[Frontiers in Bioscience S5, 631-637, January 1, 2013]

Designing a peptide-based vaccine against Porphyromonas gingivalis

Alberta Lucchese1, Agostino Guida1, Giovanni Capone2, Massimo Petruzzi3, Dorina Lauritano4, Rosario Serpico1

1Department of Odontostomatological, Orthodontics and Surgical Disciplines, Second University of Naples SUN, Naples, Italy, 2Department of Biosciences, Biotechnologies and Pharmacological Sciences, University of Bari, Bari, Italy, 3Dental Clinic, University of Bari, Bari, Italy, 4Neuroscience Department, Milano-Bicocca University, Monza, Monza e Brianza, Italy


1. Abstract
2. Introduction
3. Methods
4. Results
4.1. Peptide-peptide profiling of Porphyromonas gingivalis fimA type I protein versus the human proteome
4.2. Peptide sequences unique to Porphyromonas gingivalis fimA type I protein: immunogenicity analysis
5. Discussion
6. References


Using proteome databases and exploiting the concept that a rare sequence is a potential epitope, epitopic sequences derived from Porphyromonas gingivalis fimA type I protein were examined for pentapeptide sequence similarity score to the human proteome. We obtained data showing that most of the linear bacterial determinants are (or are formed by) peptide fragment(s) absent (or rarely found) in the human proteins. These results seem to confirm the hypothesis that low-sequence similarity may contribute to shape the epitope repertoire and provides a potential tool for designing new immunotherapeutic approaches to apply in Porphyromonas gingivalis infected periodontitis.


Porphyromonas gingivalis, a black pigmented gram-negative anaerobic bacterium, is an important etiologic agent of chronic inflammatory disease of periodontium (1, 2). In particular, it has been associated with aggressive forms of periodontitis and its presence in patients' saliva is nowadays considered of high sensitivity in diagnosing parodontitis (3). In recent years, P. gingivalis-mediated periodontal disease has been linked to several systemic conditions such as atherosclerotic cardiovascular disease (4, 5), pregnancy complications (6), diabetes (7, 8), pulmonary disease (9, 10), osteoporosis (11) and cancer (12, 13).

P. gingivalis expresses fimbriae on the cell surface, which are recognized as major virulence factors influencing disease initiation and progression (14-18) and, consequently, are considered as promising candidate antigens for vaccine development (18). This consideration is supported by the following observations. First, anti-P. gingivalis fimbriae antibodies occur in the serum of patients with adult periodontitis (19, 20), and antibody-secreting cells specific for P. gingivalis fimbriae have been found in the inflamed gingival tissue of periodontitis patients (21, 22); second, monoclonal antibodies against a particular subunit of P. gingivalis fimbriae, the so-called major fimbrial subunit protein type-1 (fimA, type I) blocked bacterial adhesion to human buccal epithelial cells (23-25). As a further note, immunization in a rat animal model with purified P. gingivalis fimbriae or a fimbriae-derived synthetic peptide (aa sequence: GKTLAEVKALTTELTAENQE and VAPAADAPQGFTVLENDYSA, respectively), has been reported to induce protective immunity against periodontal destruction (26).

Fimbriae of P. gingivalis are classified into six genotypes (types I to V and Ib), based on the genotype of the fimA genes encoding the fimbrial subunits (27). FimA type I P. gingivalis strains, as well as synthetic fimA type I peptide segments, exhibit chemotactic activity, induce production of pro-inflammatory cytokines such as tumour necrosis factor-a, and interleukins 1, 6, and 8 in human monocyte and macrophage cultures, and haemagglutinating activity (28).

Given these premises, P. gingivalis fimbriae appear to be highly immunogenic and, consequently, might be an ideal target for vaccine. Recent studies have provided convincing evidence that antibodies can protect against P. gingivalis infections (16-18, 29). Passive immunization using mono- and polyclonal antibodies, and humoral immune responses against specific P. gingivalis antigens in experimental animals have shown that antibodies may play an anti- P. gingivalis role. However, in face of such encouraging data, the epitopic characterization of P. gingivalis antigens is performed antigen-by-antigen, searching for specific epitope features for each P. gingivalis protein antigen (1, 2, 14-18, 29, 30). More in general, the molecular basis that determine the immunogenicity of specific peptide sequences remain unclear (31, 32). Little is known about the structure-function relationship(s) of protein sequences in immunology. Such a context makes difficult the development of preventive/therapeutic vaccines against infectious agents. Within this framework, we follow the rationale that rare peptide sequences (that is, peptide motifs rarely found in the host proteins), have the potential to elicit immune response(s). Unique protein sequences are more likely to evoke an immune response than highly repeated motifs, which are expected to be immunologically silenced by the host's tolerance mechanisms. The relationship between sequence rarity and peptide immunoreactivity has been already validated in cancer, autoimmunity, and infectious disease models; specific targeting of peptide regions with no or limited sequence similarity to the host proteome was demonstrated using mono- and/or polyclonal antibodies against EC Her-2/Neu oncoprotein (33), desmoglein-3 (34), melan-a/MART-1 (35), high-molecular-weight melanoma associated-antigen (36, 37), tyrosinase (38, 39), prostate specific-antigen (40), HPV16 E7 (41), HCV (42), and influenza A (43) proteins. In addition, the data received substantial support from epitope mapping literature revealing that most peptide epitopes obey the low-similarity rule (44-48).

In the present study, we analyze P. gingivalis fimA type I protein searching for potential immunogenic peptides that might be used in anti-P. gingivalis immunotherapies. We compare validated P. gingivalis fimA type I epitopes currently cataloged at the Immune Epitope Database and Analysis Resources (IEDB) (http://www.immuneepitope.org/) (49), and report that most of P. gingivalis epitopes involved in the immune response, and already experimentally validated by Ogawa (28), are characterized by a low level of similarity to the host proteome.


The primary amino acid (aa) sequence of P. gingivalis fimA type I protein, corresponding to GenBank accession number: M19405.1; NCBI Taxonomic identifier: 837; UniProtKB/Swiss-Prot accession number: P0C940; length: 347aa (50); was used in the similarity analysis to the human proteome.

The bacterial sequence under analysis was dissected into 343 sequential pentapeptides, overlapping by 4 residues, that is MVLKT, VLKTS, LKTSN, KTSNS etc.

Each bacterial pentapeptide was used as a probe to scan the entire set of proteins forming the human proteome for identical matches (51). The pentapeptide matching analysis utilized PIR protein database and perfect peptide match program (http://pir.georgetown.edu/pirwww/) (52). The number of matches of each bacterial pentamer to the human proteome varied in a wide range, from no matches to hundreds of matches. A pentapeptide that has five (or less than five) perfect matches to the host proteome was considered to be a low-similarity sequence, that is, a rare fragment (33-44, 53). Pentapeptides were used because the literature indicates that five to six amino acids are a sufficient minimal determinant for an epitope-paratope interaction, and thus a pentapeptide can act as an immune unit and play a crucial role in cell immunoreactivity and antigen-antibody recognition (54, 55).

Immunological potential of bacterial pentapeptides was investigated by analyzing P. gingivalis fimA type I protein epitopes already experimentally validated and currently cataloged in the Immune Epitope Database and Analysis Resources (IEDB) (http://www.immuneepitope.org) (49). At the time of the analysis, IEDB contained numerous P. gingivalis epitopes derived from various strains and with different characteristics. Specifically, the IEDB contains B- and T-cell epitopes that are (a) linear or conformational; (b) derived from P. gingivalis fimA; and (c) have sequences that were negative, positive, or produced mixed negative/positive results in immunoassays. The present report focused on B-cell linear epitopes derived from P. gingivalis fimaA type I protein that were reported to be positive in immunoassays.


4.1. Peptide-peptide profiling of Porphyromonas gingivalis fimA type I protein versus the human proteome

The histogram in Figure 1 shows how many times each bacterial pentapeptide occurs in the human proteome. Immunologically, Figure 1 indicates that utilizing the entire fimbrial antigen in anti-P. gingivalis immunotherapeutic approaches carries a high risk of potential cross-reactions with the human proteins. In fact, it can be seen that a vast pentapeptide sharing exists between P. gingivalis fimA type I protein and the human proteome. Only 14 out of 343 bacterial fimbrial pentapeptides are uniquely owned by the bacterial protein. The 14 zero-similarity pentapeptides are, in the order: IENDP, IYTFV, FNGAY, NVPWL, ENDYS, QAANW, ANWVD, SNNYT, YDSNY, YTPKN, NHKYD, NVQCT, VAEWV, and QNATW.

On the whole, exact peptide-peptide profiling of the fimbrial antigen versus the human proteome shows that the P. gingivalis fimA type I protein pentapeptide overlap to the human proteins amounts to 329 bacterial pentapeptides repeatedly occurring throughout the human proteome for a total of 2,292 occurrences (Figure 1). Hence, it is logical to conclude that a vaccine based on the bacterial pentapeptides not present in the human proteome might have the potential of hitting exclusively the bacterial antigen without cross-reacting with the human host.

4.2. Peptide sequences unique to Porphyromonas gingivalis fimA type I protein: immunogenicity analysis

To test the feasibility of utilizing peptide fragments unique to the fimbrial antigen in anti-P. gingivalis vaccine design, we analyzed the similarity level of experimentally validated P. gingivalis fimA type I epitopes currently cataloged at the IEDB. At the time of the analysis, the IEDB contained 23 P. gingivalis fimA epitopes that had tested as positive in immunoassays (28).

Table 1 clearly shows that all P. gingivalis fimA type I immunoreactive epitopes are characterized by the presence of pentapeptides rarely (or never) found in human proteins.


Utilization of short peptide modules rather than full-length P. gingivalis antigens in vaccines may increase specificity and efficacy. It has been understood since the 1980s that chemically synthesized small peptides can induce antibodies that react with intact proteins (56). Furthermore, peptide-based vaccines have been successfully used against several pathologies and infectious diseases. For example, tumour antigen-derived peptides evoked potent antitumour immunity in the murine melanoma M-3 (57); cytotoxic CD4+ and CD8+ T lymphocytes generated by mutant p21-ras (12Val) peptide vaccination selectively killed autologous tumour cells carrying this mutation (58); Her-2/neu peptide (aa 657-665) is an immunogenic epitope of Her-2/neu oncoprotein with potent antitumour properties (59); synthetic peptides identified as antigenic sites on the S1 subunit of pertussis toxin induced especially high antibody titres against native pertussis toxin in mice (60); a linear peptide containing minimal T- and B-cell epitopes of Plasmodium falciparum circumsporozoite protein provided protection against a transgenic sporozoite challenge (61); the 15-mer amino-acid sequence 101-115 (PPAYEKLSAEQSPPP) of the Melan-A/MART-1 melanoma antigen has been shown to be a good target for a vigorous and safe immunotherapy (62).

Based on these scientific premises, this study explored the primary sequence of P. gingivalis fimA type I protein to define and characterize P. gingivalis epitopes that could be used for effective and safe anti-P. gingivalis immunotherapy. We observed that the immunological potential carried by the P. gingivalis antigens is localized in rare peptide fragments, thus confirming the relationship between low-similarity and immunogenicity (33-44). Sequences containing pentapeptide fragment(s) with low similarity to the host proteome appear to be those involved in the humoral antibody recognition of the P. gingivalis antigen, thus indicating that P. gingivalis antigenic motifs rarely found in host proteins are more likely to evoke an immune response. In short, these findings provide a method for investigating the immune potential of the P. gingivalis proteome, and, thus, may help fight P. gingivalis infection, one of the primary challenges in current periodontitis research. This study might also contribute to accelerate the epitopic characterization of P. gingivalis antigens which advances slowly, antigen-by-antigen (1, 2, 14-18, 28, 29).

Moreover, using exact immunogenic P. gingivalis peptide sequences may provide not only effective active or passive immunotherapeutic anti-P. gingivalis approaches but, in addition, might abolish the risk of adverse effects, which remains a major obstacle to antibody-based therapies (63-67). Adverse events are possibly caused by cross-reactivity that may result from using entire microbial antigens, because of the presence of peptide sequences common to microbes and humans (68, 69) (see also Figure 1). Using low-similarity peptides may help develop effective vaccines exempt of adverse side-effects (70), since the target sequence sites are present in the microbial organism only.

In conclusion, the findings of the present study may provide guidance in the analysis, identification, and utilization of the B-cell response in vaccination against P. gingivalis-associated periodontitis.


1. WJ Chang, M Kishikawa-Kiyama, Y Shibata, SY Lee, Y Abiko: Inhibition of Porphyromonas gingivalis hemagglutinating activity by synthetic peptides derived from phage display selection using MAb against the recombinant outer membrane protein. Hybrid Hybridomics 23, 352-356 (2004)

2. Y Shibata, M Hayakawa, H Takiguchi, T Shiroza, Y Abiko: Determination and characterization of the hemagglutinin-associated short motifs found in Porphyromonas gingivalis multiple gene products. J Biol Chem 274, 5012-5020 (1999)

3. I Saygun, N Nizam, I Keskiner, V Bal, A Kubar, C A�ıkel, M Serdar, J Slots: Salivary infectious agents and periodontal disease status. J Periodontal Res 46, 235-239 (2011)

4. C Hayashi, CV Gudino, FC Gibson, CA Genco: Review: pathogen-induced inflammation at sites distant from oral infection: bacterial persistence and induction of cell-specific innate immune inflammatory pathways. Mol Oral Microbiol 25, 305-316 (2010)
PMid:20883220 PMCid:2951292

5. R Genco, S Offenbacher, J Beck: Periodontal disease and cardiovascular disease: epidemiology and possible mechanisms. J Am Dent Assoc 133, 14S-22S (2002)


6. AP Dasanayake, D Boyd, PN Madianos, S Offenbacher, E Hills: The association between Porphyromonas gingivalis-specific maternal serum IgG and low birth weight. J Periodontol 72, 1491-1497 (2001)

7. M Takeda, M Ojima, H Yoshioka, H Inaba, M Kogo, S Shizukuishi, M Nomura, A Amano: Relationship of serum advanced glycation end products with deterioration of periodontitis in type 2 diabetes patients. J Periodontol 77, 15-20 (2006)

8 N Makiura, M Ojima, Y Kou, N Furuta, N Okahashi, S Shizukuishi, A Amano: Relationship of Porphyromonas gingivalis with glycemic level in patients with type 2 diabetes following periodontal treatment. Oral Microbiol Immunol 23, 348-351 (2008)

9. FA Scannapieco: Role of oral bacteria in respiratory infection. J Periodontol 70, 793-802 (1999)

10. G Hajishengallis, M Wang, GJ Bagby, S Nelson: Importance of TLR2 in early innate immune response to acute pulmonary infection with Porphyromonas gingivalis in mice. J Immunol 181, 4141-4149 (2008)

PMid:18768871 PMCid:2625304

11. H Inaba, A Amano: Roles of oral bacteria in cardiovascular diseases-from molecular mechanisms to clinical cases: Implication of periodontal diseases in development of systemic diseases. J Pharmacol Sci 113, 103-109 (2010)

12. DS Michaud, Y Liu, M Meyer, E Giovannucci, K Joshipura: Periodontal disease, tooth loss, and cancer risk in male health professionals: a prospective cohort study. Lancet Oncol 9, 550-558 (2008)

13. J Ahn, S Segers, RB Hayes: Periodontal disease, Porphyromonas gingivalis serum antibody levels and orodigestive cancer mortality. Carcinogenesis 33, 1055-1058 (2012)

14. G Hajishengallis, P Ratti, E Harokopakis: Peptide mapping of bacterial fimbrial epitopes interacting with pattern recognition receptors. J Biol Chem 280, 38902-38913 (2005)

15. L Du, P Pellen-Mussi, F Chandad, C Mouton, M Bonnaure-Mallet: Conservation of fimbriae and the hemagglutinating adhesin HA-Ag2 among Porphyromonas gingivalis strains and other anaerobic bacteria studied by epitope mapping analysis. Clin Diagn Lab Immunol 4, 711-714 (1997)

PMid:9384294 PMCid:170645

16. T Ogawa, K Yasuda, K Yamada, H Mori, K Ochiai, M Hasegawa: Immunochemical characterisation and epitope mapping of a novel fimbrial protein (Pg-II fimbria) of Porphyromonas gingivalis. FEMS Immunol Med Microbiol 11, 247-255 (1995)

17. EE Brant, HT Sojar, A Sharma, GS Bedi, RJ Genco, E De Nardin: Identification of linear antigenic sites on the Porphyromonas gingivalis 43-kDa fimbrillin subunit. Oral Microbiol Immunol 10, 146-150 (1995)

18. K Oyaizu, H Ohyama, F Nishimura, H Kurihara, S Matsushita, H Maeda, S Kokeguchi, H Hongyo, S Takashiba, Y Murayama: Identification and characterization of B-cell epitopes of a 53-kDa outer membrane protein from Porphyromonas gingivalis. Oral Microbiol Immunol 16, 73-78 (2001)

19. T Ogawa, Y Kusumoto, S Hamada, JR McGhee, H Kiyono: Bacteroides gingivalis-specific serum IgG and IgA subclass antibodies in periodontal diseases. Clin Exp Immunol 82, 318-325 (1990)

20. Y Kawashima, I Ishikawa: Simple and rapid detection of serum antibody to periodontopathic bacteria by dot blotting. J Periodontal Res 37, 223-229 (2002)

21. T Ogawa, Y Kono, ML McGhee, JR McGhee, JE Roberts, S Hamada, H Kiyono: Porphyrornonas gingivalis-specific serum IgG and IgA antibodies originate from immunoglobulin-secreting cells in inflamed gingiva. Clin Exp Immunol 83, 237-244 (1991)

22. Y Noiri, L Li, F Yoshimura, S Ebisu: Localization of Porphyromonas gingivalis-carrying fimbriae in situ in human periodontal pockets. J Dent Res 83, 941-945 (2004)

23. N Hamada, K Watanabe, C Sasakawa, M Yoshikawa, F Yoshimura, T Umemoto: Construction and characterization of a fimA mutant of Porphyromonas gingivalis. Infect Immun 62, 1696-1704 (1994)

PMid:7909537 PMCid:186386

24. H Isogai, E Isogai, F Yoshimura, T Suzuki, W Kagota, K Takano: Specific inhibition of adherence of an oral strain of Bacteroides gingivalis 381 to epithelial cells by monoclonal antibodies against the bacterial fimbriae. Arch Oral Biol 33, 479-485 (1988)

25. EM Koh, J Kim, JY Lee, TG Kim: Production of monoclonal antibodies specific to FimA of Porphyromonas gingivalis and their inhibitory activity on Bacterial Binding. Immune Netw 9, 203-207 (2009)
PMid:20157608 PMCid:2816954

26. T Ogawa, H Ogo, H Uchida, S Hamada: Humoral and cellular immune responses to the fimbriae of Porphyromonas gingivalis and their synthetic peptides. J Med Microbiol 40, 397-402 (1994)

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

28. T Ogawa: The potential protective immune responses to synthetic peptides containing conserved epitopes of Porphyromonas gingivalis fimbrial protein. J Med Microbiol 41, 349-358 (1994)

29. H Maeda, M Miyamoto, S Kokeguchi, T Kono, F Nishimura, S Takashiba, Y Murayama: Epitope mapping of heat shock protein 60 (GroEL) from Porphyromonas gingivalis. FEMS Immunol Med Microbiol 28, 219-224 (2000)

30. CG Kelly, V Booth, H Kendal, JM Slaney, MA Curtis, T Lehner: The relationship between colonization and haemagglutination inhibiting and B cell epitopes of Porphyromonas gingivalis. Clin Exp Immunol 110, 285-291 (1997)

31. U Gowthaman, JN Agrewala: In silico tools for predicting peptides binding to HLA-class II molecules: more confusion than conclusion. J Prot Research 7, 154-163 (2008)

32. MJ Blythe, DR Flower: Benchmarking B cell epitope prediction: underperformance of existing methods. Protein Sci 14, 246-248 (2005)
PMid:15576553 PMCid:2253337

33. A Mittelman, A Lucchese, AA Sinha, D Kanduc: Monoclonal and polyclonal humoral immune response to EC HER-2/neu peptides with low similarity to the host's proteome. Int J Cancer 98, 741-747 (2002)

34. A Lucchese, A Mittelman, MS Lin, D, Kanduc, AA Sinha: Epitope definition by proteomic similarity analysis: identification of the linear determinant of the anti-Dsg3 MAb5H10. J Transl Med 2, 43 (2004)
PMid:15588331 PMCid:544587

35. R Tiwari, J Geliebter, A Lucchese, A Mittelman, D Kanduc: Computational peptide dissection of Melana/MART-1 oncoprotein antigenicity. Peptides 25, 1865-1871 (2004)

36. A Mittelman, R Tiwari, G Lucchese, J Willers, R Dummer, D Kanduc: Identification of monoclonal anti-HMWMAA antibody linear peptide epitope by proteomic database mining. J Invest Dermatol 123, 670-675 (2004)

37. R Dummer, A Mittelman, FP Fanizzi, G Lucchese, J Willers, D Kanduc: Non-self-discrimination as a driving concept in the identification of an immunodominant HMW-MAA epitopic peptide sequence by autoantibodies from melanoma cancer patients. Int J Cancer 111, 720-726 (2004)

38. A Lucchese, J Willers, A Mittelman, D Kanduc, R Dummer: Proteomic scan for tyrosinase peptide antigenic pattern in vitiligo and melanoma: role of sequence similarity and HLA-DR1 affinity. J Immunol 175, 7009-7020 (2005)


39. J Willers, A Lucchese, A Mittelman, R Dummer, D Kanduc: Definition of anti-tyrosinase MAb T311 linear determinant by proteome-based similarity analysis. Exp Dermatol 14, 543-550 (2005)

40. A Stufano, D Kanduc: Proteome-based epitopic peptide scanning along PSA. Exp Mol Pathol 86, 36-40 (2009)

41. D Kanduc, A Lucchese, A Mittelman: Individuation of monoclonal anti-HPV16 E7 antibody linear peptide epitope by computational biology. Peptides 22, 1981-1985 (2001)

42. D Kanduc, L Tessitore, G Lucchese, A Kusalik, E Farber, FM Marincola: Sequence uniqueness and sequence variability asmodulating factors of human anti-HCV humoral immune response. Cancer Immunol Immunother 57, 1215-1223 (2008)

43. G Lucchese, A Stufano, D Kanduc: Proteome-guided search for influenza A B-cell epitopes. FEMS Immunol Med Microbiol 57, 88-92 (2009)

44. D Kanduc: "Self-nonself " peptides in the design of vaccines. Curr Pharm Des 15, 3283-3289 (2009)

45. D Kanduc: Immunogenicity in peptide-immunotherapy: from self/nonself to similar/dissimilar sequences. Adv Exp Med Biol 640, 198-207 (2008)

46. D Kanduc: The self/nonself issue: A confrontation between proteomes. Self Nonself 1, 255-258 (2010)
PMid:21487482 PMCid:3047788

47. G Lucchese, AA Sinha, D Kanduc: How a single amino acid change may alter the immunological information of a peptide. Front Biosci (Elite Ed) 4, 1843-1852 (2012)

48. G Lucchese, M Calabro', D Kanduc: Circumscribing the conformational peptide epitope landscape. Curr Pharm Des 18, 832-839 (2012)

49. R Vita, L Zarebski, JA Greenbaum, H Emami, I Hoof, N Salimi, R Damle, A Sette, B Peters: The immune epitope database 2.0. Nucleic Acids Res 38, D854-862 (2010)
PMid:19906713 PMCid:2808938

50. DP Dickinson, MA Kubiniec, F Yoshimura, RJ Genco: Molecular cloning and sequencing of the gene encoding the fimbrial subunit protein of Bacteroides gingivalis. J Bacteriol 170, 1658-1665 (1988)

PMid:2895100 PMCid:211014

51. D Kanduc: Homology, similarity, and identity in peptide epitope immunodefinition. J Pept Sci (2012) in press. doi: 10.1002/psc.2419.

52. CH Wu, LS Yeh, H Huang, L Arminski, J Castro-Alvear, Y Chen, Z Hu, P Kourtesis, RS Ledley, BE Suzek, CR Vinayaka, J Zhang, WC Barker: The Protein Information Resource. Nucleic Acids Res 31, 345-347 (2003)
PMid:12520019 PMCid:165487

53. G Capone, A De Marinis, S Simone, A Kusalik, D Kanduc: Mapping the human proteome for non-redundant peptide islands. Amino Acids 35, 209-216 (2008)

54. MBA Oldstone: Molecular mimicry and immune-mediated diseases. FASEB J 12, 1255-1265 (1998)


55. G Lucchese, A Stufano, B Trost, A Kusalik, D Kanduc: Peptidology: short amino acid modules in cell biology and immunology. Amino Acids 33, 703-707 (2007)

56. HL Niman, RA Houghten, LE Walker, RA Reisfeld, IA Wilson, JM Hogle, RA Lerner: Generation of protein-reactive antibodies by short peptides is an event of high frequency: implications for the structural basis of immune recognition. Proc Natl Acad Sci U S A 80, 4949-4953 (1983)

57. W Schmidt, M Buschle, W Zauner, H Kirlappos, K Mechtler, B Trska, ML Birnstiel: Cell-free tumor antigen peptide-based cancer vaccines. Proc Natl Acad Sci U SA 94, 3262-3267 (1997)

58. MK Gjertsen, J Bjorheim, I Saeterdal, J Myklebust, G Gaudernack: Cytotoxic CD4+ and CD8+ T lymphocytes, generated by mutant p21-ras (12Val) peptide vaccination of a patient, recognize 12Val-dependent nested epitopes present within the vaccine peptide and kill autologous tumour cells carrying this mutation. Int J Cancer 72, 784-790 (1997)

59. AD Gritzapis, A Fridman, SA Perez, N La Monica, M Papamichail, L Aurisicchio, CN Baxevanis: HER-2/neu (657-665) represents an immunogenic epitope of HER-2/neu oncoprotein with potent antitumor properties. Vaccine 28, 162-170 (2009)

60. P Askelöf, K Rodmalm, G Wrangsell, U Larsson, SB Svenson, JL Cowell, A Undén, T Bartfai: Protective immunogenicity of two synthetic peptides selected from the amino acid sequence of Bordetella pertussis toxin subunit S1. Proc Natl Acad Sci U S A 87, 1347-1351 (1990)

61. JM Calvo-Calle, GA Oliveira, CO Watta, J Soverow, C Parra-Lopez, EH Nardin: A linear peptide containing minimal T- and B-cell epitopes of Plasmodium falciparum circumsporozoite protein elicits protection against transgenic sporozoite challenge. Infect Immun 74, 6929-6939 (2006)
PMid:17030584 PMCid:1698101

62. E Balasse, G Gatouillat, D Patigny, MC Andry, C Madoulet: In vivo anti-melanoma activities of the Melan-A/MART-1(101-115) T CD4+ cell peptide. Vaccine 27, 6107-6109 (2009)

63. K Farsinejad, M Daneshpazhooh, H Sairafi, M Barzegar, M Mortazavizadeh: Lupus vulgaris at the site of BCG vaccination: report of three cases. Clin Exp Dermatol 34, e167-169 (2009)

64. M Enserink: Public health: in the HIV era, an old TB vaccine causes new problems. Science 318, 1059 (2007)

65. E Attia: BCG vaccine-induced lupus vulgaris. Eur J Dermatol 17, 547-548 (2007)


66. A Hristea, A Neacsu, D A Ion, A Streinu-Cercel, F Staniceanu: BCG-related granulomatous hepatitis. Pneumologia 56, 32-34 (2007)


67. A Mandavilli: When the vaccine causes disease. Nat Med 13, 274 (2007)

68. A Spratt, T Key, AJ Vivian: Chronic anterior uveitis following bacille Calmette-Guerin vaccination: molecular mimicry in action? J Pediatr Ophthalmol Strabismus 45, 252-253 (2008)

69. D Kanduc, A Stufano, G Lucchese, A Kusalik: Massive peptide sharing between viral and human proteomes. Peptides 29, 1755-1766 (2008)

70. D Kanduc: Epitopic peptides with low similarity to the host proteome: towards biological therapies without side effects. Expert Opin Biol Ther 9, 45-53 (2009)

Expert Opin Biol Ther 9, 45-53 (2009)

Key Words: P. gingivalis, Periodontitis, Bacterial versus human peptide overlap, Low-similarity peptides, Peptide vaccine

Send correspondence to: Dorina Lauritano, Neuroscience Department, University of Milan-Bicocca, Via Cadore, 48 -20052 Monza (MB), Italy, Tel: 393356790163, Fax: 390392332301, E-mail: dorina.lauritano@unimib.it