Abstract
Group A Streptococcus (GAS) is a major cause of global infection-related morbidity and mortality. A modern controlled human infection model (CHIM) of GAS pharyngitis can accelerate vaccine development and pathogenesis research. A robust rationale for strain selection is central to meeting ethical, scientific, and regulatory requirements. Multifaceted characterization studies were done to compare a preferred candidate emm75 (M75) GAS strain to three other strains: an alternative candidate emm12 (M12) strain, an M1 strain used in 1970s pharyngitis CHIM studies (SS-496), and a representative (5448) of the globally disseminated M1T1 clone. A range of approaches were used to explore strain growth, adherence, invasion, delivery characteristics, short- and long-term viability, phylogeny, virulence factors, vaccine antigens, resistance to killing by human neutrophils, and lethality in a murine invasive model. The strains grew reliably in a medium without animal-derived components, were consistently transferred using a swab method simulating the CHIM protocol, remained viable at -80°C, and carried genes for most candidate vaccine antigens. Considering GAS molecular epidemiology, virulence factors, in vitro assays, and results from the murine model, the contemporary strains show a spectrum of virulence, with M75 appearing the least virulent and 5448 the most. The virulence profile of SS-496, used safely in 1970s CHIM studies, was similar to that of 5448 in the animal model and virulence gene carriage. The results of this multifaceted characterization confirm the M75 strain as an appropriate choice for initial deployment in the CHIM, with the aim of safely and successfully causing pharyngitis in healthy adult volunteers.IMPORTANCE GAS (Streptococcus pyogenes) is a leading global cause of infection-related morbidity and mortality. A modern CHIM of GAS pharyngitis could help to accelerate vaccine development and drive pathogenesis research. Challenge strain selection is critical to the safety and success of any CHIM and especially so for an organism such as GAS, with its wide strain diversity and potential to cause severe life-threatening acute infections (e.g., toxic shock syndrome and necrotizing fasciitis) and postinfectious complications (e.g., acute rheumatic fever, rheumatic heart disease, and acute poststreptococcal glomerulonephritis). In this paper, we outline the rationale for selecting an emm75 strain for initial use in a GAS pharyngitis CHIM in healthy adult volunteers, drawing on the findings of a broad characterization effort spanning molecular epidemiology, in vitro assays, whole-genome sequencing, and animal model studies.
Highlights
Group A Streptococcus (GAS) is a major cause of global infection-related morbidity and mortality
Drawing on the record of historical controlled human infection model (CHIM) studies that included 172 participants [5,6,7], a modern pharyngitis CHIM in healthy adult volunteers has been proposed as part of a reenergized global effort to accelerate GAS vaccine development [8]
We present a multifaceted characterization of the preferred CHIM candidate M75 strain and compared it to three others: GAS M12 611025 (M12), an alternative challenge candidate; M1T1 5448 (5448), representative of the M1T1 clone recently responsible for most pharyngitis and invasive disease globally [10]; and Centers for Disease Control and Prevention (CDC) SS-496 (SS-496), an M1 strain administered to 88 subjects in 1970s pharyngitis CHIM studies [5, 7]
Summary
Group A Streptococcus (GAS) is a major cause of global infection-related morbidity and mortality. A modern controlled human infection model (CHIM) of GAS pharyngitis can accelerate vaccine development and pathogenesis research. We outline the rationale for selecting an emm strain for initial use in a GAS pharyngitis CHIM in healthy adult volunteers, drawing on the findings of a broad characterization effort spanning molecular epidemiology, in vitro assays, whole-genome sequencing, and animal model studies. Group A Streptococcus (GAS; Streptococcus pyogenes) is a major contributor to global infection-related mortality and morbidity It causes a diverse spectrum of human disease syndromes, from superficial infections (e.g., pharyngitis and impetigo) to invasive disease (e.g., necrotizing fasciitis and toxic shock syndrome) and autoimmune complications (acute rheumatic fever, rheumatic heart disease, and glomerulonephritis) [1]. We present a multifaceted characterization of the preferred CHIM candidate M75 strain and compared it to three others: GAS M12 611025 (M12), an alternative challenge candidate; M1T1 5448 (5448), representative of the M1T1 clone recently responsible for most pharyngitis and invasive disease globally [10]; and CDC SS-496 (SS-496), an M1 strain administered to 88 subjects in 1970s pharyngitis CHIM studies [5, 7]
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