Multiple antigen-presenting system (MAPS) to induce comprehensive B- and T-cell immunity

Abstract

Vaccines are among the most effective approaches to prevent and control many infectious diseases. Because of safety and reproducibility concerns, whole-cell vaccines (WCVs), made from live or killed microorganisms and including hundreds of antigenic components, have been mostly replaced by acellular or subunit vaccines composed of well-defined, purified antigen components. The efficacy of acellular vaccines is inferior to that of WCVs, however, for two major reasons: limited antigen diversity and reduced immunogenicity, especially in a lack of activation of antigen-specific T-cell immunity, which plays an important role in protection against mucosal and intracellular pathogens. Here we present the multiple antigen-presenting system (MAPS), which enables the creation of a macromolecular complex that mimics the properties of WCVs by integrating various antigen components, including polysaccharides and proteins, in the same construct and that induces multipronged immune responses, including antibody, Th1, and Th17 responses. Using antigens from various pathogens ( Streptococcus pneumonia e, Salmonella typhi , and Mycobacterium tuberculosis ), we demonstrate the versatility of the MAPS system and its feasibility for the design of unique defined-structure subunit vaccines to confer comprehensive protection via multiple immune mechanisms. Moreover, MAPS can serve as a tool for structure-activity analysis of cellular immunogens.

Conjugate-like immunogens produced as protein capsular matrix vaccines

“…Although this is one mechanism by which T-cell help may be activated by a polysaccharide-protein conjugate antigen, the results presented in our PCMV studies suggest that there are other pathways for eliciting T-cell help that do not require polysaccharides to be covalently coupled to carrier proteins. A recent report by Zhang et al (22) supports this conclusion. In this case, immunogens that had properties comparable to conjugate vaccines were prepared by noncovalently binding an avidin-related carrier protein to a biotin-modified polysaccharide.…”

“…Comparable to a PCMV, this noncovalent association between polysaccharide and protein was effective at eliciting a T-dependent immune response. Thus, more work will be needed to define the presentation pathway for "virtual conjugate vaccines" such as PCMV particles and the immunogens prepared by Zhang et al (22).…”

“…Unlike other approaches for synthesis of virtual conjugate vaccines such as the one described by Zhang et al (22), the PCMV procedure does not require any covalent modifications of polysaccharides and therefore is predicted to neither introduce chemical linkages that alter polysaccharide epitopes nor introduce neo-epitopes (e.g., biotin) that may engender unfavorable immune responses following immunization. Thus, it is anticipated that antibiotin antibodies will be induced by the Zhang et al (22) virtual conjugate approach.…”

“…Thus, it is anticipated that antibiotin antibodies will be induced by the Zhang et al (22) virtual conjugate approach.…”

“…Furthermore, the PCMV approach is predicted to invoke T-cell help using any immunogenic matrix protein, whereas other procedures (22) require binding proteins such as rhizavidin, whose safety as immunogens has yet to be established in human subjects. Thus, PCMV immunogens offer many practical and theoretical advantages over both conventional and virtual conjugate vaccines that have been previously reported and characterized.…”