Abstract
Genetically inactivated, Gram-negative bacteria that express malaria vaccine candidates represent a promising novel self-adjuvanting vaccine approach. Antigens expressed on particulate bacterial carriers not only target directly to antigen-presenting cells but also provide a strong danger signal thus circumventing the requirement for potent extraneous adjuvants. E. coli expressing malarial antigens resulted in the induction of either Th1 or Th2 biased responses that were dependent on both antigen and sub-cellular localization. Some of these constructs induced higher quality humoral responses compared to recombinant protein and most importantly they were able to induce sterile protection against sporozoite challenge in a murine model of malaria. In light of these encouraging results, two major Plasmodium falciparum pre-erythrocytic malaria vaccine targets, the Cell-Traversal protein for Ookinetes and Sporozoites (CelTOS) fused to the Maltose-binding protein in the periplasmic space and the Circumsporozoite Protein (CSP) fused to the Outer membrane (OM) protein A in the OM were expressed in a clinically relevant, attenuated Shigella strain (Shigella flexneri 2a). This type of live-attenuated vector has previously undergone clinical investigations as a vaccine against shigellosis. Using this novel delivery platform for malaria, we find that vaccination with the whole-organism represents an effective vaccination alternative that induces protective efficacy against sporozoite challenge. Shigella GeMI-Vax expressing malaria targets warrant further evaluation to determine their full potential as a dual disease, multivalent, self-adjuvanting vaccine system, against both shigellosis, and malaria.
Highlights
While traditional whole-cell, killed, or live-attenuated microorg anism-based vaccines have been the most effective for disease prevention, a large number of subunit vaccines are currently in development and are being evaluated for their ability to elicit protective immune responses
Using bacteria as recombinant vectors to mount an immune response against xenogeneic transgenes has several advantages: [1] pathogen-associated molecular patterns (PAMPs) on the bacteria are recognized by specialized pattern recognition receptors (PRRs) of the host and lead to the activation of strong innate immune responses [15]
COLI GENE-MEDIATED-INACTIVATION VACCINE EXPRESSING MALARIA ANTIGENS Gram-negative E. coli were selected as the bacterial vector system to evaluate the GeMI-Vax approach for malaria
Summary
While traditional whole-cell, killed, or live-attenuated microorg anism-based vaccines have been the most effective for disease prevention, a large number of subunit vaccines are currently in development and are being evaluated for their ability to elicit protective immune responses These approaches include DNA vaccines, recombinant protein (with adjuvant or as conjugates), viral vectors, and bacteria expressing full-length or immunologically crucial antigens [1,2,3,4,5,6,7,8,9,10,11]. Using bacteria as recombinant vectors to mount an immune response against xenogeneic transgenes has several advantages: [1] pathogen-associated molecular patterns (PAMPs) on the bacteria are recognized by specialized pattern recognition receptors (PRRs) of the host and lead to the activation of strong innate immune responses [15] This is the crucial first step in initiating an antigen-specific adaptive immune response. Binding with complement mediates the targeting of the bacteria to the complement receptors www.frontiersin.org
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