Developing a vaccine for Burkholderia pseudomallei - a Phase I Clinical Trial
Lead Research Organisation:
University of Oxford
Department Name: Tropical Medicine
Abstract
Every year an estimated 89,000 people die from a neglected tropical disease that most people have never heard of: melioidosis. This infection is caused by bacteria called Burkholderia pseudomallei, that live in the soil in warm climates. Around 165,000 people around the globe become unwell with melioidosis each year, mainly in the world's poorest communities in low and middle income countries. Melioidosis is common in Asia and Northern Australia, but is also grossly under-diagnosed in Sub-Saharan Africa and South America. The infection is resistamt to first-line antibiotics, and up to half of people who get melioidosis will die despite receiving hospital treatment. Two-thirds of people with melioidosis have diabetes mellitus, and a vaccine given to people with diabetes who live in melioidosis regions is predicted to be a worthwhile public health intervention that would save lives.
The bacteria has also been identified as a potential bioweapon, with Burkholderia pseudomallei is classifed as a Tier 1 Biodefence pathogen, meaning research to protect healthy soldiers against an airborne attack is a priority for the US Defense Threat Reduction Agency (DTRA). Researchers at the University of Nevada, Reno have developed a vaccine that we wish to test in healthy human volunteers. This vaccine has two key parts. Firstly the capsule of the bacteria, called capsule polysaccharide (CPS) is joined to part of the diptheria vaccine to train the body to make a strong antibody response to the bacteria. Secondly, the vaccine targets a key protein called Hcp1, which is part of an attacking mechanism called Type 6 Secretion System (T6SS) used by the bacteria to move proteins from inside the bacteria to nearby cells in order to invade them. When people are given this vaccine, the aim is to train the body's immune system to make antibodies attacking the bacteria's CPS and white blood cells called "T cells" attacking Hcp1, to stop infection. In experiments in mice in Nevada, all mice reveiveing the vaccine made these immune responses and were protected against infection with the bacteria.
A group of scientists in UK, USA and Thailand, brought together by the MRC's VALIDATE Network, propose a first-in-man clincial trial of 36 healthy human volunteer subjects in Oxford, UK. Volunteers will be randomised to one of three groups: Group 1 will receive the CPS part of the vaccine, Group 2 will receive the Hrcp1 part of the vaccine, and Group 3 will both CPS and Hrp1 together (CPS-CRM197 / Hcp1 combination). The clincial trial will check that the vaccine does not have bad side effects, and will measure the body's immune responses (antibody and T cell responses). If the vaccine is shown to be safe and successful in making immune responses in people who receive it, the next step will be to test the vaccine in a clinical trial in Thailand, to look at immune responses in people with and without diabetes in a region affected by melioidosis.
This proposal is an opportunity to bring this leading vaccine candidate to a Phase I Clinical Trial, which would represent the world's first human vaccine trial for melioidosis. This is in partnership with DTRA who will fund the manufacture of the vaccine to the required regulatory standard, and will allow Oxford University to develop the vaccine for public health.
The bacteria has also been identified as a potential bioweapon, with Burkholderia pseudomallei is classifed as a Tier 1 Biodefence pathogen, meaning research to protect healthy soldiers against an airborne attack is a priority for the US Defense Threat Reduction Agency (DTRA). Researchers at the University of Nevada, Reno have developed a vaccine that we wish to test in healthy human volunteers. This vaccine has two key parts. Firstly the capsule of the bacteria, called capsule polysaccharide (CPS) is joined to part of the diptheria vaccine to train the body to make a strong antibody response to the bacteria. Secondly, the vaccine targets a key protein called Hcp1, which is part of an attacking mechanism called Type 6 Secretion System (T6SS) used by the bacteria to move proteins from inside the bacteria to nearby cells in order to invade them. When people are given this vaccine, the aim is to train the body's immune system to make antibodies attacking the bacteria's CPS and white blood cells called "T cells" attacking Hcp1, to stop infection. In experiments in mice in Nevada, all mice reveiveing the vaccine made these immune responses and were protected against infection with the bacteria.
A group of scientists in UK, USA and Thailand, brought together by the MRC's VALIDATE Network, propose a first-in-man clincial trial of 36 healthy human volunteer subjects in Oxford, UK. Volunteers will be randomised to one of three groups: Group 1 will receive the CPS part of the vaccine, Group 2 will receive the Hrcp1 part of the vaccine, and Group 3 will both CPS and Hrp1 together (CPS-CRM197 / Hcp1 combination). The clincial trial will check that the vaccine does not have bad side effects, and will measure the body's immune responses (antibody and T cell responses). If the vaccine is shown to be safe and successful in making immune responses in people who receive it, the next step will be to test the vaccine in a clinical trial in Thailand, to look at immune responses in people with and without diabetes in a region affected by melioidosis.
This proposal is an opportunity to bring this leading vaccine candidate to a Phase I Clinical Trial, which would represent the world's first human vaccine trial for melioidosis. This is in partnership with DTRA who will fund the manufacture of the vaccine to the required regulatory standard, and will allow Oxford University to develop the vaccine for public health.
Technical Summary
Melioidosis is a grossly neglected tropical disease, caused by the Gram-negative bacterium Burkholderia pseudomallei (Bp). An estimated 89,000 deaths occur annually across tropical regions, chiefly affecting the world's poorest communities in low and middle income countries. Up to two-thirds of people with melioidosis have diabetes mellitus, and a vaccine targeting this well defined at-risk group is predicted to be a cost-effective public health intervention.
In addition, Bp is a Tier 1 Biodefence pathogen, and a vaccine to protect healthy soldiers against aerosol dissemination is a priority for the US Defense Threat Reduction Agency (DTRA) who have invested in development of candidate vaccines. The leading candidate vaccine is CPS-CRM197 / Hcp1 - a combination candidate sub-unit vaccine developed at University of Nevada, Reno (UNR). This vaccine combines the bacterial capsule polysaccharide (CPS) conjugated to the immunogenic diphtheria toxin mutant CRM197 with recombinant B. pseudomallei Hcp1 protein in an Alhydrogel-CpG adjuvant. In a mouse model, the combined vaccine generated high levels of opsonising anti-CPS antibodies, alongside high T cell responses to Hcp1, and protected 100% of mice against a robust lethal inhalational Bp challenge.
A group of investigators in UK, USA and Thailand, brought together by the MRC VALIDATE Network, propose a first-in-man study of 36 human volunteer subjects in Oxford, UK, randomised to receive either the CPS-CRM197 alone, Hcp1 alone, or the CPS-CRM197 / Hcp1 combination. Endpoints will be safety and immunogenicity (antibody and T cell responses).
This proposal is an opportunity to bring this leading vaccine candidate to a Phase I Clinical Trial, which would represent the world's first human vaccine trial for melioidosis. This is in partnership with DTRA who will fund the Good Manufacturing Practice (GMP) manufacture of the vaccine, and will allow Oxford University to develop the vaccine for public health.
In addition, Bp is a Tier 1 Biodefence pathogen, and a vaccine to protect healthy soldiers against aerosol dissemination is a priority for the US Defense Threat Reduction Agency (DTRA) who have invested in development of candidate vaccines. The leading candidate vaccine is CPS-CRM197 / Hcp1 - a combination candidate sub-unit vaccine developed at University of Nevada, Reno (UNR). This vaccine combines the bacterial capsule polysaccharide (CPS) conjugated to the immunogenic diphtheria toxin mutant CRM197 with recombinant B. pseudomallei Hcp1 protein in an Alhydrogel-CpG adjuvant. In a mouse model, the combined vaccine generated high levels of opsonising anti-CPS antibodies, alongside high T cell responses to Hcp1, and protected 100% of mice against a robust lethal inhalational Bp challenge.
A group of investigators in UK, USA and Thailand, brought together by the MRC VALIDATE Network, propose a first-in-man study of 36 human volunteer subjects in Oxford, UK, randomised to receive either the CPS-CRM197 alone, Hcp1 alone, or the CPS-CRM197 / Hcp1 combination. Endpoints will be safety and immunogenicity (antibody and T cell responses).
This proposal is an opportunity to bring this leading vaccine candidate to a Phase I Clinical Trial, which would represent the world's first human vaccine trial for melioidosis. This is in partnership with DTRA who will fund the Good Manufacturing Practice (GMP) manufacture of the vaccine, and will allow Oxford University to develop the vaccine for public health.
Planned Impact
The goal of this project is to develop a vaccine to prevent melioidosis in people with diabetes and other immunocompromise in regions around the world with melioidosis, and to build knowledge about the immune responses induced by this vaccine.
We anticipate the output of this project being of interest to a wide range of academics including those working in the basic science of bacterial virulence factors, animal models of melioidosis, immunology, vaccinology, clinical trials and diabetes.
The project will evaluate the safety and immune responses of the leading vaccine candidate to protect against melioidosis, which will be of interest to industry, such as Sanofi and middle-sized enterprises. Health economic analysis have supported a vaccine being a cost effective intervention to prevent melioidosis when given to adults with diabetes in endemic regions. Maintaining leadership in vaccine development promotes UK's competitiveness in pharmaceutical development, and our plans for a Phase II trial in Thailand for the next stage will allow development of Thailand's skills capacity in immunology and the vaccine development pipeline.
A vaccine against melioidosis would be a game changer in the fight against this neglected tropical disease which kills an estimated 89,000 people per year, mostly in low- and middle-income countries. An effective vaccine would stimulate awareness and funding for melioidosis and its prevention via national Ministries of Health, academics, WHO and the media.
One in twelve adults in the world is estimated to have diabetes now, and in melioidosis-endemic areas this group is a well-defined market for a vaccine. I will reach out to the population in UK and Thailand through public engagement activities including science festivals, schools talks and work with diabetes patient groups in Thailand.
This research will benefit the effectiveness of public services by providing a prevention solution for melioidosis, and provide stimulus for public awareness campaigns.
We anticipate the output of this project being of interest to a wide range of academics including those working in the basic science of bacterial virulence factors, animal models of melioidosis, immunology, vaccinology, clinical trials and diabetes.
The project will evaluate the safety and immune responses of the leading vaccine candidate to protect against melioidosis, which will be of interest to industry, such as Sanofi and middle-sized enterprises. Health economic analysis have supported a vaccine being a cost effective intervention to prevent melioidosis when given to adults with diabetes in endemic regions. Maintaining leadership in vaccine development promotes UK's competitiveness in pharmaceutical development, and our plans for a Phase II trial in Thailand for the next stage will allow development of Thailand's skills capacity in immunology and the vaccine development pipeline.
A vaccine against melioidosis would be a game changer in the fight against this neglected tropical disease which kills an estimated 89,000 people per year, mostly in low- and middle-income countries. An effective vaccine would stimulate awareness and funding for melioidosis and its prevention via national Ministries of Health, academics, WHO and the media.
One in twelve adults in the world is estimated to have diabetes now, and in melioidosis-endemic areas this group is a well-defined market for a vaccine. I will reach out to the population in UK and Thailand through public engagement activities including science festivals, schools talks and work with diabetes patient groups in Thailand.
This research will benefit the effectiveness of public services by providing a prevention solution for melioidosis, and provide stimulus for public awareness campaigns.
