Applying Convergent Immunity to Innovative Vaccines Targeting Staphylococcus aureus

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.

Mechanisms of NDV-3 vaccine efficacy in MRSA skin versus invasive infection

“…Collectively, the present findings support the concepts of unnatural immunity (77) or convergent immunity (44) as novel means to protect against infections caused by normal flora pathogens. NDV-3 is a recombinant fungal antigen that is expressed in a heterologous host, making it nonidentical to Als3 naturally expressed by Candida.…”

“…bacteremia (43)(44)(45)(46)(47)(48). The adoptive transfer of CD4 + T cells but not B220 + B cells from immunized mice afforded protection (47,48).…”

“…Further, the roles of B lymphocytes and functional antibodies, and particularly the class switching that is dependent on antigenrestricted T-cell approval (e.g., IgG 1 in humans or IgG 2 in mice), remain to be fully understood with respect to NDV-3 efficacy in SSSI due to S. aureus. Nonetheless, the NDV-3 vaccine exploits convergent immunity (44) and thus may have advantages in overcoming limitations experienced in recent clinical trials of S. aureus vaccines.…”

“…In humans, host defense peptides including β-defensins 2 and 3 can enhance adaptive immunity (e.g., dendritic cell or lymphocyte function) (70) and potentiate opsonophagocytosis and intracellular killing of pathogens by granulocytes (71). Likewise, complementary or compensatory mechanisms including Th1 responses (41)(42)(43)(44), functional antibodies, as well as complement fixation (72) may also contribute to NDV-3 efficacy. Studies to further define the regulation (73-76) of natural and NDV-3-induced cutaneous and invasive host defense against MRSA are ongoing in our laboratory.…”

“…Its immunogen is engineered from the agglutinin-like sequence 3 (Als3) adhesin/invasin of Candida albicans, which we discovered to be a structural homolog of S. aureus adhesins (43). NDV-3 is believed to cross-protect against S. aureus and C. albicans due to sequence (T-cell) and conformational (B-cell) epitopes paralleled in both organisms (44). Our prior data have shown that NDV-3 is efficacious in murine models of hematogenous and mucosal candidiasis (45), as well as S. aureus bacteremia (46)(47)(48).…”