Development of a Live Attenuated Vaccine Against Salmonella Paratyphi (VASP)

Enteric fever is a disease affecting more than 20 million people every year and is a particular problem for young children. Two types of Salmonella cause the diseases, typhoid and paratyphoid, and while there is a vaccine available for typhoid, there is no vaccine for paratyphoid. Paratyphoid affects more than 5 million people annually, and accounts for 50% of cases of enteric fever in returning travellers in the UK. Paratyphoid is expected to become the main cause of enteric fever following the roll out of new generation of typhoid vaccines in the next few years. There is also a fear that paratyphoid is important in antibiotic resistance and could take over the place of typhoid and become more common but not preventable and with reduced options for treatment as a result of antibiotic resistance. There are no licensed paratyphoid vaccines but we have recently shown in n MRC research project that individuals experimentally infected with paratyphoid can become resistant to reinfection. We have therefore proposed testing a weakened strain of paratyphoid, which cannot cause disease, as a live vaccine to be taken by mouth. The vaccine has already been given to volunteers and shown to be safe and make an immune response. In this application we propose to manufacture this live attenuated vaccine (CVD 1902) under strict conditions and test it with volunteers to see if it can prevent infection. We will ask volunteers to take the vaccine by mouth in a drink and then, one month later, try and infect them with paratyphoid by getting them to drink the bacteria in a bicarbonate solution. If the vaccine works it will stop the volunteers developing early signs of paratyphoid (before we treat them). We will also study the immune responses to understand how the vaccine works to protect our volunteers. We will define whether CVD 1902 can provide protection and, if it does so, develop the vaccine for use to control this disease.

Salmonella Paratyphi A is the major cause of paratyphoid and causes more than 5 million cases of enteric fever annually, and accounts for 50% of enteric fever cases in returning travellers in the UK. Cases may increase as a result of replacement disease after deployment of typhoid vaccines. There are no licensed paratyphoid A vaccines, and two approaches are being considered - namely development of live-attenuated vaccines or LPS conjugates. There are currently no efficacy data for either approach but phase I data, available only for the live attenuated vaccine, indicates that it is highly immunogenic. Furthermore, our recent data from an MRC funded experimental medicine challenge grant shows that individuals experimentally infected with paratyphoid A are resistant to reinfection, providing support for the development of an oral live attenuated vaccine which mimics natural infection, without causing disease. In this application we propose to manufacture a live attenuated guaBA/clpX deletion strain oral vaccine, CVD 1902, to GMP. This vaccine, engineered at the University of Maryland's Center for Vaccine Development, was well tolerated and highly immunogenic in phase I providing immune responses against S. Paratyphi A and B. We will orally immunise volunteers with the strain, or a placebo of bicarbonate solution, and then challenge them with 1-5000 CFU of wild-type Salmonella Paratyphi A one month later in our controlled human paratyphoid infection model. Volunteers will then be followed for 2 weeks to identify paratyphoid infection. All those developing disease, defined as fever for 12 hours or a positive blood culture, will be treated with ciprofloxacin and all volunteers who remain uninfected will be treated on day 14. We will measure the protective efficacy of the vaccine in the model and study the cellular and humoral immune response to Salmonella serovars to identify correlates of protection and drive development of the first efficacious paratyphoid vaccine.

Academic Impact: In the proposed project we will investigate whether a novel live attenuated paratyphoid vaccine can prevent infection with Salmonella Paratyphi. If efficacy is shown in the model, the further development of the vaccine and potential licensure could be based on the data generated in this project. Beyond this specific paratyphoid vaccine, the planned project will provide a benchmark for efficacy of future paratyphoid vaccines. The immunological observations from this study will provide evidence on the correlates of protection which will accelerate vaccine development.
The information will also more broadly benefit the scientific community by providing evidence that human challenge models can be safely used to support vaccine development and shortcut time to demonstration of efficacy. We also anticipate that the work will benefit the UK by attracting further funding on assessment of alternative approaches to paratyphoid prevention.
The information will also more broadly benefit the scientific community by providing evidence that human challenge models can be safely used to support vaccine development and shortcut time to demonstration of efficacy. We also anticipate that the work will benefit the UK by attracting further funding on assessment of alternative approaches to paratyphoid prevention.
The results will be presented at the relevant conferences (including the International Conference on Typhoid and Non-typhoidal Salmonella Infection) and published in peer-reviewed journals.
The project will also serve as a training platform for clinical and laboratory researchers in vaccine development and evaluation.
Economic impact: This programme will provide data on which further development of paratyphoid vaccines will be based bringing further investment in the development cycle. There will also be strengthening of IP if the data show the vaccine to be efficacious with potential income generation once marketed. The results of the study could lead to funding by research councils and other translational research funders for further development of bacterial vaccines. In the regions where this vaccine would be deployed there are huge economic benefits of use of the vaccine by reducing out of pocket expenses for those requiring treatment and loss of income for those affected and their carers.
Maximising potential impacts:
Exploitation: The investment from funding in this proposal will build on research skills and infrastructure that has been developed in vaccine and human challenge studies in Oxford and build capacity in vaccinology and experimental medicine. We will also build on our programme in vaccine evaluation and growing understanding of correlates of protection against Salmonella infection. The data will be exploited to further develop the live attenuated paratyphoid vaccine and to provide evidence that will encourage development of alternative approaches to control of this infection.
Future research: The samples collected in human challenge studies provide a unique resource, not readily replicated, to interrogate correlates of protection. For this reason we have established a biobank at the Oxford vaccine Centre for curation of serum, cellular and genetic samples. We have an established process for sharing of data and clinical material that protects the integrity of the samples/data.
End-users: Should the approach be successful, demonstrate efficacy and lead to the identification of a correlate further development could be rapidly completed with larger scale safety and immunogenicity studies and a product in 5-10 years. The ultimate beneficiaries of this research are the children and adults in regions of the world with access to poor quality water and sanitation and travellers to these regions.