Defining immunogenic antigens in patients with Escherichia Coli and klebsiella pneumoniae bacteraemia in Vietnam and the UK

Summary 

Escherichia coli and Klebsiella pneumoniae are among the top three pathogens responsible for global deaths related to antimicrobial resistance (AMR). In Vietnam, a low and middle-income country (LMIC) with high rates of AMR, these two pathogens are leading causes of bloodstream infections (BSIs), with mortality rates exceeding 35%. Developing vaccines against E. coli and K. pneumoniae is challenging due to the presence of many disease-causing bacterial components (virulence factors) to target, significant variability between bacterial strains (serotypes), and the potential impact on the balance of healthy bacteria people carry in their gut (commensal strains). There are several vaccine candidates currently in clinical trials, and pre-clinical studies have highlighted virulence factors of interest, such as adhesins and iron acquisition proteins. We will use clinical cohorts of patients with BSIs and build on our experience in vaccine target discovery for other pathogens to define target proteins for E. coli and K. pneumoniae for development into vaccine candidates by our collaborating team. We will assess the immune responses (T-cell and antibodies) in patients with BSIs in Vietnam and the UK compared to responses in healthy individuals.

Project Outcomes

Each year many people around the world die from bacterial infections and increasing rates of antimicrobial resistance (AMR) indicate an emerging crisis where infections are becoming harder to treat and may become untreatable. Escherichia coli and Klebsiella pneumoniae are among the top bacteria responsible for global deaths related to AMR. In low and middle-income countries (LMIC) with high rates of AMR, access to antibiotics to treat these infections is difficult. The World Health Organization has recommended research on developing vaccines to prevent or reduce the impact of these infections as an important priority.Developing vaccines against these bacteria is challenging due to the presence of many disease-causing bacterial components (virulence factors) to target, significant variability between bacterial strains, and the potential impact on the balance of healthy bacteria people carry in their gut (commensal strains). There are several vaccine candidates currently in clinical trials, and studies in the bacteria themselves and in mouse models have highlighted virulence factors of interest. However, there is a crucial gap in knowledge around how humans respond to infection – especially which bacterial components are targeted during infection, and the contribution of the cellular arm of the immune response (T-cells) to protection.In this project we recruited patients and healthy volunteers from both UK and Vietnam. We used blood samples from patients with bloodstream infections (BSIs) and built on our experience in vaccine target discovery for other infections to define target proteins for E. coli and K. pneumoniae for development into vaccines and monoclonal antibody therapies. Our goal is to design “anti-disease” vaccines that stop people getting severely ill and reduce the chance of needing antibiotics or allow shorter courses of antibiotics. We assessed the immune responses in patients with BSIs in UK and Vietnam compared to responses in healthy individuals. We looked at antibody and T cell responses to 6 proteins from E. coli and 5 proteins from K. pneumoniae. We were able to identify antibody responses to all the proteins in both patients and healthy volunteers, in both UK and Vietnam, with higher antibody responses seen in patients compared to healthy controls in Vietnam but not in UK. T cell immune responses to the bacterial proteins were particularly interesting, because healthy volunteers in both UK and Vietnam had higher responses than patients with BSI. This supports the concept that boosting T cell immunity to key bacterial proteins in people at risk of infection could be helpful. In the future we plan to scale up the work to include bigger numbers of people. This will allow us to see if higher antibody and T cell responses are associated with better outcomes during BSI. This will allow us to select the most promising bacterial targets and make candidate vaccines using adenovirus vector and mRNA technologies established during the COVID-19 pandemic.