Table 3.

Summary of studies using CEPs as vaccine antigens for immunization against streptococcal species

Target	Vaccine	Model	Findings	Reference
SpyCEP	Recombinant SpyCEP with alum adjuvant	IP immunisation with M1 GAS IN challenge	Increased survival after challenge	[88]
	Recombinant SpyCEP with Freund's adjuvant	IP immunization followed by intranasal lethal challenge with M23 GAS of CD1 mice	Increased survival to 70%	[99]
	Recombinant SpyCEP with Freund's adjuvant	BALB/c mice immunized IM, followed by IM and IN challenge with GAS and S. equi	No reduction in bacterial burden at the site of infection. Decreased dissemination of GAS and S. equi following both IM and IN challenge	[52]
	Combo (SpyCEP, SpyAD, and streptolysin O) adjuvanted with Freund's or alum hydroxide	CD1 mice immunized IP, challenged with Ml, M6, M12, and M23 GAS	Cross serotype protection against GAS 50-80% survival following IN and IM challenge Decreased bacterial burden in subcutaneous air pouch infection Induced antibodies that mediated opsonophagocytic killing in whole blood assay	[101]
	SpyCEP with Freund's adjuvant	FVB/n mice immunized IM and IN challenge	Reduced signal of bioluminescent M75 GAS, but no difference in bacterial burden in the nasopharynx	[112]
	SpyCEP with J8-DT (M protein conserved epitope)	BALB/c mice immunized SC, GAS skin challenge following scarification	Protection against pyoderma and bacteraemia Protection against GAS hypervirulent CovRS mutants	[105, 106]
ScpA	Recombinant ScpA unadjuvanted	Intranasal immunization of CD1 mice, intranasal challenge with M1, M2, M6, M11, and M49 GAS	Reduced nasopharyngeal colonization	[24]
	Recombinant ScpA adjuvanted with alum or monophosphoryl lipid A	SC immunization of CD1 mice, IN challenge with M49 and M1 GAS	ScpA-specific antibodies neutralized protease activity of ScpA and ScpB Increased clearance of GAS from lungs and nasal mucosa	[109]
	ScpA adjuvanted with cholera toxin	Intranasal immunization of BALB/c mice, intranasal challenge with M49 GAS	Reduction of colonization of nasal-associated lymphoid tissue Immunized sera gave passive protection against GAS IN infection in naïve mice	[110]
SpyCEP and ScpA	Spy7 (ScpA, and 6 other highly conserved surface antigens) with Freund's adjuvant vs SpyCEP	FVB/n mice immunized IM, IM challenge with M1 and M3 GAS	Reduction in systemic dissemination	[102]
	Combo 5 (ScpA, SpyCEP, arginine deaminase, streptolysin O, and trigger factor) with Alum adjuvant	IM immunization of rhesus macaques, M1 GAS IN challenge	Robust antigen-specific antibody response and reduction in both pharyngitis and tonsillitis following an M1 intranasal challenge	[100]
ScpB	ScpB adjuvanted with alum and mycobacterial phospholipid, SC immunisation	CD1 mice, GBS serotype VI IN challenge	Reduced lung bacterial burden Conjugation of recombinant ScpB to a nonhomologous polysaccharide (III) can increase the immunogenicity of the polysaccharide when challenged with another serotype (VI) and reduced inflammatory damage to the lungs	[111]
	ScpB encapsulated in biodegradable polymer	ICR mice immunized IN or IM, vaginal challenge	Strong IgG response after administration of ScpB by both intranasal and intramuscular routes, with an increased response when encapsulated Intranasal administration elicited a secretory IgA in the vaginal mucosa Mice immunized with encapsulated ScpB fully resisted vaginal colonization after exposure to serotype III GBS. Parental immunization conferred neonate protection	[114]
SspA	SspA with ScpCL and 3 other S. suis virulence factors adjuvanted with CpG	IN immunization of C57BL6/6JCnc mice, followed by IN, IP, or IV challenge with SS2, SS3, and SS7 serotype S. suis	Significantly reduced NALT bacterial burden Serotype-dependent protection against systemic dissemination Reduced mortality in mice given a lethal IV dose of SS2 S. suis	[120]
PrtA	PrtA with Freund's adjuvant	C3h/HeJ mice, SC immunisation and IP challenge	Mice were protected from lethal challenge of serotypes 6A and 6B but not 4 S. pneumoniae strains Serum from immunized mice was able to protect naive mice from lethal challenge in a serotype- specific manner	[121]
	PrtA with ISCOMATRIX	IM immunization of BALB/c and CBA/n mice, followed by IN challenge with serotype 3 or 8 S. pneumoniae	Reduced serotype 3 bacterial burden in the lungs of BALB/c mice Protected CBA/n mice from a lethal intranasal dose of serotype 3 Protective effect against non-lethal serotype 8 infection	[122]
	PrtA with Curdlan adjuvant	IN immunization of BALB/c mice, followed by IN challenge with serotype 2 S. pneumoniae	Increased PrtA-specific IgG and IgA levels in BALF and increased IgA levels in saliva and nasal washes Did not protect against acute pneumonia and systemic dissemination; no significant reduction in lung bacterial burden or blood multiplication	[123]

CEPs, cell-envelope proteases; GAS, group A streptococcus; SpyCEP, Streptococcus pyogenes CEP.