Abstract
Recent perspectives forecast a new paradigm for future “third generation” vaccines based on commonalities found in diverse pathogens or convergent immune defenses to such pathogens. For Staphylococcus aureus, recurring infections and a limited success of vaccines containing S. aureus antigens imply that native antigens induce immune responses insufficient for optimal efficacy. These perspectives exemplify the need to apply novel vaccine strategies to high-priority pathogens. One such approach can be termed convergent immunity, where antigens from non-target organisms that contain epitope homologs found in the target organism are applied in vaccines. This approach aims to evoke atypical immune defenses via synergistic processes that (1) afford protective efficacy; (2) target an epitope from one organism that contributes to protective immunity against another; (3) cross-protect against multiple pathogens occupying a common anatomic or immunological niche; and/or (4) overcome immune subversion or avoidance strategies of target pathogens. Thus, convergent immunity has a potential to promote protective efficacy not usually elicited by native antigens from a target pathogen. Variations of this concept have been mainstays in the history of viral and bacterial vaccine development. A more far-reaching example is the pre-clinical evidence that specific fungal antigens can induce cross-kingdom protection against bacterial pathogens. This trans-kingdom protection has been demonstrated in pre-clinical studies of the recombinant Candida albicans agglutinin-like sequence 3 protein (rAls3) where it was shown that a vaccine containing rAls3 provides homologous protection against C. albicans, heterologous protection against several other Candida species, and convergent protection against several strains of S. aureus. Convergent immunity reflects an intriguing new approach to designing and developing vaccine antigens and is considered here in the context of vaccines to target S. aureus.
Highlights
Staphylococcus aureus infections are ubiquitous, potentially lifethreatening, and a rising public health issue [1,2,3]
Neutrophils and other host cells Neutrophils represent the predominant cellular effectors of host-defense against S. aureus. This fact is supported by numerous clinical conditions in which lack of functional neutrophils, or dysfunctions in neutrophils are associated with increased risks of S. aureus infection: (a) neutropenia [60,61,62,63]; (b) dysfunctions in granulocyte oxidative burst [e.g., chronic granulomatous disease; [64, 65]]; (c) dysfunctions in Th17 polarization, which recruits/activates neutrophils [e.g., Job Syndrome; [66, 67]); and (d) dysfunctions in leukocyte adhesion molecule expression or function as required for neutrophil margination and diapedesis to target sites of infection [e.g., LAD-1 and -2; [68, 69]]
Such examples suggest that historically unappreciated molecules and cells are likely integral to host defense against S. aureus, and may be integral to creating efficacious vaccines
Summary
Staphylococcus aureus infections are ubiquitous, potentially lifethreatening, and a rising public health issue [1,2,3]. Neutrophils and other host cells Neutrophils (or polymorphonuclear leukocytes) represent the predominant cellular effectors of host-defense against S. aureus This fact is supported by numerous clinical conditions in which lack of functional neutrophils, or dysfunctions in neutrophils are associated with increased risks of S. aureus infection: (a) neutropenia [60,61,62,63]; (b) dysfunctions in granulocyte oxidative burst [e.g., chronic granulomatous disease; [64, 65]]; (c) dysfunctions in Th17 polarization, which recruits/activates neutrophils [e.g., Job Syndrome; [66, 67]); and (d) dysfunctions in leukocyte adhesion molecule expression or function as required for neutrophil margination and diapedesis to target sites of infection [e.g., LAD-1 and -2; [68, 69]]. Mice exposed to heat-killed S. aureus generate robust CD8+ T-cell responses when CD40 ligand is co-stimulated with specific antibody, yielding protective efficacy in a mastitis model Such examples suggest that historically unappreciated molecules and cells are likely integral to host defense against S. aureus, and may be integral to creating efficacious vaccines. Much of the data remain proprietary, all of these antigens had to have been successfully evaluated in one or more animal challenge studies and shown to be safe and immunogenic when evaluated in pre-clinical toxicity
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