Helicobacter pylori in Vietnam: Prevalence, AMR and Vaccination
Lead Research Organisation:
Royal Holloway University of London
Department Name: Biological Sciences
Abstract
Helicobacter pylori (HP) infection currently afflicts over half the world's population. Typically children are infected with this bacterium and carry it without symptoms. Only much later in life a percentage (~15%) of people go on to develop symptoms typically gastritis reducing the quality of life. Unfortunately, for some, gastric cancer can also manifest with HP-induced gastritis being the most common underlying cause. There remains no preventative measure for this disease and only antibiotics are used. However, HP is remarkably resistant to antibiotics and in some cases they no longer work making the need for a vaccine of great importance. In Asia and Vietnam in particular HP infection is widespread with over 70% of people carrying the bacterium.
Here we propose to develop an oral vaccine candidate to HP infection. The UK-Vietnam initiative will use a novel method for oral vaccination which has been shown to be effective with a number of similar intestinal diseases. The vaccine candidate will be evaluated in animals to show that it performs and will then be optimised. The consortium includes a renowned Vietnamese vaccine manufacturing group where there exist possibilities for post-project development and technology transfer. This proposal will also bring together a large collection of HP strains isolated from humans into a central depository. These strains will then be examined for their capacity for resist antibiotics with the aim of providing a useful understanding of the prevalence of antibiotic resistant HP in Vietnam.
Here we propose to develop an oral vaccine candidate to HP infection. The UK-Vietnam initiative will use a novel method for oral vaccination which has been shown to be effective with a number of similar intestinal diseases. The vaccine candidate will be evaluated in animals to show that it performs and will then be optimised. The consortium includes a renowned Vietnamese vaccine manufacturing group where there exist possibilities for post-project development and technology transfer. This proposal will also bring together a large collection of HP strains isolated from humans into a central depository. These strains will then be examined for their capacity for resist antibiotics with the aim of providing a useful understanding of the prevalence of antibiotic resistant HP in Vietnam.
Technical Summary
Control of H. pylori (HP) infection is problematic because the pathogen carries multiple AMR and there is no vaccine. This consortium will address two aspects of the disease.
First, we will characterise a large collection of HP strains previously collected from biopsies of dyspeptic patients in Vietnam. These strains are present in a number of national hospitals and will be collated and characterised for their genotype and AMR profile. For genotype we will examine the ureA, ureB, vacA and csgA genes since there exist considerable variation between strains of different virulence as well as geographic/regional variations. This data will provide important information regarding virulent HP strains within Vietnam and may help influence decisions regarding use of antibiotics.
Second, we will construct and evaluate an oral vaccine candidate to HP infection using bacterial spores for antigen display. Bacillus spores have been shown able to stably display HP antigens and in this project we will construct recombinant spores that are unable to proliferate should spores germinate. This is an innovative system for gene expression in B. subtilis developed by the UK partner and addresses long-term issues over biological containment of recombinant spores. The multivalent spore vaccines will carry combinations of the UreA, UreB, VacA and CsgA HP antigens all of which are considered protective. The best performing vaccines will be evaluated in two animal models, the mouse colonisation model and gerbils. For the mouse model the aim is to determine if oral or sublingual administration of the spore vaccine can prevent colonisation of HP while for the gerbil model the best performing spore vaccine candidate will be evaluated to determine whether it can prevent 'human' symptoms of HP infection, i.e., gastritis (histopathology).
First, we will characterise a large collection of HP strains previously collected from biopsies of dyspeptic patients in Vietnam. These strains are present in a number of national hospitals and will be collated and characterised for their genotype and AMR profile. For genotype we will examine the ureA, ureB, vacA and csgA genes since there exist considerable variation between strains of different virulence as well as geographic/regional variations. This data will provide important information regarding virulent HP strains within Vietnam and may help influence decisions regarding use of antibiotics.
Second, we will construct and evaluate an oral vaccine candidate to HP infection using bacterial spores for antigen display. Bacillus spores have been shown able to stably display HP antigens and in this project we will construct recombinant spores that are unable to proliferate should spores germinate. This is an innovative system for gene expression in B. subtilis developed by the UK partner and addresses long-term issues over biological containment of recombinant spores. The multivalent spore vaccines will carry combinations of the UreA, UreB, VacA and CsgA HP antigens all of which are considered protective. The best performing vaccines will be evaluated in two animal models, the mouse colonisation model and gerbils. For the mouse model the aim is to determine if oral or sublingual administration of the spore vaccine can prevent colonisation of HP while for the gerbil model the best performing spore vaccine candidate will be evaluated to determine whether it can prevent 'human' symptoms of HP infection, i.e., gastritis (histopathology).
Planned Impact
Who might benefit from this research?
Societal:
HP infection occurs at childhood with at least 50% of people asymptomatically colonised. Symptoms typically do not manifest until later in life with 15% of infected people worldwide going on to develop gastric cancer. Infection is treated with antibiotics yet the bacterium carries multiple AMR and is some cases infections are becoming untreatable. This places a burden on treating not only HP infection but also decreases the risk of being able to treat other microbial infections. Therefore, it is clear that everyone could benefit from a prophylactic vaccine for HP infection.
While HP infection is a global problem it is developing countries that are most affected however. This is due in part to the overuse and abuse of antibiotics. Vietnam is no exception with over 70% of people carrying HP and with 10-25% exhibiting symptoms this disease is considered a national priority exceeding some of the better known tropical diseases. Vietnam is not alone and in SE Asia in particular HP imposes a tremendous burden. With no adequate control measures there is an urgent need to find prophylactic and/or therapeutic interventions. So, a HP vaccine for developing countries would be a priority.
Economic:
The economic burden of treating HP infection is substantial especially with treatment costs for gastric cancer. A vaccine would significantly reduce the effort and cost for developing countries.
How they might benefit from this research?
Societal
A prophylactic vaccine to HP infection administered to children would lead to a substantial decline in colonisation rates and ultimately more serious outcomes (e.g., gastric cancer) in later life. Even a partial reduction in infection rates would to measurable outcomes. The reduction in infection would also help reduce the burden on antibiotics. Every time antibiotics are used the risk of developing resistance and therefore reducing the efficacy of antibiotics is lessened.
Economic
The primary economic benefit would be in increasing lifespan and productivity.
Societal:
HP infection occurs at childhood with at least 50% of people asymptomatically colonised. Symptoms typically do not manifest until later in life with 15% of infected people worldwide going on to develop gastric cancer. Infection is treated with antibiotics yet the bacterium carries multiple AMR and is some cases infections are becoming untreatable. This places a burden on treating not only HP infection but also decreases the risk of being able to treat other microbial infections. Therefore, it is clear that everyone could benefit from a prophylactic vaccine for HP infection.
While HP infection is a global problem it is developing countries that are most affected however. This is due in part to the overuse and abuse of antibiotics. Vietnam is no exception with over 70% of people carrying HP and with 10-25% exhibiting symptoms this disease is considered a national priority exceeding some of the better known tropical diseases. Vietnam is not alone and in SE Asia in particular HP imposes a tremendous burden. With no adequate control measures there is an urgent need to find prophylactic and/or therapeutic interventions. So, a HP vaccine for developing countries would be a priority.
Economic:
The economic burden of treating HP infection is substantial especially with treatment costs for gastric cancer. A vaccine would significantly reduce the effort and cost for developing countries.
How they might benefit from this research?
Societal
A prophylactic vaccine to HP infection administered to children would lead to a substantial decline in colonisation rates and ultimately more serious outcomes (e.g., gastric cancer) in later life. Even a partial reduction in infection rates would to measurable outcomes. The reduction in infection would also help reduce the burden on antibiotics. Every time antibiotics are used the risk of developing resistance and therefore reducing the efficacy of antibiotics is lessened.
Economic
The primary economic benefit would be in increasing lifespan and productivity.
Publications
Ferreira WT
(2022)
Environmentally Acquired Bacillus and Their Role in C. difficile Colonization Resistance.
in Biomedicines
Ferreira WT
(2021)
Micellar Antibiotics of Bacillus.
in Pharmaceutics
Katsande P
(2023)
Prophylactic immunization to Helicobacter pylori infection using spore vectored vaccines
in Helicobacter
Nguyen TKC
(2024)
Genomic and vaccine preclinical studies reveal a novel mouse-adapted Helicobacter pylori model for the hpEastAsia genotype in Southeast Asia.
in Journal of medical microbiology
| Description | Bacterial spores have been shown able to confer protective immunity in animal models of colonisation. We have engineered spores to express antigens and when spores are then administered orally to mice they show significant reductions in colonisation of H. pylori. This, in principle we have made an oral vaccine that could reduce H pylori infection in the stomach. In addition we have discovered and characterised antimicrobials that are produced by Bacillus bacteria and when these antimicrobials are administered to mice they reduce H. pylori infection. Our data shows that this approach could be used for therapeiutic treatment of H pylori infection. |
| Exploitation Route | The data will be submitted for publication this year. The next step would be to establish GMP production of these spores, complete toxicology studies and then use them in a phase 1 clinical study. In the absence of any other treatment bacterial spore vaccines, being heat stable and suitable for oral delivery could be used for prophylactic vaccination. We are establishing links with our Vietnamese partners to do exactly this and will look for funding possibilities. |
| Sectors | Pharmaceuticals and Medical Biotechnology |