Abstract
SummaryObjectivesDespite over a century of research and the careful scrutiny of many promising targets, there is currently no vaccine available for the prevention of Streptococcus pyogenes infection. Through analysis of the protective, anti-streptococcal components of pooled human immunoglobulin, we previously identified ten highly conserved and invariant S. pyogenes antigens that contribute to anti-streptococcal immunity in the adult population. We sought to emulate population immunity to S. pyogenes through a process of active vaccination, using the antigens targeted by pooled human immunoglobulin.MethodsSeven targets were produced recombinantly and mixed to form a multicomponent vaccine (Spy7). Vaccinated mice were challenged with S. pyogenes isolates representing four globally relevant serotypes (M1, M3, M12 and M89) using an established model of invasive disease.ResultsVaccination with Spy7 stimulated the production of anti-streptococcal antibodies, and limited systemic dissemination of M1 and M3 S. pyogenes from an intramuscular infection focus. Vaccination additionally attenuated disease severity due to M1 S. pyogenes as evidenced by reduction in weight loss, and modulated cytokine release.ConclusionSpy7 vaccination successfully stimulated the generation of protective anti-streptococcal immunity in vivo. Identification of reactive antigens using pooled human immunoglobulin may represent a novel route to vaccine discovery for extracellular bacteria.
Highlights
Streptococcus pyogenes is often overlooked as a major cause of human disease owing to the rarity of severe S. pyogenes infection in the developed world
A third group was vaccinated with the SpyCEP fragment CEP-5 that has previously been shown to provide protection against experimental S. pyogenes infection.[6,16 41] d following the start of the vaccination protocol, the anti-streptococcal activity of plasma from Spy7-vaccinated and sham-vaccinated mice was compared by whole bacterial cell ELISA (Fig. 1A)
Each of the seven recombinant vaccine components reacted with plasma from Spy7-vaccinated mice; indicating that each antigen had stimulated the humoural immune response, and was potentially contributing to the anti-streptococcal antibody response elicited by Spy[7] (Fig. 1BeH)
Summary
Streptococcus pyogenes is often overlooked as a major cause of human disease owing to the rarity of severe S. pyogenes infection in the developed world. While the attendant morbidity and mortality of invasive syndromes such as necrotizing fasciitis and toxic shock are considerable, it is the rheumatogenic sequelae of non-invasive S. pyogenes infections that represent the most pressing global health burden. Such sequelae account for the majority of the >500,000 deaths per year worldwide attributed to streptococcal infection.[1] Much of the burden of rheumatic heart disease (RHD) exists in developing countries where poverty and limited access to prompt antibiotic treatment may contribute to the development of autoimmunity.[2] S. pyogenes remains exquisitely sensitive to beta-lactam antibiotics, the development of an effective vaccination is widely regarded as the most reliable way to reduce the global S. pyogenes disease burden. With the exception of the M protein, no vaccine candidates have reached clinical trials to date
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