Feasibility and therapeutic strategies of vaccines against Porphyromonas gingivalis

Figures & data

Figure 1. Schematic composition of the cell envelope of Porphyromonas gingivalis.

A P. gingivalis vaccine might be based on surface antigens: capsule, LPS, fimbriae, OMPs, gingipains and hemagglutinin, of which LPS and gingipains could also be localized within the outer membrane vesicles [21].

LPS: Lipopolysaccharide; OMP: Outer membrane protein.

Figure 2. Recognition of Porphyromonas gingivalis-specific surface antigens, LPS, fimbriae and hemagglutinin by TLRs.

LPS: Lipopolysaccharide; MyD88: Myeloid differentiation primary response gene 88; TLR: Toll-like receptor; TRIF: TIR-domain-containing adapter-inducing IFN-β.

From [41,45,46,61].

Table 1. Immunization with Porphyromonas gingivalis surface antigens.

Antigen type	Modification	Administration	Model	Immunization results	Ref.
Capsule	Whole CPS	sc.	Mouse	CPS-specific IgG and IgM titers elevated. Protection against P. gingivalis-elicited alveolar bone loss	[31]
	Polysaccharide–BSA conjugate	ip.	Mouse	Induction of serum antibodies and reduced severity of infection after challenge with P. gingivalis	[32]
	Polysaccharide–fimbriae protein conjugate	ip.	Mouse	Higher serum IgG and highest protection against P. gingivalis-induced infection compared with CPS or fimbriae alone	[33]
LPS	LPS	ip.	Mouse	No induction of serum IgG, antigen-reactive lymphocytes and protection against P. gingivalis-induced infection	[47]
	LPS/dose-response study	ip.	Mouse	Unresponsiveness is antigen-specific and could be induced by a single injection of LPS	[48]
Fimbriae	Fimbriae accompanied by fimbriae-specific antibodies	sc.	Rat	Protection against periodontal destruction	[65]
	Fimbriae of a single fimbria variation	sc., im.	Rabbit	Induced polyclonal antibody only binds closely to related strains of the same fimbrial biovar	[66]
	Fimbriae in combination with CT	Oral	Mouse	In addition to serum IgM, IgG and IgA antibodies, salivary IgA specific for fimbriae was significantly increased	[25]
	Fimbriae coadministration with rCTB	in.	Mouse	Stimulation of both systemic and mucosal immune responses and reduced P. gingivalis-induced alveolar bone loss	[68]
	DNA vaccine: plasmid pIRES-fimA, coexpression plasmid pIRES-fimA:IL-15	im, in.	Mouse	in. and im. administration both induced FimA-specific IgG in serum. Only in. administration was able to enhance FimA-specific IgA in saliva, which was further increased by including IL-15 as an adjuvant	[69]
	DNA vaccine: plasmid pcDNA3/fimA	Injection into salivary gland	Mouse	Enhanced fimbriae-specific IgA and IgG in saliva and IgG in serum	[70]
	DNA vaccine: Streptococcus gordonii vectors	Oral	Rat	Enhanced FimA-specific serum IgG, IgA and salivary IgA	[71]
OMPs	OmpA-like protein: PG32/33	sc.	Rat, mouse	Significantly reduced the lesion size and therefore induced protection against P. gingivalis	[80]
	Anti-r40-kDa OMP hMAb	Oral	Rat	Protects against P. gingivalis-induced alveolar bone loss	[81]
	40-kDa OMP and CT	tc., in.	Mouse	Induced serum IgG, IgA and IgG in saliva	[82,83]
	40-kDa OMP	tc.	Rat	Induced serum IgG, IgA and IgG in saliva. Protection against challenge with P. gingivalis 381	[84]
	40-kDa OMP with mCTA/LTB	in.	Mouse	Induced high levels of 40-kDa-specific serum IgG, IgA and IgA in saliva. Reduction of P. gingivalis-induced alveolar bone loss	[85]
	40-kDa OMP with pFL	sl.	Mouse	Induced high levels of 40-kDa-specific serum IgG, IgA and IgA in saliva. Reduction of P. gingivalis-induced alveolar bone loss	[86]
Gingipains	Purified cysteine protease	sc.	Macaque	Induction of serum IgG and reduction of P. gingivalis in subgingival plaque. Onset and progression of alveolar bone loss was inhibited	[91]
	RgpA, RgpB, H-K whole cells	sc.	Rat, mouse	All vaccines induced specific serum IgG, but only RgpA induces protection against P. gingivalis- induced alveolar bone loss	[93]
	RgpA, RgpB, multiple antigenic peptide conjugate Rgp	ip.	Mouse	P. gingivalis-specific serum IgG against functionally defined peptide fragments derived from the catalytic and hemagglutinin/adhesion domains of RgpA	[94]
	RgpA-Kgp protease–adhesin complex	sc.	Mouse	Protects against challenge with invasive and noninvasive P. gingivalis strains	[96]
	Active site and ABM peptides from RgpA-Kgp complex conjugated to diphtheria toxoid	sc.	Mouse	Protection against P. gingivalis-induced alveolar bone loss	[98]
	A1 adhesin domain, rRgpAcat	sc.	Rat, mouse	Adhesin domains significant attenuate P. gingivalis infection, while rRgpAcat does not	[99]
	rgpA DNA vaccine	in., id.	Mouse	in. administration results in higher serum IgG, additional IgA in saliva and reduction of alveolar bone loss, when compared with id. administration	[101]
	rgpA DNA vaccine	id.	Mouse	Reduced lethality against infection by a lethal dose of P. gingivalis	[104]
	DNA vaccine: plasmids pSeq2A/kgpcd and pSeq2B/rgpcd	im.	Mouse	Preventive inflammatory responses, serum IgG, and prolonged survival rate	[105]
Hemagglutinin	rHagB	sc.	Rat	No HagB-specific salivary IgA, slight serum IgM, while serum IgG was actively enhanced. Reduction of bone loss	[107]
	rHagB alone or with MPL	in.	Mouse	Significant increase of HagB-specific salivary IgA and serum IgG compared with rHagB alone	[114]
	Salmonella typhimurium strain χ4072 expressing hagB	ig.	Mouse	Induced HagB-specific Hag serum IgG and salivary IgA	[115]
	S. typhimurium strain expressing hagB fused to Lpp-OmpA	oral	Mouse	Higher serum anti-HagB IgG and IgA, than by the cytoplasmic expressing strain	[116]
	130-kD HMGD	id.	Mouse	hMAb significantly inhibits hemagglutination by P. gingivalis and its vesicles	[117]

ABM: Adhesin-binding motif peptides; BSA: Bovine serum albumin; CPS: Capsule polysaccharide; CT(B): Cholera toxin (B subunit); H-K: Heat-killed; (h)MAb: (Human) monoclonal antibody; HMGD: Hemagglutinin domain; id.: Intradermal; ig.: Intragastric; im.: intramuscular; in.: Intranasal; ip.: Intraperitoneal; Kgp: Lysine gingipain; LPS: Lipopolysaccharide; mCTA/LTB: Mutant A subunit cholera toxin/B subunit heat-labile toxin; MPL: Monophosporyl lipid A; OMP: Outer membrane protein; pFL: Plasmid containing the Flt3 ligand; pIRES: Plasmid containing an internal ribosome entry site; rCTB: Recombinant cholera toxin B; Rgp(A/B): Arginine gingipain (A/B); (r)Hag: (Recombinant) hemagglutinin; sc.: Subcutaneous; sl.: Sublingual; tc.: Transcutaneous.

Table 2. Antigenic variation among Porphyromonas gingivalis strains.

P. gingivalis strain	Capsular serotype	LPS serotype	Fimbrial variation	Invasive/virulent	Ref.
1112	ND	ND	I	ND	[29]
1432	ND	ND	I	ND	[29]
2561	ND	ND	I	No	[29]
34–4	K7	ND	ND	Yes	[27]
381	K^-	O1	I	No	[22,23,27,29,36]
6/26	ND	ND	III	ND	[56]
9–14K-1	ND	ND	IV	Yes	[29]
A7A1–28/ATCC 53977	K3	ND	II	Yes	[22,23,29,57]
A7A2–10	ND	ND	II	Yes	[29]
ATCC 33277	ND	ND	I	No	[29,56]
ATCC 49417/RB22D-1	K4	ND	II	Yes	[22,23,57]
HG 1690	K5	ND	II	Yes	[22,23,29,57]
HG 1691	K6	O2	Ib	Yes	[22,23,36,57]
HG 1694	ND	ND	ND	No	[29]
HG 184	K2	ND	II	Yes	[22,23,57]
HG 564	ND	ND	IV	ND	[57]
HG 565	ND	ND	I	ND	[58]
HNA-99	ND	ND	V	Yes	[29,56]
HW24D1	ND	ND	II	ND	[56]
W50	K1	O3	IV	Yes	[22,23,29]
W83 / HG 66	K1	ND	IV	Yes	[22,23,29]

LPS: Lipopolysaccharide; ND: Not documented.

Holt SC, Kesavalu L, Walker S, Genco CA. Virulence factors of Porphyromonas gingivalis. Periodontol. 200020, 168–238 (1999).

 PubMed Web of Science ®Google Scholar

Gonzalez D, Tzianabos AO, Genco CA, Gibson FC 3rd. Immunization with Porphyromonas gingivalis capsular polysaccharide prevents P. gingivalis-elicited oral bone loss in a murine model. Infect. Immun.71(4), 2283–2287 (2003).

 PubMed Web of Science ®Google Scholar

Schifferle RE, Chen PB, Davern LB, Aguirre A, Genco RJ, Levine MJ. Modification of experimental Porphyromonas gingivalis murine infection by immunization with a polysaccharide–protein conjugate. Oral Microbiol. Immunol.8(5), 266–271 (1993).

 PubMedGoogle Scholar

Choi JI, Schifferle RE, Yoshimura F, Kim BW. Capsular polysaccharide–fimbrial protein conjugate vaccine protects against Porphyromonas gingivalis infection in SCID mice reconstituted with human peripheral blood lymphocytes. Infect. Immun.66(1), 391–393 (1998).

 PubMed Web of Science ®Google Scholar

Chen PB, Davern LB, Schifferle R, Zambon JJ. Protective immunization against experimental Bacteroides (Porphyromonas) gingivalis infection. Infect. Immun.58(10), 3394–3400 (1990).

 PubMedGoogle Scholar

Elkins KL, Stashak PW, Baker PJ. Prior exposure to subimmunogenic amounts of some bacterial lipopolysaccharides induces specific immunological unresponsiveness. Infect. Immun.55(12), 3085–3092 (1987).

 PubMedGoogle Scholar

Evans RT, Klausen B, Sojar HT et al. Immunization with Porphyromonas (Bacteroides) gingivalis fimbriae protects against periodontal destruction. Infect. Immun.60(7), 2926–2935 (1992).

 PubMed Web of Science ®Google Scholar

Fan Q, Sims T, Sojar H, Genco R, Page RC. Fimbriae of Porphyromonas gingivalis induce opsonic antibodies that significantly enhance phagocytosis and killing by human polymorphonuclear leukocytes. Oral Microbiol. Immunol.16(3), 144–152 (2001).

 PubMedGoogle Scholar

Nagasawa T, Aramaki M, Takamatsu N, Koseki T, Kobayashi H, Ishikawa I. Oral administration of Porphyromonas gingivalis fimbriae with cholera toxin induces anti-fimbriae serum IgG, IgM, IgA and salivary IgA antibodies. J. Periodontal Res.34(3), 169–174 (1999).

 PubMedGoogle Scholar

Takahashi Y, Kumada H, Hamada N et al. Induction of immune responses and prevention of alveolar bone loss by intranasal administration of mice with Porphyromonas gingivalis fimbriae and recombinant cholera toxin B subunit. Oral Microbiol. Immunol.22(6), 374–380 (2007).

 PubMedGoogle Scholar

Guo H, Wang X, Jiang G, Yang P. Construction of a sIgA-enhancing anti-Porphyromonas gingivalis FimA vaccine and nasal immunization in mice. Immunol. Lett.107(1), 71–75 (2006).

 PubMedGoogle Scholar

Kawabata S, Terao Y, Fujiwara T, Nakagawa I, Hamada S. Targeted salivary gland immunization with plasmid DNA elicits specific salivary immunoglobulin A and G antibodies and serum immunoglobulin G antibodies in mice. Infect. Immun.67(11), 5863–5868 (1999).

 PubMed Web of Science ®Google Scholar

Sharma A, Honma K, Evans RT, Hruby DE, Genco RJ. Oral immunization with recombinant Streptococcus gordonii expressing porphyromonas gingivalis FimA domains. Infect. Immun.69(5), 2928–2934 (2001).

 PubMed Web of Science ®Google Scholar

Ross BC, Czajkowski L, Hocking D et al. Identification of vaccine candidate antigens from a genomic analysis of Porphyromonas gingivalis. Vaccine19(30), 4135–4142 (2001).

 PubMed Web of Science ®Google Scholar

Hamada N, Watanabe K, Tahara T et al. The r40-kDa outer membrane protein human monoclonal antibody protects against Porphyromonas gingivalis-induced bone loss in rats. J. Periodontol.78(5), 933–939 (2007).

 PubMedGoogle Scholar

Koizumi Y, Kurita-Ochiai T, Yamamoto M. Transcutaneous immunization with an outer membrane protein of Porphyromonas gingivalis without adjuvant elicits marked antibody responses. Oral Microbiol. Immunol.23(2), 131–138 (2008).

 PubMedGoogle Scholar

Momoi F, Hashizume T, Kurita-Ochiai T, Yuki Y, Kiyono H, Yamamoto M. Nasal vaccination with the 40-kilodalton outer membrane protein of Porphyromonas gingivalis and a nontoxic chimeric enterotoxin adjuvant induces long-term protective immunity with reduced levels of immunoglobulin E antibodies. Infect. Immun.76(6), 2777–2784 (2008).

 PubMedGoogle Scholar

Zhang T, Hashizume T, Kurita-Ochiai T, Yamamoto M. Sublingual vaccination with outer membrane protein of Porphyromonas gingivalis and Flt3 ligand elicits protective immunity in the oral cavity. Biochem. Biophys. Res. Commun.390(3), 937–941 (2009).

 PubMed Web of Science ®Google Scholar

Page RC, Lantz MS, Darveau R et al. Immunization of Macaca fascicularis against experimental periodontitis using a vaccine containing cysteine proteases purified from Porphyromonas gingivalis. Oral Microbiol. Immunol.22(3), 162–168 (2007).

 PubMedGoogle Scholar

Gibson FC 3rd, Genco CA. Prevention of Porphyromonas gingivalis-induced oral bone loss following immunization with gingipain R1. Infect. Immun.69(12), 7959–7963 (2001).

 PubMed Web of Science ®Google Scholar

Genco CA, Odusanya BM, Potempa J, Mikolajczyk-Pawlinska J, Travis J. A peptide domain on gingipain R which confers immunity against Porphyromonas gingivalis infection in mice. Infect. Immun.66(9), 4108–4114 (1998).

 PubMed Web of Science ®Google Scholar

O’Brien-Simpson NM, Paolini RA, Reynolds EC. RgpA–Kgp peptide-based immunogens provide protection against Porphyromonas gingivalis challenge in a murine lesion model. Infect. Immun.68(7), 4055–4063 (2000).

 PubMed Web of Science ®Google Scholar

O’Brien-Simpson NM, Pathirana RD, Paolini RA et al. An immune response directed to proteinase and adhesin functional epitopes protects against Porphyromonas gingivalis-induced periodontal bone loss. J. Immunol.175(6), 3980–3989 (2005).

 PubMed Web of Science ®Google Scholar

Frazer LT, O’Brien-Simpson NM, Slakeski N et al. Vaccination with recombinant adhesins from the RgpA–Kgp proteinase–adhesin complex protects against Porphyromonas gingivalis infection. Vaccine24(42–43), 6542–6554 (2006).

 PubMedGoogle Scholar

Miyachi K, Ishihara K, Kimizuka R, Okuda K. Arg-gingipain A DNA vaccine prevents alveolar bone loss in mice. J. Dent. Res.86(5), 446–450 (2007).

 PubMedGoogle Scholar

Yonezawa H, Kato T, Kuramitsu HK, Okuda K, Ishihara K. Immunization by Arg-gingipain A DNA vaccine protects mice against an invasive Porphyromonas gingivalis infection through regulation of interferon-γ production. Oral Microbiol. Immunol.20(5), 259–266 (2005).

 PubMedGoogle Scholar

Kuboniwa M, Amano A, Shizukuishi S, Nakagawa I, Hamada S. Specific antibodies to Porphyromonas gingivalis Lys-gingipain by DNA vaccination inhibit bacterial binding to hemoglobin and protect mice from infection. Infect. Immun.69(5), 2972–2979 (2001).

 PubMed Web of Science ®Google Scholar

Katz J, Black KP, Michalek SM. Host responses to recombinant hemagglutinin B of Porphyromonas gingivalis in an experimental rat model. Infect. Immun.67(9), 4352–4359 (1999).

 PubMed Web of Science ®Google Scholar

Yang QB, Martin M, Michalek SM, Katz J. Mechanisms of monophosphoryl lipid A augmentation of host responses to recombinant HagB from Porphyromonas gingivalis. Infect. Immun.70(7), 3557–3565 (2002).

 PubMed Web of Science ®Google Scholar

Dusek DM, Progulske-Fox A, Brown TA. Systemic and mucosal immune responses in mice orally immunized with avirulent Salmonella typhimurium expressing a cloned Porphyromonas gingivalis hemagglutinin. Infect. Immun.62(5), 1652–1657 (1994).

 PubMed Web of Science ®Google Scholar

Isoda R, Simanski SP, Pathangey L, Stone AE, Brown TA. Expression of a Porphyromonas gingivalis hemagglutinin on the surface of a Salmonella vaccine vector. Vaccine25(1), 117–126 (2007).

 PubMed Web of Science ®Google Scholar

Shibata Y, Hosogi Y, Hayakawa M, Hori N, Kamada M, Abiko Y. Construction of novel human monoclonal antibodies neutralizing Porphyromonas gingivalis hemagglutination activity using transgenic mice expressing human Ig loci. Vaccine23(29), 3850–3856 (2005).

 PubMed Web of Science ®Google Scholar

Amano A, Nakagawa I, Okahashi N, Hamada N. Variations of Porphyromonas gingivalis fimbriae in relation to microbial pathogenesis. J. Periodontal Res.39(2), 136–142 (2004).

 PubMed Web of Science ®Google Scholar

d’Empaire G, Baer MT, Gibson FC 3rd. The K1 serotype capsular polysaccharide of Porphyromonas gingivalis elicits chemokine production from murine macrophages that facilitates cell migration. Infect. Immun.74(11), 6236–6243 (2006).

 PubMedGoogle Scholar

Nakagawa I, Amano A, Kimura RK, Nakamura T, Kawabata S, Hamada S. Distribution and molecular characterization of Porphyromonas gingivalis carrying a new type of fimA gene. J. Clin. Microbiol.38(5), 1909–1914 (2000).

 PubMed Web of Science ®Google Scholar

Nakagawa I, Amano A, Ohara-Nemoto Y et al. Identification of a new variant of fimA gene of Porphyromonas gingivalis and its distribution in adults and disabled populations with periodontitis. J. Periodontal Res.37(6), 425–432 (2002).

 PubMed Web of Science ®Google Scholar

Amano A, Nakagawa I, Kataoka K, Morisaki I, Hamada S. Distribution of Porphyromonas gingivalis strains with fimA genotypes in periodontitis patients. J. Clin. Microbiol.37(5), 1426–1430 (1999).

 PubMed Web of Science ®Google Scholar