|Year : 2011 | Volume
| Issue : 5 | Page : 698-705
Ranjan Malhotra, Anoop Kapoor, Vishakha Grover, Aaswin Kaur Tuli
Department of Periodontology and Oral Implantology, National Dental College and Hospital, Gulabgarh, Derabassi, Distt. SAS Nagar, Mohali, Punjab, India
Click here for correspondence address and email
|Date of Submission||05-Aug-2010|
|Date of Decision||21-Dec-2010|
|Date of Acceptance||29-Jul-2011|
|Date of Web Publication||7-Mar-2012|
| Abstract|| |
Vaccine is the name applied generally to a substance of the nature of dead or attenuated living infectious material introduced into the body with the object of increasing its power to resist or get rid of a disease. Vaccines are generally prophylactic, i.e. they ameliorate the effects of future infection. One such vaccine considered here is the "Periodontal vaccine". Till date, no preventive modality exists for periodontal disease and treatment rendered is palliative. Thus, availability of periodontal vaccine would not only prevent and modulate periodontal disease, but also enhance the quality of life of people for whom periodontal treatment cannot be easily obtained. The aim of the research should be development of a multispecies vaccine targeting the four prime periodontal pathogens, viz. Porphyromonas gingivalis, T. forsythus, T. denticola and A. comitans. Success is still elusive in case of periodontal vaccine due to the complex etiopathogenesis of the disease.
Keywords: Multispecies, periodontal disease, vaccine
|How to cite this article:|
Malhotra R, Kapoor A, Grover V, Tuli AK. Periodontal vaccine. Indian J Dent Res 2011;22:698-705
It had long been recognized that individuals who recovered from a disease developed subsequent resistance to the same. Simulating the above thought, it was seen that vaccines, which contain milder infectious agents when given, evoke an immune response and induce specific immunity and have successfully prevented several infectious diseases for many years, and are still being investigated for many others. Vaccination is induction of immunity by injecting a dead or attenuated form of a pathogen.  The key features of a successful vaccine are safety, effectiveness, stability, a long shelf life and relatively low cost.
Vaccination against bacterial/viral infectious diseases has progressed immensely throughout the 20 th century.
Periodontal diseases are one such group of infectious bacterial diseases, against which vaccine research is still going on. The complexities in the etiopathogenesis of the periodontal diseases have been the prime obstacle in the hunt for vaccine. Till date, no preventive modality exists for periodontal disease and treatment rendered is palliative.
A new milestone was achieved after the prime pathogens, Porphyromonas gingivalis Actinobacillus actinomycetemcomitans, were implicated in the etiology of periodontal disease. Now, the vaccine research has shifted toward identification of valid antigenic targets/molecules of P. gingivalis and A. actinomycetemcomitans involved and thus induction of suitable immune response. The availability of periodontal vaccine would not only prevent or modulate the course of periodontal diseases, but also enhance the quality of life of people for whom periodontal treatment cannot be easily obtained.
| How Immunity Develops?|| |
Immunologic response is an outcome of the mechanism in which an antigen, directly or through antigen presenting cells, recognizes lymphocytes and differentiates into effector cells and memory cells specific to that particular antigen. This response takes two forms, humoral and cell mediated. Humoral immunity depends on the appearance of antibodies produced by plasma cells in the blood. Cell-mediated immunity depends mainly on the development of T cells that are specifically responsive to the inducing agent and is generally active against intracellular organisms. The antibody produced by effector B lymphocytes following contact with an antigen for the first time, is usually of short duration and is characterized by a slow rise and rapid fall of immunoglobulin in the serum and this response is known as primary response. The clone of cells, which carry memory, can then be reactivated on subsequent contact with the same antigen to give rise to an accelerated long-lasting antibody response and this is known as secondary response.
The response can be mediated either by neutralization of microbes and toxins, opsonization and phagocytosis of microbes, antibody-dependent cellular cytotoxicity or by phagocytosis of microbes opsonized with complement fragments, e.g. C3b. 
| Need for Development of Periodontal Vaccine|| |
The mouth and the nose are the principal portals of entry of infectious agents and allergens into the human body. Approximately two-thirds of all the pathogens infect humans via these routes.
The combined mucosal surfaces of the body comprise a considerable area of some 400 m 2 to which mouth contributes about 240 cm 2 , which must be protected from invasion by infectious agents and penetration by toxins and allergens. Though in humans a highly sophisticated and complimentary host defense system is present, there are some microorganisms that evade the host defenses and are responsible for disease production. 
The need for vaccine development arose due to the following reasons.
For bacteria which are capable of evading host immune responses and invading the tissues
P. gingivalis produces proteases that not only provide peptides needed for its propagation, but also degrade serum antibacterial components (i.e. antibodies, complement proteins) and immune cell derived peptides (e.g. cytokines) aimed at promoting antibacterial immune responses.
Furthermore, these bacteria can hide from elements of local gingival immune system by invading epithelial cells and can escape into the systemic circulation by invading endothelial cells.
The second destructive bacterial species is A. actinomycetemcomitans which has special characteristics of being able to produce a protein (leukotoxin) that is specifically toxic to host immune cells (e.g. neutrophils and monocytes) and also produces factors that can inhibit immune responses, thus guaranteeing their survival.
Additionally, A. actinomycetemcomitans invades epithelial and endothelial cells, which provide a protected environment, facilitate entry into the circulation and offer a base from where it can seed into other tissues.
Thus, evasion of elements of the immune system by periodontal pathogens permits their growth and accumulation to critical levels, setting the stage for the initiation of destructive disease processes in response to infection  [Table 1].
|Table 1: Select bacterial properties involved in evasion of host defense mechanisms|
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To decrease the incidence of periodontal disease related systemic diseases
It has now been well documented that periodontal diseases are not isolated lesions affecting the tooth and its supporting tissues, but have various systemic sequelae. 
Periodontal diseases result in higher systemic levels of inflammatory markers, viz. C-reactive protein , and fibrinogen. , These systemic changes predispose the individual to various conditions, viz. myocardial infarction , [Figure 1], cerebrovascular stroke, , preterm low birth weight infants, , and pneumonia. ,
|Figure 1: Relation between periodontal disease and atherosclerosis leading to myocardial infarction|
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Another link can be the microbial front. There is evidence that P. gingivalis antigen heat shock protein (HSP) is an immunodominant antigen of many microorganisms. HSP-60 (GroEL) has been associated with atherosclerosis and Chlamydia pneumoniae infection.
Some studies have shown that subjects with high anti-HSP (HSP 60, Dna K, and Gro El) antibody concentrations tended to have significantly healthier periodontal tissues.
Thus, it might be feasible to develop a vaccine against periodontitis based on P. gingivalis, specific HSP or HSP epitopes. 
Periodontal treatment puts a financial burden on the individuals suffering from it.
Availability of vaccine for preventing or modulating periodontal disease would be of great benefit in both developing and developed countries.
| Experimental Models for Vaccine Development|| |
Humans have not yet been used as experimental subjects in studies for vaccine development against periodontal pathogenic bacteria. Nonhuman primates and humans are similar in both periodontal structure and microflora composition. However, ligatures must be tied around the teeth to elicit periodontitis in nonhuman primates because it is difficult to colonize the oral cavity with P. gingivalis and establish periodontal lesions.
McArthur et al., suggested that squirrel monkeys could be used as a model for studying the parameters of black pigmented anaerobic rods in gingival crevices. However, the mechanisms of bacterial retention around ligated teeth are totally different from those of adhesion around the teeth or gingival tissue in humans.
Person et al., investigated the constituents of subgingival microflora and immune reactions (antibody titers and avidities against P. gingivalis) in experimental Macaca fascicularis periodontitis and concluded that M. fascicularis was a useful model for testing and developing vaccine for periodontal diseases.
There are some advantages of using rats for adhesion experiments. Since rats resemble humans in periodontal anatomy and bacterial composition, bone loss can be evaluated. Furthermore, P. gingivalis quickly colonizes the rat oral cavity and induces bone loss. 
| Active Immunization for Periodontal Disease|| |
Active immunization has been carried out using whole bacterial cells, outer components or synthetic peptides as antigens [Figure 2]. 
|Figure 2: Summary of three types of immunization: active, passive and DNA vaccination|
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Antigen: Whole cell
Klausen et al., reported that the levels of serum antibodies to both whole cells and partially purified fimbriae from P. gingivalis were elevated in rats immunized with P. gingivalis cells, and the activities of collagenase and cysteine proteases in gingival tissues as well as periodontal tissue loss were decreased.
In squirrel monkeys, immunization with whole cells of monkey isolates (P. gingivalis strain 1-372) increased the level of anti-P. gingivalis IgG antibody in serum and significantly reduced colonization in gingival crevice.
Bone density was significantly decreased in ligated teeth from nonhuman primates immunized with whole cell antigens of P. gingivalis and Prevotella intermedia. 
Primary antigenic model for vaccine development
P. gingivalis , Tanerella forsythia, Treponema denticola the RED COMPLEX) and Aggregatibacter actinomycetem comitans have been consistently and strongly associated with progression of disease, suggesting that these four bacterial species may be the major pathogens of periodontitis in humans. 
P. gingivalis has emerged as the leading candidate pathogen in the development of chronic periodontitis. It is a gram-negative, non-spore/forming, nonmotile, assacharolytic, obligate anaerobic coccobacillus. 
The virulence factors of P. gingivalis which have been used as subunits for the development of active immunization are: 
Outer membrane protein
- outer membrane protein,
- fimbriae and
- heat shock protein.
It was seen that transcutaneous injection of 40 kDa of outer membrane protein (OMP) inhibits co-aggregation of P. gingivalis with Streptococcus gordonii.
This also can be used for vaccine development for passive immunization. Polyclonal anti-40 kDa OMP antibody exhibited potentially protective, complement-mediated bactericidal effect. 
These are cysteine proteinases which cleave synthetic and natural substrates after arginine or lysine residues and are referred to as arginine gingipain (Rgp) and lysine gingipain (Kgp), respectively. ,,,
Cysteine proteinases are the major weapons in the arsenal of attack on periodontal region.  They are expressed on the outer membrane of P. gingivalis. Rgp and Kgp are key determinants in the growth and virulence of P. gingivalis.
Therefore, it is likely that virulence of P. gingivalis can be attenuated by inactivation of Rgp and Kgp with proteinase inhibitors of antibodies specific to Rgp and Kgp.
Therefore, Rgp and Kgp may be useful as vaccine against periodontal diseases.
Gingipain vaccines are mainly DNA vaccines.  DNA vaccines induce both humoral and cellular immunity. 
Mechanism showing production of gingipain vaccine [Figure 3]
Cysteine proteinases are the most potent antigens for vaccine development.
- Genco et al., showed that immunization of mice with a peptide derived from the amino terminal sequence of catalytic domains of gingipains resulted in protection from P. gingivalis invasion. 
- Gibson et al., showed that immunization with Rgp A stimulates the production of hemagglutinin domain specific antibodies which contribute to the prevention of P. gingivalis mediated oral bone loss. 
These are cell surface structure components and serve as a critical antigen. These are the most advanced immunogens.
Functions of fimbriae are the following:
Biologically active domains of P. gingivalis fimbrillin can be expressed on the surface of S. gordonii. Immunization with recombinants expressing terminal epitopes of Fim A using S. gordonii vectors results in induction of Fim A species specific serum IgG and salivary IgA antibody responses.
- Adherence to host: Adherence is the first step regarding the virulence of microorganisms. Fimbriae bind to saliva-coated hydroxyapatite and mediate binding of P. gingivalis to the substrate.
- Invasion of oral epithelial cells and fibroblasts.
- Modulation of inflammation by release of interleukin (IL)-1α, IL-1β, tumor necrosis factor (TNF)-α. 
Currently, five P. gingivalis fimbrial types (I-V) have been described based on their antigenicity. However, a vaccine based on one fimbrial type may be strain specific and hence ineffective against other P. gingivalis strains of different fimbrial types.
Nasal immunization of rats with fimbriae with the mucosal adjuvant cholera toxin induced a fimbriae-specific IgA response and these antibodies inhibited the attachment of P. gingivalis strain 381 to oral epithelial cells and decreased cytokine inflammatory response of epithelial cells to P. gingivalis. 
Okuda et al., showed that antibodies elicited against fimbriae composed of a 54 kDa protein derived from A. comitans 310a protect against continued infection by this microorganism. They postulated that the IgG responses to fimbriae antigen elicited by the initial contact with A. comitans played an important role for eliminating organisms from the periodontal pockets of patients harboring high IgG antibody avidity. 
GroEL heat shock protein
Heat shock proteins have an important role in inflammatory mechanism, autoimmune disease and atherosclerosis. Homologues of specific stress protein families have been demonstrated to be present in oral bacteria including Fusobacterium nucleatum, Prevotella intermedia, Prevotella melaninogenica, A. comitans and P. gingivalis.
- Rats immunized with P. gingivalis HSP60 showed decrease in bone loss induced by infection with multiple periodontopathic bacteria.
- Significant association between HSP90 concentration and microbial colonization has been observed. 
Non-fimbrial adhesion hemagglutinin B (HagB) is a potential vaccine candidate.
Hemagglutinin mediates bacterial attachment and penetration into the host cells, as well as agglutinates and lyses erythrocytes to intake heme, an absolute requirement for growth.
Mice intragastrically inoculated within avirulent strain of Salmonella More Details typhimurium expressing HagB gene mounted both systemic and mucosal antibody response and this response could be boosted indicating that a memory T-cell or B-cell response was induced.
Furthermore, rats immunized subcutaneously with recombinant HagB were protected against periodontal bone loss induced by P. gingivalis strain ATCC 33277.
Mouse monoclonal antibody is not suitable for repeated passive immunotherapy due to induction of human antibodies against the mouse antigens. Human antibody against hemagglutinin should be ideal for practical use in immunotherapy.
Such treatments significantly decrease recolonization of P. gingivalis for up to 9 months.
Development of this monoclonal antibody may be useful for passive immunization as well as assessment of treatment for periodontal disease caused by P. gingivalis infection. 
Antigen: Synthetic peptide
Mapping the adhesion, T-cell and B-cell epitopes are essential for investigating synthetic peptide vaccines.
Since IgG and secretory IgA may play a role in preventing bacterial adhesion to salivary glycoproteins or mucosal receptors, adhesion epitopes are also indispensable to the immune responses elicited by synthetic peptide vaccine. Synthetic peptides based on the protein structure of fimbrillin inhibit the adhesion of P. gingivalis to saliva-coated hydroxyapatite crystals.
Furthermore, gingival tissue enzyme levels and horizontal bone loss were reduced by immunization with 20-mer synthetic fimbrial peptide in the gnotobiotic rat model.
Also, they suggest that peptide immunogens would be effective as vaccines since they adopt a more native conformation to produce effective antibodies. 
| Passive Immunization|| |
Chronic disease is not generally an indication for passive immunization.
In essence, this approach employs preformed antibodies administered to "at risk" individuals or to individuals during "at risk" intervals to interfere with microbial pathogenic processes.
A vaccination concept was developed using molecular biologic techniques to enable plants to synthesize and assemble antibody molecules, including antigen-binding domains, complete antibodies, and multimeric antibodies, i.e. plantibodies.
Ma et al., characterized a secretory IgG antibody produced in transgenic plants. This antibody was more stable and exhibited a higher functional affinity than the native antibody, and provided protection against Streptococcus mutans tion in humans. 
Passive immunization against periodontal diseases has been attempted because of the success of active and passive immunization against P. gingivalis and S. mutans, respectively.
Passive immunization is thought to be comparatively safer than active immunization.
A. actinomycetemcomitans specific T-cell clone, isolated and transferred into rats, elevated serum IgG and IgM antibodies to A. actinomycetemcomitans and significantly decreased bone loss. Thus, T-cell regulation seems to affect periodontal disease and T helper cells apparently interfered with periodontal bone loss.
- Okuda et al., reported that repeated passive immunization with rabbit antiserum to P. gingivalis hemagglutinin into the oral cavities of hamsters reduced colonization by exogenous P. gingivalis in the periodontal region.
- Passive immunization with monoclonal antibodies against P. gingivalis selectively prevents recolonization by this organism in humans. 
Monoclonal antibodies have been used for passive immunization against periodontitis. Passive immunization with a monoclonal antibody (61BG1.3) was shown to prevent selective colonization by P. gingivalis in humans. 
It is important to realize that for vaccination to be successful, it should limit the transmission and/or intraoral dissemination of periodontopathic bacteria, and it would appear advantageous for an effective vaccine to induce immunity at three levels:
The following results have been achieved by immunization, which indicate a positive preventive response:
- local mucosal secretory IgA,
- local draining lymph nodes, and
- circulating specific T- and B-cell responses [Figure 4]. 
- Potentiation of humoral immune response.
- Increased mucosal immunity, viz. increased levels of IgA and IgG2.
- Decreased levels of P. gingivalis and other species in the subgingival flora by inhibiting invasion into tissues and colonization of the periodontal tissues.
- Decreased bone loss was observed in the immunized group as compared to the group not immunized and this has been associated with decreased levels of prostaglandin E2 (PGE 2 ) in the gingival crevicular fluid (GCF). 
| Other Preventive Strategies Employed for Periodontal Disease|| |
Use of probiotics
The Food and Agriculture Organization of the United Nations has defined probiotics as "live microorganisms administered in adequate amounts conferring beneficial health effect on host". 
It has been seen that despite mechanical subgingival debridement in combination with improved oral hygiene, there is a temporary shift toward less pathogenic composition of bacteria within 1-2 weeks of baseline. There is re-establishment of a more aggressive microbiota within weeks to months. Therefore, focus started on the "reduction or absence of the so-called beneficial bacteria".
It was thought that restoring the decreased number of beneficial bacteria via probiotics might be of considerable interest in the treatment of plaque-related periodontal diseases.
In 1954, the first attempt was made in Russia on the use of probiotics in the treatment of periodontitis. The use of Russian probiotics preparation called ACILACT, a complex of five lyophilized lactic acid bacteria with or without "Bifidumbacterium", is claimed to improve both clinical and microbiological parameters in patients with gingivitis and periodontitis.
Recently, it has been seen that inoculation of Streptococcus sanguis inhibits the growth of periopathogens, P. gingivalis, A. comitans and T. forsythia. 
Gene therapy as a future perspective
Gene therapy is the insertion of genes into an individual's cells and tissues to treat a disease.
For many years, researchers have been exploring vaccination techniques in animal models to eradicate periodontal disease with mixed success. In the last decade, gene transfer research has led to a novel way to achieve vaccination as discussed below:
Though these results encourage us to look further into this therapy, periodontal disease, being a polygenic disease, can provide a challenge.
- Salivary gland of mouse, when immunized using plasmid DNA encoding the P. gingivalis fimbrial gene, produces fimbrial protein locally in the salivary gland tissue, resulting in subsequent production of specific salivary immunoglobulins, IgA, IgG and serum IgG antibodies. This secreted IgA could neutralize P. gingivalis and limit its ability to participate in plaque formation. Similarly, secreted fimbrillin in saliva could bind to pellicle components, blocking the attachment.
- Scientists have also demonstrated the efficacy of immunization with genetically engineered S. gordonii vectors expressing P. gingivalis fimbrial antigen as vaccine against P. gingivalis associated periodontitis in rats.
- The gene hemagglutinin, which is an important virulence factor of P. gingivalis, has been identified, cloned and expressed in Escherichia More Details coli. The recombinant hemagglutinin B (rHagB), when injected subcutaneously in Fischer rats infected with P. gingivalis, showed serum IgG antibody and IL-2, 10 and 4 production which gave protection against P. gingivalis induced bone loss.
| Modes of Immunization|| |
No injectable vaccine is 100% safe; therefore, mucosal immunization, in which no material is systemically injected, may represent a substantially safer method of all.
Various modes of inducing mucosal immunization that have been proposed for periodontal vaccine are listed in [Table 2].
| Human Periodontal Vaccine|| |
Three types of vaccines were employed for the control of periodontal diseases. 
These include the vaccines prepared from:
- pure cultures of streptococci and other oral organisms,
- autogenous vaccines and
- stock vaccines such as
- Van Cott's vaccine
- Goldenberg's vaccine or Inava Endocorps vaccine.
These are prepared from dental plaque samples of patients with destructive periodontal diseases.
Plaque samples are removed from the diseased site. They are sterilized by heat or by immersion in iodine or formalin solution and reinjected into the same patient either locally at the site or systemically.
| Why Success is Still Elusive for Humans for Periodontal Vaccine?|| |
Though success has been achieved in the case of animal models, there are several reasons which still have to be overcome to make the dream of periodontal vaccine for humans a reality.
Some of them are enlisted below:
- Complexity and uncertainty of the different forms of periodontal diseases.
- To accurately differentiate between primary colonizers and secondary invaders.
- The relative difficulty in growing and identifying many of the disease-associated microorganisms and the variability of the plaque composition from one individual to the other and between sites in the same individual.
- Presumptive periodontal pathogenic microorganisms are members of the normal subgingival bacterial flora in humans and are not indigenous to the normal flora of the rodents.
- Variations in disease state and chronicity of the diseases.
- Difficulty in clinically detecting and quantitating active periodontal disease.
- The location of gingival sulcus at the interface between the systemic immunity and the local immune responsive tissues, and the oral cavity bathed by the secretory immune system.
- The nonfatal nature of the disease. 
| Conclusion|| |
The current treatment of periodontitis is nonspecific and is centered on the removal of subgingival plaque by mechanical debridement. This ongoing therapy is costly, painful and has variable prognosis, in part due to poor compliance of the patients.
The elucidation of the specific bacterial etiology of periodontitis suggests that the development of specific treatment modality to target site colonization or virulence of P. gingivalis, T. denticola, T. forsythia and A. comitans is now a more rational approach to treat disease.
The significant reduction in periodontal disease progression in the nonhuman primates and rodents by immunization with either killed whole P. gingivalis cells or P. gingivalis antigens suggests that vaccination may be an important adjunctive therapy to mechanical debridement in humans to prevent colonization of periodontal pathogens.
The development of multispecies vaccine that is able to target all four prime bacterial species, which have been implicated in the development of periodontitis, may be more successful than a vaccine against a single species.
Vaccination may also have a therapeutic benefit even in the situations where the bacteria are more resistant to adaptive immune response. When present in subgingival plaque as an undisturbed biofilm, specific antibodies may still restrict the progression of disease by blocking the penetration of major virulence factors into the gingival tissues and neutralizing the key virulence factors associated with acquisition of essential nutrients, thereby restricting proliferation.
The development of vaccine is dependent on the identification of bacterial antigens that are expressed in vivo and induction of a protective response.
Thus, it is important to use a combined proteomic, genomic and immunologic strategy to identify bacterial antigens of periodontopathogens and evaluate their potential as vaccine candidates for the development of a multispecies vaccine for periodontitis as an adjunct to current periodontal therapies.
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Department of Periodontology and Oral Implantology, National Dental College and Hospital, Gulabgarh, Derabassi, Distt. SAS Nagar, Mohali, Punjab
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]
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