TABLE 1.

Preferred strain characteristics for a controlled human infection model of GAS pharyngitis^a

Desirable strain characteristic(s)	Rationale	M75 611024 details
Definite but uncommon contemporary cause of symptomatic pharyngitis	Pharyngitis is the critical early target for GAS vaccine development; historical CHIM studies offer a template for a reliable and safe protocol; GAS pharyngitis is most common in childhood and adolescence, suggesting previous exposure and immune memory could prevent experimentally induced disease in adult volunteers	From a child with symptomatic GAS pharyngitis in Melbourne, 2011; preexisting immunity in adults is unknown (no correlate of protection); ≤5% of strains in most recent pharyngitis studies are emm75
Should cause skin infection	Common GAS skin infections (e.g., impetigo) will also be important in initial vaccine field trials; ideally, the pharyngitis CHIM strain(s) should also be suitable for use in a potential future human model of cutaneous GAS infection	E pattern generalist (throat and skin infections); cluster E6 is linked phylogenetically to D pattern skin isolates
Uncommon cause of invasive GAS disease and immunological sequelae	GAS pharyngitis can lead to locally invasive infectious complications (e.g., retropharyngeal abscess), severe invasive infection (e.g., streptococcal toxic shock syndrome), acute rheumatic fever, and glomerulonephritis	≤5% of isolates in recent reports of invasive GAS are emm75; from 2000 to 2016, 403/17,002 (2.4%) typeable invasive isolates reported to the U.S. CDC’s Active Bacterial Core surveillance were emm75 (Chris A. Van Beneden, personal communication, 11 September 2018) (41, 42); emm75 strains rarely associated with ARF/RHD or APSGN (1)
Should have predictable and limited virulence and be suitable for use in animal models	Whole-genome sequencing, in vitro assays, and animal models may inform understanding of a GAS strain’s relative virulence, although none fully predict human disease patterns	CovR/S virulence regulator, wild type (nonmutant); does not bind plasminogen and fibrinogen; emm75 strains have been used in animal nasopharyngitis and invasive disease models
Should have limited antibiotic resistance	Ideally, the challenge strain should be eradicated from the pharynx by antibiotic treatment; resistance to penicillin has not been documented in GAS, but it does not reliably eradicate GAS from the pharynx; observed resistance to other drugs is variable	See the text
Challenge strain should possess a wide array of candidate vaccine antigens	For greatest impact, a GAS pharyngitis CHIM should be suitable for early use as a preliminary testing ground for vaccines	See the text

^aSee Table S1 for a detailed and referenced version of this table. ARF, acute rheumatic fever; APSGN, acute poststreptococcal glomerulonephritis; RHD, rheumatic heart disease.