Introduction to vaccination
Vaccination is a process that induces specific immune resistance to a bacterial or viral infection. In vaccination, dead or attenuated living infectious material is introduced into the body with the object of increasing resistance or eliminating the disease. The first and foremost step in making a vaccine is the identification of the antigenic component of a pathogenic microorganism that can provide immune protection. Various antigens have been identified in periodontal pathogens which can be used to make a vaccine. These antigens induce clonal expansion in specific T- or B-cells, leaving behind a population of memory cells which confer long term protection against infection. Vaccines may be synthetic or natural monovalent or polyvalent. Vaccination is of three types,
- Active Immunization: Here an individual immune system is stimulated by administrating killed or live attenuated products derived from micro-organisms.
- Passive immunization: Here, the antibodies formed in one individual are transferred to another.
- DNA vaccination: Here, DNA plasmids encoding genes required for antigen production are transferred to an individual.
Ideal characteristics of a vaccine:
- It should be safe to administer.
- It should induce the right sort of immunity.
- The vaccine should be effective against the particular infectious agent and prevent the disease.
- It should have the ability to provide sustained protection.
- It should be stable and have a long shelf life.
- The vaccines should be affordable by the population at which they are aimed.
Process of making vaccine
Vaccines can be prepared by various procedures. The first method involves killing the organism using formalin and using it as a vaccine. It is also called as inactivated or killed vaccine. The second method involves using only antigenic part of the disease-causing organism, for example, the capsule or the flagella or a part of the protein cell wall. This type of vaccine is called the acellular vaccine. The third method involves weakening a live microorganism by aging it or altering growth condition. This type of vaccine is called attenuated vaccine. Finally, toxins produced by the bacteria can be used to make vaccines. These vaccines are called toxoids. The toxins are first adsorbed onto aluminum salts to decrease their harmful effects and are administered with an “adjuvant” which can have effects on antigen delivery, immune-modulatory cytokines, and antigen-presenting cells (APCs).
Many attempts have been made to make a vaccine against periodontal pathogens. The primary difficulty in making a periodontal vaccine is the polymicrobial etiology of periodontal diseases. More than 700 bacterial species have been found in the oral cavity, most of which are commensals. Many bacterial species have been implicated in the etiopathogenesis of periodontal diseases. These species include A. actinomycetemcomitans, tannerella forsythia, Porphyromonas gingivalis, Prevotella intermedia, Campylobacter rectus, Fusobacterium nucleatum, and Treponema denticola, etc. 1
Initially, three periodontal vaccines were employed, which include pure cultures of streptococcus and other organisms, autogenous vaccines and stock vaccines (e.g. Vancott’s vaccine and Inava endocarp vaccine). However, with advancing research various periodontal pathogens were identified and studied. The major microorganisms which have been studied for making periodontal vaccine include P. gingivalis and A. actinomycetemcomitans.
Immunization against Porphyromonas gingivalis:
As discussed above, P. gingivalis is a major periodontopathogen in human periodontitis 2. This bacterium is equipped with multiple virulence factors, including cysteine proteases, fimbriae, capsular polysaccharide (CPS), lipopolysaccharide, and outer membrane vesicles 3. Both active and passive immunization vaccines have been tested for P. gingivalis.
The active immunization attempts have used formalin-killed P. gingivalis whole-cell vaccines, either alone or conjugated with syntax adjuvant. Studies on non-human primates with these vaccines have reported inhibition of progression of periodontal disease and elevated serum immunoglobulin G (IgG) and IgA titers 4-6. Gibson et al. (2004) 7 performed a study on mice immunized with heat-killed P. gingivalis. They reported the induction of P. gingivalis-specific IgG with optimal levels of opsonization of the microorganism and the prevention of alveolar bone loss. However, these studies could not provide any evidence regarding the long term immune memory and cell-mediated immune responses that would allow these vaccines to be adopted as a feasible vaccine strategy.
Another important component of P. gingivalis that can be used for active immunization is “Gingipains” (for details, read “Microbiology of periodontal diseases”. These are cysteine proteases consisting of two components: gingipain R (RgpA and RgpB) that cleaves proteins at arginine residues, and gingipain K (porphypain 2, Kgp) that cleaves proteins at lysine residues 8. Structurally, gingipains have …………. Contents available in the book……….. Contents available in the book………. Contents available in the book………. Contents available in the book….
The hemagglutinin domain of P. gingivalis is important for the survival of this bacteria because it facilitates the heme acquisition. Hence, it is a good candidate for making a vaccine. Hemagglutinin 2 (HA2) based vaccine has been developed and tested in animal models. DeCarlo et al. (2003) 13 conducted an experiment in a rat periodontitis model to investigate the use of P. gingivalis binding domain, recombinant heme acquisition rHA2 as an immunogen for periodontitis vaccine. It was concluded that subcutaneous administration of rHA2, without the addition of an adjuvant, stimulated an immune response which was significant enough to provide some clinical protection from periodontitis.
Another important virulence factor of P. gingivalis is fimbriae. The bacteria have one major fimbriae and two minor fimbriae of 67 kDa and 72 kDa, respectively. In a study 14, rats were parenterally immunized with purified 43-kDa fimbrial protein. The results demonstrated the presence of fimbrial A-specific antibodies in serum and saliva, which gave a satisfactory level of protection against P. gingivalis induced alveolar bone loss. In another study, a conjugate vaccine consisting of capsular polysaccharide and both fimbriae was tested. The results of the study demonstrated the production of a high IgG response and which was effective in protecting against P. gingivalis infection 15. However, it was not clear from this study whether the IgG response was due to the capsular polysaccharide or fimbriae.
The passive immunization involves the administration of monoclonal antibodies against the selected antigenic component of the pathogen. Outer membrane proteins (OMPs) of P. gingivalis have been used for this purpose. It has been shown that IgG specific for the 40 kDa-OMP inhibited coaggregation of P. gingivalis vesicles and S. gordonii. It means that OMPs can be utilized for protection against P. gingivalis infection 16. Another component of P. gingivalis investigated for passive immunization are hemagglutinins. As already stated, hemagglutinins of P. gingivalis facilitate its attachment to the erythrocyte cell surface, allowing it to access protoheme. Hence, antibodies generated against hemagglutinins can be used for passive immunization. In an animal study, passive immunization with rabbit antiserum against P. gingivalis hemagglutinin resulted in reduced colonization by exogenous P. gingivalis in the subgingival area over a 3-week period 17.
Immunization against Aggregatibacter Actinomycetemcomitans:
Various antigenic components of Aggregatibacter Actinomycetemcomitans have been used to provide passive/active immunization. In a study, Harano et al. (1995) 18 prepared an antiserum against a synthetic fimbrial peptide of A. actinomycetemcomitans. The results of the study demonstrated that antiserum inhibited the adhesion of the organism to saliva-coated hydroxyapatite beads, to buccal epithelial cells, and to a fibroblast cell line. In another study, Takamatsu-Matsushita et al. (1996) 19 immunized mice with capsular serotype b-specific polysaccharide through its subcutaneous and intranasal administration. The results of the study demonstrated a specific antibody response that efficiently opsonized the organism.
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Our quest for making a vaccine against periodontitis as a polymicrobial infection
Most of the immunization studies that have been performed so far are on a single periodontal pathogen. To prepare a vaccine that provides protection against multiple periodontal pathogens requires identification of those antigenic determinants which are shared by pathogens. The potential candidates for these determinants include phosphorylcholine 20, capsular polysaccharides 21, and heat-shock protein (HSP) 22, 23. Out of these, heat shock proteins are the most suitable candidates for making the vaccine. This is because Phosphorylcholine has not been identified in P. gingivalis and capsular polysaccharide is not a potent inducer of T-cell-mediated immunity and would require protein conjugation in any vaccine design 15. Thus, the most suitable proposed candidate for making a vaccine against multiple periodontal pathogens is P. gingivalis HSP60. In a study, rats with experimentally induced infection were immunized by P. gingivalis HSP60. The results of the study demonstrated significantly higher levels of anti-P. gingivalis HSP IgG antibody titer and a substantial reduction in alveolar bone loss induced by either P. gingivalis or by multiple bacterial infections 24. Choi et al. (2005) 25 have proposed that P. gingivalis HSP60 could potentially be developed as a vaccine to inhibit periodontal disease induced by multiple pathogenic bacteria. Furthermore, P. gingivalis HSP60 can also be conjugated with capsular polysaccharides to make an efficient vaccine against multiple periodontal pathogens. However, a lot of clinical research is required to test the efficacy of these vaccines. We are still far from making an efficient vaccine against periodontitis and a lot of research in this field of Periodontology is expected in the near future.
References available in the hard-copy of the website.