An Important Step Forward Towards a Vaccine for Periodontal Disease

The various types of gum disease and periodontal conditions create insidious forms of damage, caused by the presence of unwanted but very persistent species of bacteria found in the mouth. Most people suffer inflammation of the gums to some degree, and this is due to the activities of bacteria such as Porphyromonas gingivalis. While it is true that there are a large number of ways to remove the bacterial species found in the mouth, the challenge is that they always return, and do so very quickly, often within days. This is obviously important from the point of view of the quality of your teeth over the long term, but arguably the real reason to pay attention here is because inflammation and damage in the gums directly correlates with inflammation and damage to the heart and the rest of the cardiovascular system. Research has shown that the presence and prevalence of bacterial species associated with gum disease correlates with mortality rates, while gum disease itself correlates with cognitive decline and the presence of amyloid in the brain, to pick a few examples. If you don't keep dental health under control, your risk of suffering all of the cardiovascular diseases that are driven by chronic inflammation increases significantly, and it appears that your chances of suffering dementia get a boost as well. Unfortunately, for the whole of human history, dental health has proven to be a real challenge: gains have been incremental and still require a fair amount of ongoing work on the part of the individual.

Yet we live in an age of biotechnology and rapid, revolutionary progress. It is unthinkable that immunology, genetics, gene therapies, and advanced medical applications of the life sciences can continue to coexist with the fact that we can't get rid of a few simple bacterial species that are causing us considerable harm. Sooner or later the research community will bring all undesirable bacteria under medical control. For some years now, a number of dental research groups have been working on potential methods of permanently excluding the bacteria that cause periodontitis and other inflammatory damage to gums, teeth, and the underlying bone. This has proven to be slow going, unfortunately. Nonetheless there have been signs of progress of late. To pick an example from earlier this year, one research team has managed to rouse the innate immune system into attacking and destroying bacterial species that cause gum disease, reversing the progression of periodontitis. Similarly, the research linked below takes the form of a vaccine, training the immune system to attack one of the problem molecules produced by the Porphyromonas gingivalis bacteria that contribute to periodontitis. The dental research community tends to have a faster time to market and less of a regulatory burden than the rest of the broader medical community, so we might expect to see something along these lines reaching clinics within the next few years.

Scientists publish evidence for world-first therapeutic dental vaccine

A world-first vaccine which could eliminate or at least reduce the need for surgery and antibiotics for severe gum disease has been validated. A team of dental scientists has been working on a vaccine for chronic periodontitis for the past 15 years. Clinical trials on periodontitis patients could potentially begin in 2018. Moderate to severe periodontitis affects one in three adults and more than 50 per cent of Australians over the age of 65. It is associated with diabetes, heart disease, rheumatoid arthritis, dementia and certain cancers. It is a chronic disease that destroys gum tissue and bone supporting teeth, leading to tooth loss.

The findings represent analysis of the vaccine's effectiveness by collaborating groups. The vaccine targets enzymes produced by the bacterium Porphyromonas gingivalis, to trigger an immune response. This response produces antibodies that neutralise the pathogen's destructive toxins. P. gingivalis is known as a keystone pathogen, which means it has the potential to distort the balance of microorganisms in dental plaque, causing disease. "We currently treat periodontitis with professional cleaning sometimes involving surgery and antibiotic regimes. These methods are helpful, but in many cases the bacterium re-establishes in the dental plaque causing a microbiological imbalance so the disease continues. Periodontitis is widespread and destructive. We hold high hopes for this vaccine to improve quality of life for millions of people."

A therapeutic Porphyromonas gingivalis gingipain vaccine induces neutralising IgG1 antibodies that protect against experimental periodontitis

From epidemiological surveys moderate to severe forms of periodontitis affect one in three adults and the disease has been linked to an increased risk of cardiovascular diseases, certain cancers, preterm birth, rheumatoid arthritis and dementia related to the regular bacteremia and chronic inflammation associated with the disease. The global prevalence of severe periodontitis has been estimated from 2010 epidemiological data to be 10.5-12.0% and the global economic impact of dental diseases, of which periodontitis is a major component, has been estimated to be US$442 billion per year. The conventional therapy for periodontitis involves scaling and root planing to remove plaque microorganisms. Treatment can sometimes involve surgery to improve access and/or to reduce pocket depth and can also include the use of antibiotics and/or antimicrobials. However, treatment outcomes are variable and heavily dependent on patient compliance. Even in patients on a periodontal maintenance program involving regular professional intervention sites continue to progress and teeth are lost.

Although chronic periodontitis is associated with a polymicrobial biofilm, specific bacterial species of the biofilm such as Porphyromonas gingivalis, Treponema denticola and Tannerella forsythia as a complex or consortium have been closely associated with clinical measures of disease. P. gingivalis is found at the base of deep periodontal pockets as microcolony blooms in the superficial layers of subgingival plaque adjacent to the periodontal pocket epithelium, which helps explain the strong association with underlying tissue inflammation and bone resorption at relatively low proportions (10-15%) of the total bacterial cell load in the pocket. Furthermore, it has been shown from studies using the mouse periodontitis model that P. gingivalis is a keystone pathogen, which dysregulates the host immune response to favour the polymicrobial biofilm disrupting homeostasis with the host to cause dysbiosis and disease.

The extracellular Arg- and Lys-specific proteinases 'gingipains' (RgpA/B and Kgp) of P. gingivalis have been implicated as major virulence factors that are critical for colonisation, penetration into host tissue, dysregulation of the immune response, dysbiosis and disease. The gingipains, in particular the Lys-specific proteinase Kgp is essential for P. gingivalis to induce alveolar bone resorption in the mouse periodontitis model. The gingipains have also been found in gingival tissue at sites of severe periodontitis at high concentrations proximal to the subgingival plaque and at lower concentrations at distal sites deeper into the gingival tissue. This has led to the development of a cogent mechanism to explain the keystone role played by P. gingivalis in the development of chronic periodontitis.

The role of P. gingivalis as a keystone pathogen in the initiation and progression of chronic periodontitis suggests that a strategy of targeting the major virulence factors of the bacterium, the gingipains, by vaccination may have utility in the prevention of P. gingivalis-induced periodontitis. Indeed, studies using the gingipains as a prophylactic vaccine that induces a high-titre antibody response in naive animals before superinfection with the pathogen have shown protection against alveolar bone resorption. However, patients with P. gingivalis-associated periodontitis harbour the pathogen at above threshold levels in subgingival plaque and exhibit an inflammatory immune response, hence it is possible that therapeutic vaccination could exacerbate inflammation and bone resorption in these patients. Here we show that therapeutic vaccination with a chimera antigen targeting the gingipains protects against alveolar bone resorption in P. gingivalis-associated experimental periodontitis and that this protection is mediated via a predominant Th2 anti-inflammatory response with the production of gingipain-neutralising IgG1 antibodies.


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