Development of an oral Helicobacter Pylori vaccine

Final Report Summary - HELICOVAXOR (Development of an oral Helicobacter Pylori vaccine.)

Executive Summary:
According to the World Health Organisation, the incidence of Helicobacter pylori (H pylori) infection exceeds 50 % in developed countries and 80 % in developing countries. It is spread through casual contact and can persist for life, inducing active and chronic inflammation of the gastric mucosa. Although most infections respond to antibiotics, some patients develop resistance and are at higher risk of disease.
To address this medical issue, the EU-funded 'Development of an oral Helicobacter pylori vaccine'
project focused in developing an oral H. pylori vaccine. The project aimed at developing a vaccine effective at both preventing and treating H. pylori infection.
Prior immunisation attempts with H. pylori protein subunits in humans have shown adjuvant-related adverse effects and only moderate effectiveness. Having learnt from these, at its conception the HELICOVAXOR® project based its concept on the convergence of unique and proven technologies through the combination of the proprietary innovations of the consortium SMEs into a ‘virtual’ vaccine innovator.
The critical needs for successful oral vaccine product development are to 1) find a broadly protective vaccine antigen, 2) find or develop a useful safe yet effective mucosal adjuvant, and 3) being the special advantage of this project through the use of the SmPill® integrative oral drug delivery technology, develop a useful formulation for oral use that would allow the vaccine-adjuvant mixture to be a) combined in a single co-administration formulation, b) be protected against negative pH effects, and c) allow effective intestinal-mucosal co-delivery of vaccine and adjuvant stimulating immune responses and immune protection in the stomach mucosa against challenge infection with virulent H. pylori bacteria.
The HELICOVAXOR® project achieved remarkable progress towards the set goal despite some scientific hurdles encountered in relation to the initially selected adjuvant(s). Indeed, the project: 1) identified a useful inactivated whole-cell vaccine formulation; 2) identified a novel attractive adjuvant (as alternative to the initially proposed adjuvant technology) which demonstrated its capacity also when dissolved/dispersed in a pharmacologically attractive novel oil composition to potentiate intestinal-mucosal immune responses to the whole-cell vaccine and most importantly to significantly potentiate its protective efficacy against H. pylori infection; 3) been able to co-incorporate the whole-cell vaccine and adjuvant in the oral-use-attractive SmPill® delivery vehicle with retained immunological activities and retained or enhanced immune-protective efficacy; 4) assessed the toxicological impact of the developed vaccine prototype in mice; and 5) developed a suitable scaled-up manufacturing process for the oral vaccine product.
However, there are still some development pieces which remain to be filled in to enable the advancement of the program to first in human trials, and these are: 1) data to convince that the chosen vaccine strain would protect against all or most “global” clinical H. pylori isolates; 2) data supporting the scaling-up production potential for some of the vaccine components; and 3) the potential for further improving the immunogenicity and efficacy by adding yet another mucosal adjuvant (here the SME partner Gotovax has done significant development in constructing and showing the potential of a novel enterotoxin-derived adjuvant) to the formulation.
The results achieved within the HELICOVAXOR® program lay the foundation for the proposed oral vaccine product development and contribute towards the long-term plan of of moving to first in human clinical trials; the latter achievable once convincing promising data that the highlighted hurdles have been overcome. It is the intention of the relevant HELICOVAXOR® partners to seek further funding either from the EU or from the pharma industry to progress the program.

Project Context and Objectives:
The HELICOVAXOR® project aimed at developing a novel adjuvanted, multivalent H. pylori vaccine to be administered orally using an advanced oral delivery system, SmPill®, that is stable at ambient temperature and is expected to be effective in both preventing and treating H pylori infection.
H pylori infection is one of the most common infections in human beings worldwide. It is spread by casual contact and causes chronic gastritis, produces duodenal and gastric ulcers. Current treatments revolve around antibiotics and while patients often respond, many develop resistance which results in a more virulent strain and higher risk of disease. Consequently, a solution for reducing the incidence or even eradicate H pylori infection worldwide as well as reducing antibiotic use is a significant unmet need.
The main objective of the consortium was to develop an H. pylori oral vaccine prototype and initiate activities towards first in human clinical studies. The HELICOVAXOR® concept was based on the convergence of unique and proven technologies, namely: 1) a broadly protective vaccine antigen, 2) a safe and effective mucosal adjuvant, and 3) an integrative oral drug delivery system; all essential components of a viable vaccine.
In order to achieve its main goal the project was subdivided in a number of objectives: 1) development of a suitable formulation oral vaccine prototype combining the SME partners’ technologies informed by physical chemistry characterization and analytical testing of the different formulations developed; 2) ensure scalability and manufacturability of vaccine product by re-design of existent equipment; 3) establish efficacy of selected prototype formulation through in vivo immunisation studies in suitable mice model; 3) confirm safety of oral vaccine prototype; 4) obtain regulatory support to inform clinical development path and first in human filling dossier requirements; and 5) promote project externally for further development of the program.

Project Results:
The S/T activities and results of the HELICOVAXOR® project were the following:
i. The development of an oral vaccine prototype by the incorporation of advanced antigens and adjuvant technologies into SmPill® integrative oral drug delivery technology
ii. The identification of a novel attractive adjuvant (as alternative to the initially proposed adjuvant technology) which potentiates intestinal-mucosal immune responses and its protective efficacy against H. pylori infection
iii. Equipment modifications performed tailored to allow the processing of biotechnological materials followed by scale-up considerations through process development and validation
iv. Development of analytical (qualitative and quantitative) methods for antigen and adjuvant determination when incorporated into SmPill® format
v. The physical chemical characterisation of formulations developed and selected prototype
vi. Assessment of antigen and adjuvant toxicity in vivo when administered to mice in the SmPill® format
vii. Pre-clinical evaluation of the immune response of the developed formulations and selected prototype
viii. Pre-clinical evaluation of protective effect of prototype vaccine against H pylori exposure
ix. Preparation of a regulatory dossier highlighting requirements for first in human clinical studies
x. Development of an exploitation plan identifying next steps to progress towards clinical development of prototype vaccine and commercial
The results achieved lay the foundation for the proposed product development and contribute towards the long-term plan of moving to first in human clinical trials although the latter will required further work and funding as highlighted previously.

Potential Impact:
The world health organization (WHO) estimates indicate high H. pylori infection rates among the world populations, ~50% in developed countries and ~80-100% in developing countries. Most H. pylori infections persist for life and can induce active and chronic inflammation of the gastric mucosa in all subjects in variable forms with subset of approximately 15% of infected individuals will develop severe complications such as peptic ulcer, gastric malignancies, adenocarcinoma and lymphoma. The unmet clinical need is therefore evident and so it is the benefit to society once a safe and efficacious oral vaccine product reaches the market place.
The global vaccines sales in 2010 were $28 billion as compared to $26 billion in 2009, $24 billion in 2008 and $18.5 billion in 2007. Interestingly, market research highlighted that two gastrointestinal pathogen vaccines against rotavirus, RotaTeq and Rotarix are likely to reach sales of $ 1 billion in the next few years, while the two approved cervical cancer vaccines, developed for prevention and to be administered to pre-pubescent girls, attained global sales of $3Bn in 2010. Thus the potential economic impact of developing a successful oral vaccine product is clear.
During the HELICOVAXOR® project a number of discussions with specialist vaccines companies for full clinical development took place, and while these companies are interested in the product, at this time no proposal to license or co-develop the vaccine has been received. The feedback from vaccine companies recommends further preclinical optimisation to achieve higher immunisation and protection rates. Moreover, an evaluation of the most appropriate indication for the vaccine would be required, but this can only be informed once the results of optimisation work are available.
Therefore, if the current lead prototype can be successfully optimised, the HELICOVAXOR® product has the potential to be adopted as the leading H. pylori vaccine on the market, saving lives and improving quality of living in a cost-effective manner.
The HELICOVAXOR® project advancements towards clinical development of an oral vaccine product against H. pylori infection resulted in significant know-how and innovation generation which is protected by background intellectual property of the lead SME participants allowing the further exploitation of the project results by the lead partners involved.

Furthermore, a draft dossier has been prepared for submission to the regulatory authorities in addition to a plan to seek scientific advice from regulatory authorities to inform the clinical and scale up plan, and this will be updated with the results of further scientific optimisation work that is ongoing. This will provide a clear clinical development path for the HELICOVAXOR® oral vaccine product clinical development path to reach the market effectively.

List of Websites:
Information on the Helicovaxor project progress can be found at http://www.helicovaxor.com/.
Contact details: Ivan Coulter, CEO and founder, Ivan.Coulter@SigmoidPharma.com

Final Report Summary - HELICOVAXOR (Development of an oral Helicobacter Pylori vaccine.)

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