Pump-Priming Project Awards - Round 10 Awardees

Dr Prisca Benedicto-Matambo

Lecturer
Kamuzu University of Health Sciences
Malawi

Collaborators:

Dr Khuzwayo Jere, Senior Lecturer, University of Liverpool, UK

Professor Nigel Cunliffe, Professor, University of Liverpool, UK

Summary

Shigellosis remains one of the leading bacterial aetiologies of diarrhoea associated mortality and morbidity globally. One third of these deaths occur in children under the age of 5 and the burden is significantly high in low-and middle-income countries such as Malawi. Vaccination against shigellosis is one practical means of lessening disease burden in endemic settings and yet no licenced Shigella vaccines are available to date. Several promising candidate vaccines are being evaluated at different stages of preclinical and clinical development. Comprehensive understanding of host immune responses to Shigella through robust and well-established immunological assays is pivotal to accelerate shigella vaccine development. Whilst significant advances are underway towards unravelling correlates of protection against shigella, fewer studies have dissected the role of T cell mediated Immunity in naturally exposed individuals in an African context.

Successful evaluation of T cell mediated immunity against Shigella will complement efforts aimed at deciphering correlates of protection to natural and potential shigella vaccine candidates.

We plan to conduct functional assays to dissect the role of T cell mediated immunity against Shigella in a potentially disease burdened setting (Malawi) by leveraging archived blood samples collected from a well-established diarrhoea surveillance (Diasurv) platform. Findings from this project has several important implications including advancing our knowledge on T cell mediated immunity to Shigella which is a rarely investigated and yet equally important component of adaptive immune system. In addition, this work will complement the ongoing Shigella serology underway in Malawi whilst also building in-country capacity and expertise in readiness for future vaccine trials.

Dr Caroline Chisenga

Acting Head-Enteric Disease and Vaccine Research Unit
Centre for Infectious Disease Research in Zambia
Zambia

Collaborators:

Professor Dani Cohen, Professor of Epidemiology and Preventive Medicine, Tel Aviv University, Israel

Professor Gad Frankel, Professor of Molecular Pathology, Imperial College London, UK

Summary

Shigella is a major cause of severe diarrhoea and dysentery worldwide, especially in low- and middle-income countries, where it leads to 190 million cases each year and causes 11% of diarrhoea-related deaths. It is often linked to malnutrition and can negatively affect children’s physical and mental development. Currently, no licensed vaccine exists for Shigella, and treatment relies on rehydration and antibiotics, but resistance to antibiotics is becoming a big problem.

Efforts to create a vaccine are underway, with some potential vaccines being tested in children in these countries. It’s important to understand how the disease spreads and how the body naturally fights it in areas where vaccines will be used.

In our study, we are building on earlier research in Zambia, where we tracked Shigella antibodies in infants. We will now follow a new group of children from 6 weeks to 3 years old. Our goal is to study how the body’s immune system responds to Shigella through antibodies during natural exposure to the bacteria.

We will use blood and stool samples from 214 Zambian infants who were part of a vaccine trial. These samples were taken at different ages and will help us understand how Shigella infections are linked to antibody levels and the body’s immune response. This research will inform the development of future vaccines and help characterize the antibodies needed to protect young children from Shigella.

Dr Giuseppe Ercoli

Senior Research Associate
University College London, UK

Collaborator:

Dr Brenda Anna Kwambana-Adams, Wellcome International Intermediate Fellow & Senior Lecturer (Career Track), Malawi Liverpool Wellcome Programme (MLW), Malawi

Summary

Streptococcus pneumoniae (the pneumococcus) causes pneumonia, sepsis and meningitis, particularly affecting vulnerable groups like young children, the elderly, and people with weakened immune systems (e.g. adults living with HIV). While effective vaccines are available for young children, their high cost means adults often remain unprotected, with pneumococcus representing a very common cause of serious infections and death, particularly in sub-Saharan Africa (sSA) where it has been linked to several outbreaks in the past years. Improved vaccine-based control of the pneumococcus would help to decrease antibiotic use linked to infections and reduce the spread of antimicrobial resistance.

We will tackle these challenges by developing a more affordable pneumococcal vaccine for adults based on protein antigens. All humans have antibody responses to pneumococcal proteins that can prevent infections caused by multiple pneumococcal serotypes. Our data, obtained using samples from Ghanaian and UK adults, show that antibody levels to these protein antigens fall with age. We reason that boosting antibody levels to these protein antigens by vaccination could protect older adults from pneumococcal disease. Using our protein array, we will compare systemic antibody responses to 250 pneumococcal proteins among 3 cohorts of subjects from Malawi: healthy adults, HIV infected and older adults (>65). The results will be compared with our existing data for Ghanaian and UK adults to identify against which proteins antibody levels fall with age across all three countries. These proteins will be used as a potential vaccine to reduce both pneumococcal disease and antimicrobial resistance in high-risk adults.

Dr Malick Gibani

Clinical Lecturer in Infectious Diseases
Imperial College London, UK

Collaborators:

Dr Megan Elizabeth Carey, Postdoctoral Policy Fellow, London School of Hygiene & Tropical Medicine, UK

Miss Laura Alvarado Cruz, Public Involvement and Project Officer, Patient Experience Research Centre (PERC), Imperial College London, UK

Summary

Plague – caused by the bacterium Yersinia pestis – is a historic pandemic disease that still poses a threat today. It remains endemic in several countries across Africa, South America, and Asia, where it can spread from animals to humans. There are concerns about its use in bioterrorism. Despite the need for newer, more effective plague vaccines, generating enough clinical data for their approval is difficult.

We aim to accelerate development of vaccines against Yersinia pestis by creating a human vaccine-challenge study. Although it's unethical to expose healthy people to natural disease-causing bacteria, we propose using weakened vaccine-strain bacteria (from a well-established vaccine called EV76) as a model. This vaccine has been given to millions of people and it has a good safety profile.

Our project aims to lay the groundwork for a proposed future clinical trial, with two packages of work covering public engagement and strain characterisation.

Firstly, we will undertake a programme of public engagement to explore the public attitudes to a proposed challenge study using a weakened version of the plague bacteria. Secondly, we will characterise the EV76 challenge-vaccine, by examining its genetic makeup and how it relates to circulating strains. We will establish partnerships with global collaborators in countries where plague is present, to build a consortium for future clinical trials and surveillance activities.

This project is the first step in evaluating a new model for testing plague vaccines and will help build partnerships for future research.

Project outcomes

Yersinia pestis is the causative agent of plague – the archetypal bacterial pandemic disease. Plague remains endemic in several countries in Africa, South America, and Asia, posing a high risk of epidemic spread from zoonotic spill-over. There is also a possible threat from use as a bioterrorism weapon. Generating sufficient field data for vaccine licensure is challenging, because outbreaks are unpredictable and the number of cases relatively low. The project funded by BactiVac has enabled the development of the foundations for a human vaccine-challenge study (using an old generation attenuated bacterial strain that has been deployed in some countries as a vaccine) to accelerate development of Yersinia pestis vaccines. Firstly, we were able to explore public attitudes to developing a Yersinia pestis challenge model, which generated key insight points around the overall acceptability and the importance of clear language around giving people an attenuated, non-pathogenic strain of bacteria as part of the study. Secondly, we were able to confirm that the Yersinia pestis bacterial strain we are hoping to use is closely related to currently circulating strains, both in terms of genetic sequence and conservation of key vaccine antigens. Finally, we have been able to bring together a consortium of global experts to work together on developing a Yersinia pestis challenge model.     

Dr Kristin Huse

Post Doctoral Research Associate
Imperial College London
UK

Collaborators:

Professor Shiranee Sriskandan, Professor of Infectious Diseases, Imperial College London, UK

Dr Claire E. Turner, Research Fellow, University of Sheffield, UK

Professor Thushan De Silva, Professor of Infectious Diseases, University of Sheffield, UK

Summary

Streptococcus pyogenes, also known as group A streptococcus or Strep A, causes over half a million deaths annually by triggering rheumatic heart disease and further deaths due to serious invasive infections such as sepsis and flesh-eating infections. These deaths could be prevented if there was a vaccine against Strep A. In 2018, the World Health Organisation (WHO) identified Strep A as a priority for vaccine development. For a vaccine to work as well as possible, it needs to raise an immune response against a target that is made by all strains of Strep A, made in large amounts, and ideally is located on the surface of the bacteria so that cells of the immune system can effectively find and destroy bacteria in the body. There are a few Strep A vaccines currently being developed that share targets. We have developed a test to measure the amount of each target on the surface of the Strep A bacteria that uses a tagging system known as fluorescence. We will use this test on strains of Strep A from sore throats and skin infections from London, UK, and Sukuta, the Gambia, to measure how much of each antigen is on the surface of these bacteria. This will help us predict how well the vaccines in development would protect against Strep A in different parts of the world. This will help us decide which vaccine would best protect against Strep A across the whole globe.

Project outcomes

Strep A remains a global health burden, causing a high burden of disease and mortality, especially in low and middle income communities. Despite this, there is currently no vaccine commercially available. Much of the vaccine development pipeline focuses on multicomponent vaccines, which combine a number of well conserved proteins to help increase coverage of the vaccine. While we know that these proteins are well conserved at a genetic level, little research so far has focused on the actual expression levels of these proteins – low expression would of course decrease the potential efficacy of a vaccine. We compared the expression of three potential vaccine antigens present in at least two multicomponent vaccines in development – the Strep A surface proteins SpyCEP and ScpA, and the Group A carbohydrate (GAC). We used two globally distinct collections of Strep A bacterial strains, one from West London and one from The Gambia, to capture the global diversity of strains. Employing a flow cytometry based assay, we were able to analyse over 400 strains of Strep A, representing a breadth of serotypes. Fortunately, many of the strains from The Gambia showed greater expression of vaccine antigens than those from West London, suggesting that the multicomponent vaccines in development would provide good coverage of the strains circulating in the area. We were also able to identify several serotypes which had low expression of two or all three vaccine antigens, showing that work is required to ensure that these strains would still be protected against by the multicomponent vaccines in development. 

Dr Tanya Monaghan

Clinical Associate Professor
Honorary Consultant Gastroenterologist
University of Nottingham, UK

Collaborators:

Dr Donna Bryan, Principal Scientist, MHRA, UK

Dr Kevin Markey, Head of Respiratory Bacteria and Toxin vaccines, MHRA, UK

Dr Paul Stickings, Head of Vaccine Reference Materials, MHRA, UK

Summary

Clostridioides difficile infection, termed CDI, is caused by colonisation of the human intestine by a bacterium. Normally the millions of bacteria in the gut prevent disease-causing bacteria like C. difficile from causing a problem. However, antibiotics that we may take for an infection elsewhere (e.g., a chest infection) can damage these defences, allowing C. difficile to move in, grow and produce toxins (poisons) that affect the gut lining, resulting in diarrhoea. This ability to take over and invade the intestines when other bacteria are missing makes C. difficile an ‘opportunistic’ pathogen. Hospitals diagnose CDI by detecting toxin in faeces (poo). It is important to detect the toxin rather than the bacteria because it can be present without producing toxin or causing symptoms (asymptomatic carriage). CDIs are considered an emerging health treat worldwide. Uptake of C. difficile bacterial spores through ingestion (swallowing) can result in asymptomatic carrier status or lead to CDI that could range from mild diarrhoea, eventually developing into inflammation of the bowel, and in some cases, a grossly distended bowel (toxic megacolon) that often results in high mortality. Several potential vaccines have been studied in clinical trials for CDI but there is a lack of standard or reference reagents to standardise immune, functional, or cytotoxic (toxic to cells) assays necessary for the evaluation of efficacy and quality of these vaccines. Hence the development of a human serum reference is essential. Human sera containing defined units of anti C. difficile toxins antibodies would enhance vaccine development and assist in disease surveillance.

Project outcomes

Clostridioides difficile (C. difficile) is a major cause of severe diarrhoea, particularly in people who have received antibiotics or are in hospital. It can lead to serious complications, prolonged hospital stays, and in some cases death. Although new vaccines are in development to prevent C. difficile infection, we do not yet have reliable ways to measure whether these vaccines work. Currently, laboratories use different tests to measure antibodies (the immune system’s defence proteins) against C. difficile toxins, which makes it difficult to compare results across studies.The goal of our project was to help solve this problem by developing the first World Health Organization (WHO) International Standard for human anti-C. difficile toxin neutralising serum. Such a standard will make it possible for laboratories around the world to use the same reference material, improving the consistency of results and supporting vaccine development.To achieve this, we identified and recruited 30 patients with confirmed C. difficile infection from Nottingham University Hospitals. After obtaining informed consent, we collected blood samples and processed these into serum. The serum samples were then sent to the UK Medicines and Healthcare products Regulatory Agency (MHRA), where they will be tested for safety (screened for blood-borne infections) and characterised for levels of anti-toxin antibodies.The samples collected during this project will be combined to create a single reference material that can be distributed globally to research laboratories, vaccine developers, and public health agencies. This work represents a critical first step in creating an internationally recognised standard that will reduce variability between laboratories and make future C. difficile vaccine trials more robust.Our work was completed within the planned timeframe and achieved its primary objective of recruiting the required number of donors and delivering sera for further processing. This project lays the foundation for global standardisation of C. difficile antibody testing, which is essential for developing effective vaccines to prevent this dangerous infection and reduce reliance on antibiotics.

Dr Vartul Sangal

Assistant Professor
Northumbria University, UK

Collaborators:

Professor Stephen Todryk, Professor of Immunology, Northumbria University, UK

Professor Balaji Veeraraghavan, The Hilda Lazarus Core Research Chair, Christian Medical College & Hospital, India

Dr Ankur Mutreja, Director of Strategy, Partnerships and Communications, South Asia, PATH, New Delhi, India

Summary

Diphtheria, a disease caused by the bacterium Corynebacterium diphtheriae, causes significant illness and death across the world. The numbers of cases are constantly rising, with a 5-fold increase between 2015 and 2019.

The current diphtheria toxoid vaccine induces antibodies that only neutralise the toxin but do not eliminate the pathogen. However, new toxin variants C. diphtheriae strains are in global circulation including some with high-impact mutations, introducing structural modifications to the toxin that may result in vaccine escape and failure of anti-toxin treatment. In addition, non-toxigenic strains are causing severe invasive infections which is further exaggerated by emerging multidrug resistance (MDR), limiting the choice of treatment. Therefore, a more effective vaccine is needed to address these challenges.

We have identified three proteins that are highly conserved within the species and were present in diphtheria vaccines. These proteins are essential for the bacterium’s survival and are either membrane-associated or secreted which makes them highly suitable vaccine candidates. Furthermore, they contain peptides which we have predicted to be highly immunogenic, both for antibody and T-cell immunity.

In this study, we will perform immunogenic screening of these peptides for antibody and T-cell response. The findings will help selecting highly immunogenic peptides for successfully designing a multiepitope vaccine that will be able to neutralise the pathogen and eliminate cells infected by emerging nontoxigenic, MDR and toxin variant C. diphtheriae strains.

Project outcomes

Reverse vaccinology approach is highly effective in identification of promising vaccine targets. We screened overlapping peptides spanning three proteins that were identified using reverse vaccinology approach for humoral (antibody) and cell-mediated immune response. The results are quite promising as several peptides from two of these proteins induced significant humoral and/or cell-mediated responses, some of which were comparable to the response induced by the toxin peptides. Please note that current toxoid vaccine is inactivated toxin that has been highly successful in protecting from toxin-mediated disease, diphtheria. However, it is not effective against multidrug-resistant nontoxigenic strains of Corynebacterium diphtheriae that are causing severe infections around the world. Also, mutations in the toxin encoding gene that are capable of introducing high-impact structural changes have been reported, which may influence the efficacy of current vaccine against these mutants. We found antibodies against some of the peptides were cross-reactive to the whole proteins, i.e., they have potential to eliminate the pathogen. These findings are very exciting, providing proof-of-concept for further characterisation of these peptides/proteins that may result into development of a highly effective diphtheria vaccine to address challenges posed by emerging nontoxigenic, MDR and toxin variant C. diphtheriae strains.

Dr Tahir Yousafzai

Assistant Professor
The Aga Khan University, Pakistan

Collaborators:

Dr Megan Carey, Postdoctoral Research Fellow, London School of Hygiene & Tropical Medicine, UK

Dr James Meiring, Senior Clinical Lecturer, University of Liverpool and Malawi Liverpool Wellcome Trust Clinical Research Programme, UK

Dr Farah Qamar Naz, Professor, The Aga Khan University, Pakistan

Summary

Salmonella enterica serovar Typhi (S. Typhi) is the causative agent of typhoid fever and is responsible for over 100,000 deaths annually, particularly among young children in South Asia and sub-Saharan Africa. Typhoid conjugate vaccines (TCVs) were recommended for use in typhoid-endemic areas, particularly those where AMR is a problem, by the World Health Organization (WHO) in 2018. TCVs have been shown to be safe and efficacious across multiple settings, but the evidence base for the impact of TCVs against AMR is scarce. Vaccines may have an impact on antimicrobial resistance (AMR) both through the prevention of infections caused by drug-resistant pathogens (direct effect) and through the reduction of antimicrobial use (AMU, indirect effect) through the prevention of primary and or secondary infections. TCVs have been shown to be effective against extensively drug resistant (XDR, resistant to first-line antimicrobials chloramphenicol, ampicillin, and cotrimoxazole as well as fluoroquinolones and third-generation cephalosporins) S. Typhi in Hyderabad, Pakistan, but the evidence base for the impact of TCVs is still weak. We aim to leverage an ongoing post- TCV introduction impact study in Karachi, Pakistan, where XDR typhoid is prevalent, to assess the impact of TCVs on preventing antimicrobial use among vaccine recipients. By reducing antimicrobial use, TCVs can slow the emergence and spread of AMR among S. Typhi and potentially lead to lower selection pressure on other organisms.

Project outcomes

This project looked at the impact of Typhoid Conjugate Vaccine (TCV) on antimicrobial use among children with suspected typhoid fever in Pakistan. Between 2020 and 2025, the study enrolled 29,892 children under 20 years of age. Out of these, 7,224 children (24%) had received TCV. Children were enrolled from outpatient departments (OPD), emergency, and inpatient. More than half of the enrolled children (16,512; 55.2%) were boys. Almost half (14,644; 49.0%) were under 5 years old, and 745 (2.5%) were aged 15 years or older. Children who had been vaccinated with TCV tended to be younger. Vaccinated children were also more often enrolled from OPDs (33.5% vs. 26.8%). Overall, 4,912 children (16%) had blood cultures positive for Salmonella Typhi, the bacteria that causes typhoid.
Among those enrolled through passive surveillance, 90% received at least one antibiotic on the same day they were enrolled. The types of antibiotics used included:

• Imipenem or meropenem: 4,677 children (16%)
• Third-generation cephalosporins: 19,962 children (67%)
• Azithromycin: 4,771 children (16%)

Several clinical factors affected antibiotic use. For any antibiotic, current hospitalization (OR=19.34), having taken antibiotics before arriving (OR=1.70), and having a positive S. Typhi blood culture (OR=1.54) all increased the chance of being prescribed antibiotics. For azithromycin, being hospitalized reduced its use (OR=0.39), but prior antibiotic use (OR=1.36) and a positive blood culture (OR=2.12) increased it. Carbapenem use also increased with hospitalization (OR=11.8), prior antibiotics (OR=1.59), and positive blood culture (OR=4.26). However, third-generation cephalosporin use was lower with previous hospitalization (OR=0.54) and positive blood cultures (OR=0.48).
Among unvaccinated children, 90.9% received an antibiotic at enrolment compared with 88.3% of vaccinated children. Simple comparisons showed that vaccinated children had lower odds of receiving:

• Any antibiotic (OR 0.76; 95% CI: 0.70–0.82)
• Cephalosporins (OR 0.83; 95% CI: 0.78–0.87)
• Carbapenems (OR 0.90; 95% CI: 0.84–0.97)

Azithromycin use was slightly higher among vaccinated children (OR 1.15; 95% CI: 1.07–1.23).

Multivariable analyses showed the vaccine’s effects differed by year, age, province, and hospitalization status. For overall antibiotic use, reductions among vaccinated children were strongest in 2023 (OR=0.62) and 2024 (OR=0.55). Lower use was also seen in Sindh (OR=0.74) and among children aged 5–<15 years (OR=0.71). For third-generation cephalosporins, reduced use was seen in 2023–2024 (OR=0.69–0.79) and among vaccinated children who were not hospitalized (OR=0.76). For carbapenems, reductions were seen in 2023 (OR=0.77) and 2025 (OR=0.50), especially among those without prior hospitalization (OR=0.90). For azithromycin, use increased with more time since vaccination (OR=1.23–1.60 for 2–<5 years post-vaccination). Higher use occurred in Punjab/Islamabad (OR=1.33), and among younger children: under 2 years (OR=1.63) and 2–<5 years (OR=1.16).
These results show that Pakistan’s TCV introduction is linked with meaningful reductions in antibiotic use, including important antibiotics like carbapenems. The slight increase in azithromycin use may reflect that vaccinated children are now more likely to seek care for illnesses other than typhoid. Because the study only included children who came to health facilities, the true reduction in antibiotic use due to TCV may be even greater than what was observed.