Development of a bivalent conjugate vaccine candidate against malaria transmission and typhoid fever

Abstract

Immune responses to poorly immunogenic antigens, such as polysaccharides, can be enhanced by conjugation to carriers. Our previous studies indicate that conjugation to Vi polysaccharide of Salmonella Typhi may also enhance immunogenicity of some protein carriers. We therefore explored the possibility of generating a bivalent vaccine against Plasmodium falciparum malaria and typhoid fever, which are co-endemic in many parts of the world, by conjugating Vi polysaccharide, an approved antigen in typhoid vaccine, to Pfs25, a malaria transmission blocking vaccine antigen in clinical trials. Vi-Pfs25 conjugates induced strong immune responses against both Vi and Pfs25 in mice, whereas the unconjugated antigens are poorly immunogenic. Functional assays of immune sera revealed potent transmission blocking activity mediated by anti-Pfs25 antibody and serum bactericidal activity due to anti-Vi antibody. Pfs25 conjugation to Vi modified the IgG isotype distribution of antisera, inducing a Th2 polarized immune response against Vi antigen. This conjugate may be further developed as a bivalent vaccine to concurrently target malaria and typhoid fever.

Rotavirus spike protein ΔVP8* as a novel carrier protein for conjugate vaccine platform with demonstrated antigenic potential for use as bivalent vaccine

“…Our previous studies exploring the conjugate vaccine platform using Vi conjugated to carrier proteins interestingly showed that some carrier proteins play the dual role as a carrier protein and a protective antigen 28 , 40 , 47 . In this study, we further demonstrated the potential of Vi conjugation to enhance immune responses in mice to carrier protein compared with those induced by the native protein.…”

“…Vi-ΔVP8* conjugates were prepared as previously described 28 , 40 . 8 mg of Vi was dissolved in 4 mL of MES buffer (80 mM, pH 4.9), and 250 μL of 50 mg/mL EDAC was added and mixed with agitation for 5 min.…”

“…Typhi) is the target of a protective humoral immune response. Conjugation of Vi to a carrier protein can effectively convert a T cell-independent immune response to a T cell-dependent immune response, characterized by IgM-to-IgG switching, a booster response, and sustained T cell memory to Vi 27 , 28 . Vi-recombinant non-toxic form of Pseudomonas aeruginosa exotoxin A (rEPA) and Vi-Tetanus Toxoid (TT) conjugate vaccines have been licensed and marketed in China and India 29 , 30 , while Vi-Diphtheria Toxoid (DT) and Vi-a nontoxic diphtheria cross-reacting material (CRM 197 ) are undergoing clinical trials for use in infants and children 31 , 32 .…”

Outer membrane protein complex as a carrier for malaria transmission blocking antigen Pfs230

“…Functional activity of immune sera was assayed using Standard Membrane Feeding Assay (SMFA) used for determining the transmission blocking activity. 29 A set of Anopheles mosquitos (20–25) were fed on test sera mixed with cultured P. falciparum gametocytes, through a membrane feeding apparatus. After a week delay for development, each mosquito was dissected, and the number of oocysts developed in the midgut was counted.…”

“…One strategy to improve the immunogenicity of poorly immunogenic antigens includes presentation in nanoparticles. 24–28 We have shown that chemical conjugation of some TBV antigens to carrier proteins (and other macromolecules) generates nanoparticles with enhanced immunogenicity, 29–34 and a 22 kDa recombinant protein from domain-1 of Pfs230, conjugated to EPA, is currently being evaluated in clinical trials (clinicaltrial.gov ID: NCT02334462; NCT02942277). Presentation of antigens in a particulate structure or on the particle surface allow them to be more efficiently internalized by antigen-presenting cells (APCs) than soluble antigen.…”