Vaccine based on a ubiquitous cysteinyl protease and streptococcal pyrogenic exotoxin A protects against Streptococcus pyogenes sepsis and toxic shock

Abstract

Background: The gram-positive bacterium Streptococcus pyogenes is a common pathogen of humans that causes invasive infections, toxic-shock syndrome, rheumatic fever, necrotizing fasciitis and other diseases. Detection of antibiotic resistance in clinical isolates has renewed interest in development of new vaccine approaches for control S. pyogenes sepsis. In the study presented, a novel protein vaccine was examined. The vaccine was based on a recombinant protein fusion between streptococcal pyrogenic exotoxin B (SpeB), a cysteinyl protease expressed by all clinical isolates, and streptococcal pyrogenic exotoxin A (SpeA), a superantigen produced by a large subset of isolates.

A Single, Engineered Protein Therapeutic Agent Neutralizes Exotoxins from BothStaphylococcus aureusandStreptococcus pyogenes

“…As SpeA is considered one of the major virulence factors in streptococcal TSS (12,14,46), various approaches have been explored to neutralize its toxic activity. These include efforts to develop SpeA toxoid vaccines that induce neutralizing antibodies (5,33,38,51,52) or the generation of monoclonal antibodies, potentially for passive therapy (49). Our approach has involved the use of soluble, high-affinity receptors that could neutralize the toxins in much the same way as the TNF-␣-neutralizing agent Enbrel, a soluble form of the TNF-␣ receptor, neutralizes its target (6).…”

The Majority of 9,729 Group A Streptococcus Strains Causing Disease Secrete SpeB Cysteine Protease: Pathogenesis Implications

“…However, other studies performed by multiple investigators have reported that the secreted SpeB protease is a key virulence factor contributing to tissue destruction, dissemination, and mortality in invertebrate, mouse, and nonhuman primate models (9,22,(34)(35)(36)(37)(38)(39)(40)(41). Moreover, SpeB is expressed in humans with invasive disease (42)(43)(44); infected humans generate anti-SpeB antibodies (43)(44)(45); and immunization of mice with SpeB or SpeB-derived protein fragments protects against lethal challenge (36,(46)(47)(48). Mice treated with a protease inhibitor that inactivates SpeB are similarly protected against invasive disease (49).…”

Group A Streptococcal Vaccine Candidates: Potential for the Development of a Human Vaccine

“…Murine models are the most commonly employed for both pathogenesis studies and for vaccine development, with models for pharyngeal, cutaneous and systemic infections used extensively. In recent years other animal models have been developed including rheumatic heart disease in rats (Lymbury et al 2003), invasive disease in rabbits (Piepmeier et al 1995), streptococcal septic shock in pigs (Saetre et al 2000), toxic shock in mice (Ulrich 2008), necrotizing fasciitis in mice (Matsui et al 2009), pharyngitis in non-human primates (Skinner et al 2011;Sumby et al 2008), plus a zebrafish (Neely et al 2002) and a wax worm model (Olsen et al 2011) to study GAS virulence properties.…”

“…In both cases advancement to clinical trials was based upon the success of the vaccines in eliciting systemic immunity in mouse models. Most murine models to evaluate systemic immunity in response to GAS antigens have utilized subcutaneous (Brandt et al 2000;Sabharwal et al 2006;Okamoto et al 2005;McMillan et al 2004;Kapur et al 1994;Liu et al 2007;Kawabata et al 2001;Ma et al 2009;Terao et al 2005) and less frequently intraperitoneal (Henningham et al 2012;Guzmán et al 1999), intramuscular (Ulrich 2008;Turner et al 2009), or intravenous (Gillen et al 2008;Courtney et al 2003) immunization in the presence of CFA/incomplete Freund's adjuvant (IFA). CFA is an efficient stimulator of cellmediated immunity and augments the humoral immune response, however, CFA is banned for use in humans due to toxic side effects so it can be difficult to translate the results of these studies to humans [reviewed in Lindblad 2000].…”

“…To overcome this problem, a humanized plasminogen transgenic mouse model of skin infection has been developed for virulence studies (Sun et al 2004). Other humanized transgenic mouse models used for virulence studies include a human CD46-expressing transgenic mouse model of subcutaneous infection (Matsui et al 2009) and a HLA-DQR transgenic mouse model of toxic shock (Ulrich 2008). The latter model has also been employed in vaccine studies to ascertain the protective efficacy of the streptococcal pyrogenic exotoxin A (SpeA) to protect against toxic shock (Ulrich 2008).…”