components of the gut microbiota is required to sustain steady state production of circulating anti-α-gal Abs. Therefore it is expected that those components of the gut microbiota to support the “boosting effect” provided by circulating anti-α-gal Abs on the immunogenicity of candidate malaria vaccines in which α-gal is coupled to protein antigens. The project will explore this interplay between microbiota and host immunity to sustain the production of circulating anti-α-gal Abs and in this manner enhance by an expected 10-100 fold the immunogenicity of malaria vaccines.
Jun 2016 — Sep 2019
$227,290
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