|Year : 2012 | Volume
| Issue : 4 | Page : 240-246
Periodontal vaccine: A short synopsis
Priyanka K Cholan1, D Mythireyi1, CS Anand Mohan1, P Rajapriya2
1 Department of Periodontics, SRM Dental College, Chennai, Tamilnadu, India
2 Department of Periodontics, Meenakshi Ammal Dental College, Chennai, Tamilnadu, India
|Date of Web Publication||12-Jul-2013|
Priyanka K Cholan
Department of Periodontics, SRM Dental College, Ramapuram, Chennai - 600 089, Tamilnadu
Source of Support: None, Conflict of Interest: None
Immunization using a vaccine against periodontitis decreases the number of periodontopathic bacteria in the subgingival flora and inhibits alveolar bone destruction in several animal models. The foremost step in vaccine development is identification of an antigenic component from various organisms that can provide immune protection. Identification of such an antigen is made difficult by the fact in that the periodontopathic species has a complex clonal structure with multiple serotypes, and no single type or groups of types have been documented to cause human periodontitis. This review highlights the importance of Porphyromonas gingivalis and its antigenic components as a potential candidate for periodontal vaccination.
Keywords: Periodontitis, Porphyromonas gingivalis, vaccine
|How to cite this article:|
Cholan PK, Mythireyi D, Anand Mohan C S, Rajapriya P. Periodontal vaccine: A short synopsis. SRM J Res Dent Sci 2012;3:240-6
| Periodontal Vaccine- A Vision or Mission|| |
Periodontitis has got a multifactorial etiology, with microbial, genetic, environmental and systemic factors playing an evident role. In the present scenario, periodontal therapy is focused on the elimination of periodontal pathogens with minimal surgical intervention and development of beneficial microbiota. Therefore, availability of a vaccine for preventing or modulating periodontal disease in humans, would be of immense benefit for the human society.
| Pathogenesis of Periodontitis|| |
The sessile plaque biofilm is a dynamic system composed of diverse microbial species. It is composed of viridans streptococci, Actinomyces spp., and small amounts of E. corrodens and Capnocytophaga spp within the first 12-24 h. Over the next 2-4 days, Gram-negative fusobacteria, other anaerobic rods and spirochetes start to breed. Aggregatibacter (A.) actinomycetemcomitans is the predominant cultivable organism in localized afflicted sites, whereas Porphyromonas gingivalis, Prevotella (P.) intermedia and Capnocytophaga (C.) sputigena are frequently isolated in the generalized form.  Many of these organisms may be present in periodontally healthy individuals and can live in commensal harmony with the host. Thus, disease episodes may ensue from a shift in the ecological balance between bacterial and host factors, as a result of, alteration in the absolute.
Although, periodontal diseases are primarily initiated and perpetuated by mixed biofilm (possibly also including viruses), other factors, including host-associated factors, genetic predisposition, immune dysfunction, and environmental factors can exacerbate the disease. Thus, a combined strategy, targeting both specific pathogenic species and the host immune response would have to be adopted for the sophisticated management of periodontitis subjects. 
Periodontal disease being a polymicrobial infection is one of the major causes of adult tooth loss worldwide. It also contributes to the perpetuation of systemic diseases of critical importance (atherosclerosis, diabetes mellitus, etc.). Thus, these three emerging concepts of periodontal disease may influence the development of a periodontal vaccine to alleviate the disease burden. 
| Recipe for cure by disastrous Agents-Vaccines!!!|| |
From the time of Edward Jenner's discovery of small pox vaccine in 1796, antigens of infectious pathogenic bacteria and viruses have been the targets for a variety of vaccines against a number of infectious diseases. Thus, most vaccines target one or multiple antigenic components of mono-infecting bacteria or viruses. The principle of vaccination is based on two key elements of adaptive immunity namely specificity and memory.  The antigen(s) of a vaccine induces clonal expansion in specific T and/or B cells leaving behind a population of memory cells. These enable the next encounter with the same antigen(s) to induce a secondary response which is more rapid and effective than the normal primary response. 
Vaccines may be synthetic or natural, Monovalent or polyvalent. In practice, this means isolating or creating an organism, that is unable to cause full blown disease, but that still retains the antigenic components responsible for inducing the host's immune response. One way is to kill the organism using formalin; these are called "inactivated" or "killed" vaccines. Another way is to use only the antigenic part of the disease causing organism, for example the capsule, the flagella, or part of the protein cell wall; these vaccines are called "acellular vaccines." 
A third way of making a vaccine is to "attenuate" or weaken a live microorganism by aging it or altering its growth conditions. However, these vaccines also carry the greatest risk because they can mutate back to the virulent form at any time, resulting in induction of the disease rather than protection against it. 
"Toxoids" are vaccines made from toxins, which are adsorbed onto aluminum salts to decrease their harmful effects and is administered with an "adjuvant" which can have effects on antigen delivery, immune modulatory cytokines, and antigen-presenting cells. 
Primary goals of a successful vaccine: 
- It should be safe to administer
- It should induce the right kind of immunity
- Vaccine should be effective against the particular infectious agent and prevent the disease
- It should be stable and have a long shelf-life
- Vaccines should be affordable by the general population.
Types of periodontal immunization: 
- Whole bacterial cells
- Sub unit vaccines
- Synthetic peptides as antigens.
- Murine monoclonal antibody
- Plasmid vaccines
- Live, viral vector vaccines.
Most experiments on immunization of periodontitis, despite its poly-infectious nature, have been directed towards a very limited number of antigenic components of a single specific pathogen, either P. gingivalis or A. actinomycetemcomitans.
| Trial animal Models|| |
Humans could not be used as experimental subjects in studies of periodontal vaccine development against periodontopathic bacteria. Non-human primates and humans are comparable in both periodontal structure and microflora composition. Nevertheless, ligatures must be tied around the teeth to elicit periodontitis in non-human primates, because it is not easy to colonize the oral cavity with P. gingivalis and establish periodontal lesions.
McArthur et al.  suggested that the squirrel monkey could be used as a model for studying the parameters of black-pigmented anaerobic rods colonization 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.
Persson 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 vaccines for periodontitis.
There are some advantages in using rats for adhesion experiment. 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.
Kesavalu et al. studied active immunization using whole cells or selected cell envelope components and suggested that the murine model would be useful for investigating the tissue-destructive components of P. gingivalis.
Principal antigenic model for vaccine development
Despite the considerable numbers of cultivable microorganisms identifiable in the subgingival niche, researchers have narrowed the number of putative periodontal pathogens down to six or seven, P. gingivalis, Treponema denticola, and T. forsythia, A. actinomycetemcomitans, P. intermedia, C. rectus, and Fusobacterium nucleatum, which are predominantly cultivated in sites demonstrating disease activity.  Socransky et al.  proposed the red complex namely P. gingivalis, T. denticola, and T. forsythus, as the predominant disease-associated organisms. Present researches are based on these periodontopathic bacteria, which form the basis of periodontal vaccine development. The various components of these periodontopathic bacteria tested for antigenicity are listed in [Table 1].
|Table 1: Components of periodontal bacteria tested for antigenicity and potential as vaccine candidates|
Click here to view
| Pathways to explore|| |
Aggregatibacter actinomycetum comitans-feasible vaccine?
Harano et al.  prepared an antiserum against a synthetic fimbrial peptide of A. actinomycetemcomitans and found that it blocked the adhesion of the organism to saliva-coated hydroxyapatite beads, to buccal epithelial cells, and to a fibroblast cell line. Furthermore, subcutaneous and intranasal immunization of mice with capsular serotype b-specific polysaccharide antigen of A. actinomycetemcomitans resulted in a specific antibody that efficiently opsonized the organism. 
Furthermore, when mice were immunized with anti-surface-associated material from A. actinomycetemcomitans, it yielded a raised protective opsonic antibody response and rapid healing of the primary lesions following a challenge with live A. actinomycetemcomitans. However, relatively few studies have been conducted on developing vaccines against A. actinomycetemcomitans.
An overview of P. gingivalis
P. gingivalis, a Gram-negative non-motile pleomorphic rod and obligate anaerobe is an aggressive and opportunistic periodontal pathogen producing a series of virulence factors. [Table 2] shows the antigenic structure of P. gingivalis that confers antigenicity.
|Table 2: Porphyromonas gingivalis antigenic structure that confers antigenicity|
Click here to view
Active immunization against P. gingivalis components
P. gingivalis is a potential vaccine candidate because this pathogen carries several high-potent antigens, a lipopolysaccharide (LPS) capsule, lipids, and outer membrane proteins (OMP) which are used as subunits for development of active immunization. 
Antigen: Whole cells
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 that the activities of collagenase and cysteine proteinases in gingival tissues as well as periodontal tissue losses were decreased.
Evidence of a protective mechanism from a formalin-killed whole-cell P. gingivalis vaccine with Syntex adjuvant formulation (SAF) adjuvant can be found in the reported effect that vaccine-induced serum antibody titres to P. gingivalis resulted in a blockage of prostaglandin E 2 response to LPS challenge. 
Two different independent research groups have evaluated immune modulation by immunizing F. nucleatum prior to subsequent immunization of P. gingivalis. When mice were immunized with F. nucleatum prior to P. gingivalis, a significantly decreased antibody response to P. gingivalis was observed.  At the same time, Choi et al.  demonstrated that P. gingivalis-specific helper T cell clones derived from mice immunized with P. gingivalis alone had a Th1 profile while those derived from mice immunized with F. nucleatum prior to P. gingivalis had a Th2 profile. The latter research group also reported that anti-F. nucleatum antibody elicited by immunization of F. nucleatum prior to
P. gingivalis down modulated the opsonophagocytic function of anti-P. gingivalis immune serum. , This observation may explain in part why the opsonophagocytic function of anti-P. gingivalis-specific antibodies from periodontal patients are impaired. 
Owing to the complexity of the microbial flora in periodontal lesions, studies were conducted to demonstrate elevated humoral immune response in M. fascicularis after systemic immunization with intact formalin killed P. gingivalis, P. intermedia and Bacteroides fragilis,  also oral immunization with recombinant Salmonella typhimurium expressing a cloned P. gingivalis hemagglutinin showed a boosting effect on mucosal, systemic and immunoglobulin G subclass response.  There is also a symbiotic relationship between C. rectus and P. gingivalis, which may provide additional interest in vaccine trials with potentially shared protective outcomes.
Outer membrane proteins
It was seen that transcutaneous injection of 40 kDa of 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 protective, complement mediated bactericidal effect. 
Fimbriae mediates adherence and colonization of the oral cavity by P. gingivalis and may, therefore, have potential for use as antigen in an anti-P. gingivalis vaccine. These induce opsonic antibodies that enhance phagocytosis by human leucocytes. Another option would be to combine fimbrial components from various strains to create a multivalent vaccine, but this approach makes sense only if evidence can be obtained showing that fimbrial proteins of P. gingivalis are, in fact, accessible to opsonic antibodies.  Immunization using a vaccine containing killed intact P. gingivalis cells decreases the number of organisms in the subgingival flora and inhibits alveolar bone destruction in the non-human primate M. fascicularis.  Induction of salivary immunoglobulin (IgA) antibody against P. gingivalis fimbriae using cholera toxin as an adjuvant in mice, showed elevated serum and salivary anti-fimbriae immunoglobulin Immunoglobulin G (IgG), Immunoglobulin M (IgM), Immunoglobulin A (IgA) and IgA antibody level. 
Erythrocyte-derived protoheme is known to be one of the absolute requirements for the persistent growth of P. gingivalis. It is the hemagglutinins of P. gingivalis that facilitate its attachment to the erythrocyte cell surface, allowing it to access protoheme. Hence, applying a mAb against the hemagglutinin could be seen as a potential passive immunization strategy against the persistence of P. gingivalis in the subgingival niche. Based on this concept localized administration of a P. gingivalis-specific mAb (MAb61BG1.3) at severely infected subgingival sites has been shown to significantly reduce subsequent P. gingivalis recolonization for up to 9 months in periodontal patients. 
Heat shock proteins
Heat shock proteins have an important role in inflammatory mechanism, autoimmune diseases and atherosclerosis. Homologues of specific stress protein families have been shown to be present in oral bacteria, including F. nucleatum, P. intermedia, P. melaninogenica, A. comitans, and P. gingivalis. Supporting this, P. gingivalis heat shock protein vaccine reduces the alveolar bone loss induced by multiple periodontopathogenic bacteria following immunization in rats. 
Gingipains, a group of cysteine proteases, are major weapons in its arsenal of attack on the periodontal region. Gingipains consist of Arg-gingipains (RgpA and RgpB) and Lys-gingipains , they dysregulate the host defense mechanisms, resulting in tissue destruction and alveolar bone resorption.
Gingipain vaccines are mainly DNA vaccines and these induce both humoral and cellular immunity.  Both RgpA and Kgp (but not RgpB) have a hemagglutinin domain that is essential for the adherence to erythrocytes, while the catalytic domain (in RgpA, RgpB, and Kgp) plays an important role in the evasion of the host defense system by degrading immunoglobulins and complement proteins and by disturbing the functions of neutrophils. , Spurred by these findings, an active immunization program using purified P. gingivalis cysteine protease (porphypain-2) has been carried out, which resulted in a significantly elevated specific IgG antibody response that suppressed P. gingivalis-induced bone loss in M. fascicularis. Similarly another study showing mice immunization with RgpA DNA vaccine via the nasal cavity is an effective method for preventing alveolar bone loss incurred by infection with P. gingivalis.
Antigen: Synthetic peptides
Mapping the adhesion, T-cell and B-cell epitopes is essential for investigating synthetic peptide vaccines.  Synthetic peptides based on the protein structure of fimbrillin inhibit the adhesion of P. gingivalis to saliva-coated hydroxyapatite crystals in vitro and their binding domains are located at the carboxyl-terminal region.  Furthermore, gingival tissue enzyme levels and horizontal bone loss were reduced by immunization with a 20 mer synthetic fimbrial peptide in the gnotobiotic rat model. Furthermore, they suggested that peptide immunogens would be effective as vaccines since they could adopt a more native conformation to produce effective antibodies.
Passive immunization against P. gingivalis
This approach employs preformed antibodies administered to "at risk" individuals or to individuals during "at risk" intervals to interfere with microbial pathogenic processes. Here, the antigens are injected into a vector that produces antibodies. These antibodies, when inoculated into a host, bring about passive immunization. It can be done in 2 ways: 
- Murine monoclonal antibodies
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 colonization in humans. 
Okuda et al.  reported that repeated passive immunization with rabbit antiserum to P. gingivalis hemagglutinin into the oral cavities of the hamsters reduced colonization by exogenous P. gingivalis in the periodontal region. Furthermore, passive immunization with monoclonal antibodies against P. gingivalis effect selectively prevents recolonization by this organism in humans.
Passive immunization of humans using P. gingivalis monoclonal antibodies temporarily prevents colonization of P. gingivalis. Probiotic therapy may be an alternative approach. Regulatory and safety issues for human periodontal vaccine trials must also be considered.  [Table 3] summarises the various P. gingivalis components mentioned above and potential as vaccine candidates.
|Table 3: Porphyromonas gingivalis components tested for antigenicity and potential as vaccine candidates|
Click here to view
| Preparations of 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, which are prepared from dental plaque samples of patients with destructive periodontal diseases. Plaque samples are removed from the diseased site and are sterilized by heat or by immersion in iodine/formalin and are re-injected into the same patient, either locally or systemically.
- Stock vaccines such as Van Cott's vaccine, Goldenberg's vaccine, or Inava Endocorps vaccine.
| Limitations of periodontal vaccines|| |
However, several issues should be addressed pertinent to the development of a sophisticated vaccine against human periodontitis. Firstly, human periodontal disease is multifactorial caused by manifold pathogens. The intricacy of the periodontopathic bacteria might be a problem as a substantial number of bacteria appears to be involved in periodontal disease. The multiplicity of pathogenic organisms indicates that vaccine design against periodontitis is very complex. Secondly, bacterial whole cells or crude extracts preparation for vaccination is not desirable because the antigenic determinants of bacteria potentially possess a high risk of cross-reactivity with human counterparts.
Some more serious complication may stem from the vaccine or from the patient. Vaccines may be contaminated with unwanted proteins or toxins, or even live viruses. Supposedly killed vaccines may not have been properly killed; attenuated vaccines may revert to the wild type.  The patient may be hypersensitive to minute amounts of contaminating proteins, or immuno-compromised, in which case any living vaccine is usually contraindicated.
Furthermore, importantly, animal models for vaccine trials may pose inconsistencies with human models in major histocompatibility complex-restriction of antigens presented by antigen presenting, thus obscuring the immunodominant epitope(s). A humanized mouse system has been projected that has been reconstituted with human peripheral blood lymphocytes. This system needs to meet the requirement of least leakiness of a mouse immune system. More recently, a genetically engineered mouse system, such as the non- obese diabetes Non obese diabetic mouse CB 17- colony of BALB (mouse strain used in the study)-prkdc scid /J mouse, has been initiated into the study of infectious and autoimmune diseases in humans. This model may also prove to be a valuable tool for the study of periodontal disease and putative periodontal vaccines. 
As an innovative strategy, vaccines using cross-reactive immunodominant epitopes as antigenic molecules in an attempt to stimulate antigen-specific regulatory T-cells (Tregs, CD4+, CD25+, FoxP3+), secreting IL-10 and Transforming growth factor-β, may provide new clues for periodontal disease prevention, through the induction of either immune tolerance or an effector function. 
Recently, a variety of strategies to enhance the immunogenicity of antigenic components of B-or T-lymphocytes have been adopted in vaccine trials against periodontal disease. These include, but not limited to, immunization of dendritic cells pulsed with antigens, the use of improved adjuvant formulas (e.g., the use of alum as an alternative to heat shock protein (Heat shock protein)- based adjuvant), the use of recombinant plant monoclonal antibodies (plantibodies), ,, and the use of transgenic microorganisms as antigen vectors. ,49 These efforts leave challenging areas to be chased further in the search for a more refined design that may guarantee the efficiency and safety of extended immune memory.
| A Peep into the future… beware!!|| |
Every endeavor of human started as a dream so also this notion of periodontal vaccines. With animal studies proving beyond doubt the validity of these vaccines, researches are still being undertaken to unravel the mystery with humans. Science has seen innumerous advancements in the recent decades again re-emphasizing our close proximity to success… this will soon be in public eye, soon be an actuality spoken about in every part of the world. With the periodontal vaccines taking control, who knows there might not be a chance for a periodontist…
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[Table 1], [Table 2], [Table 3]