Table 1.

List of GAS vaccine candidates in clinical and pre-clinical trials. I.M., intramuscular; I.P., intraperitoneal; S.C., subcutaneous; I.N., intranasal.

vaccine candidates	description	outcome	reference
clinical trials
6-valent vaccine	comprised N-terminal M protein fragments from serotypes M1, M3, M5, M6, M19 and M24 Phase I—immunized 28 healthy adults clinical assessment, serological responses and cross-reactive antibodies were examined post-vaccination	no tissue cross-reactive antibodies 30% increase in serum bactericidal activity post-vaccination first evidence in humans that a multi-component protein elicits opsonic antibodies against GAS	[87,88]
26-valent vaccine (StreptAvax)	comprised four recombinant proteins containing N-terminal peptides from 26 M proteins Phase I—immunized 30 healthy adults Phase II—immunized 30 healthy adults	the absence of rheumatogenicity or nephritogenicity no induction of human tissue-reactive antibodies a fourfold increase of IgG compared with control discontinued due to commercial reasons	[89–91]
30-valent vaccine (StreptAnova™)	comprised four recombinant proteins containing N-terminal peptides from 30 M proteins Phase I—immunized 23 healthy adults	no evidence of autoimmunity no tissue cross-reactive antibodies 25 out of 31 M serotypes showed significant antibody titre	[84]
J8 vaccine (MJ8VAX)	comprised a synthesized and acetylated peptide antigen (J8) from the conserved carboxyl terminus region of the M protein Phase I—immunized 10 healthy adults	13 adverse effects were classified as ‘mild’ highly immunogenic after post-immunization level of antibodies decreased with time	[85,92]
pre-clinical trails
serum opacity factor (SOF)	function: opacifies mammalian serum anti-SOF antibodies tested against M2, M4 and M28	SOF stimulates antibodies in humans, rabbits and mice provokes protective immunity by killing M4 and M28	[93–95]
Group A carbohydrate (GAC)	GAC without GlcNAc side chain (polyrhamnose) used as an immunogen purified GlcNAc-deficient GAC was tested for GAS survival GlcNAc linked to the pathogenesis of rheumatic carditis	GlcNAc-deficient GAC facilitates opsonization and phagocytosis of diverse GAS strains protects systemic and nasal challenges on mice and rabbit models GlcNAc promotes GAS survival in human blood	[29,96,97]
C5a peptidase (ScpA)	highly specific endopeptidase major virulence factor anchored on the surface of GAS samples collected from children infected with pharyngitis	children with pharyngitis had increased ScpA activity level of ScpA correlates with an increased level of anti-SLO and anti-DNase B activity	[25,98]
pyrogenic exotoxins (Spe)	SpeA and SpeC superantigen Spe linked to STSS	toxoids of SpeA stimulates protective antibody response anti-superantigen antibodies protects mice from GAS nasopharynx infection induction of variable β-specific T cells promotes GAS colonization	[24,99–101]
streptolysin O (SLO)	pore-forming toxin produced by GAS animals immunized S.C. and challenged with GAS	inactivated SLO mutant animals exhibited decreased mortality compared with wild-type GAS SLO mutant protects animals from lethal M1 challenge	[26,102]
chemokine cleaving protease (SpyCEP)	SpyCEP is expressed on the GAS surface and secreted function cleaves IL-8 SpyCEP expression upregulated in NF mice immunized I.M. with SpyCEP and challenged with GAS through I.M. and I.N.	reduced bacterial dissemination found in both GAS and S. equi offers protection against other streptococcal species	[27,103,104]
SfbI and FBP54	SfbI and FBP54 is a fibronectin-binding protein plays a key role in bacterial attachment to host cell SfbI—animals immunized I.N. and challenged with M23 and blood isolate NS239 FBP54—mice immunized either S.C or orally and challenged I.P. with GAS	SfbI vaccinated animals show 80% antibody efficacy homologous challenge and 90% in heterologous challenge FBP54 immunized mice survived significantly longer following GAS challenges	[28,105]
multi-component vaccines
Spy7	comprised highly conserved streptococcal surface antigen expressed in E. coli mice were immunized, and I.M. challenged with M1, M3, M12 and M89	production of anti-streptococcal antibodies limited the dissemination of M1 and M3	[70]
three technologies	comprised Streptolysin O, Spy0269 and SpyCEP mice immunized I.P. and challenged I.N. or I.P. with GAS	broad protective antibody response against M1, M6, M12 and M23 antibody-mediated GAS killing—classical whole blood bactericidal assay	[106]
combination vaccines	three combination vaccines were formulated I—comprised SLO, IL-8, SpyCEP, ScpA, ADI and trigger factor II—comprised conserved M protein-derived J8 peptide conjugated to ADI III—GAC without N-GlcNaC mice immunized and challenged S.C. with GAS M1 protein was used as a positive control	all experimental vaccine candidates elicited antigen-specific antibody coupled with bactericidal activity only positive control provided protection against S.C invasive disease model	[107]
Combo vaccine (Combo5)	comprised SLO, ADI, ScpA, SpyCEP and trigger factor Indian rhesus macaques immunized I.M. and challenged I.N with GAS	Combo5 immunization induced antigen-specific IgG in rhesus macaques IgG against Combo5 bind to live GAS but do not promote killing by HL-60 cells decreased severity of clinical signs but not colonization in pharyngitis infection model following work highlighted that using adjuvants containing saponin QS21 with antigens ADI, SpyCEP, ScpA, SLO and trigger factor resulted in significant protection against GAS invasive infection	[33,108]
5CP	comprised sortase A, streptococcal C5a peptidase, S. pyogenes the adhesion and division protein, a fragment of SpyCEP (CEP-5) and streptolysin O mice immunized with 5CP and challenged I.N. with GAS to study mucosal and systemic infection mice immunized I.N. with 5CP and challenged S.C with GAS for skin abscess model	5CP induced Th17 responses in the spleen of animals Th17 responses induced by 5CP resolve more rapidly than induced by GAS suggesting competent Th17 response towards 5CP	[34]