Protection against invasive non-typhoidal salmonella disease

ISRCTN	ISRCTN69516953
DOI	https://doi.org/10.1186/ISRCTN69516953
Wellcome Trust grant ref	310277/Z/24/Z
Sponsor	Imperial College London
Funder	Wellcome Trust

Submission date: 09/03/2026
Registration date: 25/03/2026
Last edited: 09/06/2026

Recruitment status: Recruiting
Overall study status: Ongoing
Condition category: Infections and Infestations

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

Background and study aims
This is a human infection challenge and re-challenge study investigating Salmonella Typhimurium, a member of the non-typhoidal Salmonella (NTS) subgroup.

NTS typically causes gastroenteritis, with symptoms such as diarrhoea, abdominal pain, and fever that resolve within a few days. In vulnerable groups, however, infection can progress to invasive non-typhoidal Salmonella (iNTS), where bacteria spread to the bloodstream or other sites. iNTS is most common in people with weakened immunity, including those with HIV, young children, the elderly, and individuals with risk factors such as malaria or sickle cell disease.

Globally, iNTS is a major health problem, particularly in sub-Saharan Africa, where it affects an estimated half a million people each year. The disease disproportionately affects children under five, many of whom are malnourished or have coexisting conditions. Preventive strategies, including vaccines, are urgently needed.

Who can participate?
Healthy adult volunteers aged between 18 and 50 years inclusive at time of the challenge.

What does the study involve?
This study, a “challenge and re-challenge” model, will expose participants to S. Typhimurium under controlled conditions. Participants will ingest a defined dose of the bacteria during a closely monitored inpatient stay, and then 3-6 months later will be re-challenged with the same strain. The aim is to understand how the immune system responds to repeated exposure, providing insights that can guide vaccine development.

Study Procedures and Visits
• Screening: Participants first attend an outpatient clinic for eligibility assessment.
• Challenge One: Seven days before the challenge, participants attend a clinic visit. On the challenge day, they are admitted to hospital quarantine for seven days. After discharge, they will receive daily telephone follow-up for six days, followed by an outpatient visit seven days later. Further visits occur on day 14 and day 28 post-challenge.
• Challenge Two: Conducted 3–6 months later, following the same schedule. Outpatient visits will also be held on day 14, day 28, and day 90 post-challenge.

Across both challenge periods, participants will be carefully monitored, with additional in-person assessments if symptoms occur or if the study team deems it necessary.

The study lasts approximately 6–9 months. Each participant will:
• Attend eight scheduled outpatient visits.
• Spend a total of 14 days in hospital quarantine.
• Receive 12 daily telephone calls after discharge.
• Additional visits may be arranged for safety reasons.

What are the possible benefits and risks of participating?
There is no direct health benefit to taking part in this Study. However, participants will receive information about their general health from screening tests. Participation in the Study will help improve understanding of Salmonella (NTS) and support the development of new vaccines, which will benefit our understanding and prevention of this disease.

The main risks that might affect participants include:
• developing a gut infection (gastroenteritis) with symptoms such as diarrhoea, stomach pain, fever, or vomiting.
• developing a more serious infection outside the gut, such as a blood infection (this is uncommon).
• side effects from antibiotics (for example, stomach upset, diarrhoea, or rash).
• rare complications after infection, such as irritable bowel syndrome (and other long-term bowel symptoms), carrying Salmonella in your gut for a long time, and reactive arthritis (joint pain or swelling after infection).
• passing the infection to close contacts if strict hygiene advice is not followed.

Where is the study run from?
Department of Infectious Disease, Imperial College London, UK.

When is the study starting and how long is it expected to run for?
August 2026 to December 2028.

Who is funding the study?
Wellcome Trust, UK.

Who is the main contact?
Dr Malick Gibani, m.gibani@nhs.net

Contact information

Dr Malick Gibani
Principal investigator, Public, Scientific

Department of Infectious Disease
Imperial College London
Sir Alexander Fleming Building (SAF.151)
Imperial College Rd
London
SW72AZ
United Kingdom

ORCID ID	0000-0003-1781-0053
Phone	+44 (0)7894 986332
Email	m.gibani@nhs.net

Study information

Primary study design	Interventional
Allocation	N/A: single arm study
Masking	Open (masking not used)
Control	Uncontrolled
Assignment	Single
Purpose	Basic science
Participant information sheet	ISRCTN69516953_PIS_V1.1_24Apr2026.pdf
Scientific title	Protection Against Invasive NTS Disease (PAiNTS) - Identifying correlates of protection and thresholds of protective immunity using a Salmonella Typhimurium challenge-rechallenge model
Study acronym	PAiNTS
Study objectives	Primary objective: To determine the attack rate of systemic Salmonellosis after challenge and re-challenge with Salmonella Typhimurium. Secondary objectives: 1. To describe the Salmonella colonisation rate following oral challenge and re-challenge with Salmonella Typhimurium. 2. To describe the rate of gastroenteritis following oral challenge or re-challenge with Salmonella Typhimurium. 3. To determine the fever rate following oral challenge or re-challenge with Salmonella Typhimurium. 4. To describe the Salmonella bacteraemia rate following oral challenge or re-challenge with Salmonella Typhimurium. 5. To describe the rate of systemic Salmonellosis according to an alternative composite diagnostic criteria following oral challenge or re-challenge with Salmonella Typhimurium. 6. To describe the safety of challenge and re-challenge with Salmonella Typhimurium. 7. To compare clinical features following oral challenge or re-challenge with Salmonella Typhimurium. 8. To compare microbiological features of gastrointestinal infection following oral challenge or re-challenge with Salmonella Typhimurium. 9. To compare microbiological features of bloodstream infection following oral challenge and re-challenge with S. Typhimurium. 10. To compare biochemical and haematological laboratory parameters following oral challenge or re-challenge with S. Typhimurium. 11. To describe and compare the serum antibody response following oral challenge and re-challenge with S. Typhimurium. Exploratory objectives: 1. To investigate how the human microbiota interacts with oral challenge of S. Typhimurium. 2. To investigate the impact of diet on the outcome of Salmonella challenge. 3. To describe and compare cell-mediated immune response following oral challenge with S. Typhimurium. 4. To describe and compare the mucosal antibody response following oral challenge and re-challenge with S. Typhimurium. 5. To investigate novel diagnostic methods for detecting S. Typhimurium infection. 6. To describe and compare additional host immune responses following oral challenge and re-challenge of S. Typhimurium D23580 strains. 7. To evaluate host-pathogen interactions following Salmonella infection including the presence and mechanisms of Salmonella persister infected macrophages. 8. To describe participant experience following oral challenge or re-challenge with S. Typhimurium. 9. To described epigenetic markers associated with susceptibility to Salmonella infection.
Ethics approval(s)	Approved 24/04/2026, London - Riverside Research Ethics Committee (2 Redman Place, Stratford, London, E20 1JQ, United Kingdom; +44 0207 104 8000; riverside.rec@hra.nhs.uk), ref: 26/LO/0316
Health condition(s) or problem(s) studied	Non-typhoidal Salmonella infection in healthy volunteers.
Intervention	This study is a challenge-rechallenge controlled human infection model of S. Typhimurium infection. After screening and a pre-challenge visit, participants will undergo their first challenge with S. Typhimurium D23580 at a dose of 1-5 x 10^5 Colony Forming Units (CFUs), termed the primary challenge. After a period of 3-6 months, participants will undergo a second challenge with S. Typhimurium D23580 at a dose of 1-5 x 10^5 CFU. The total study duration will be 6 – 9 months. Based on data from the first-in-human S. Typhimurium challenge study (CHANTS study; https://clinicaltrials.gov/study/NCT05870150), the dose used for the challenge will be 1-5 x 10^5 CFU. In volunteers without prior exposure to Salmonella, this dose is estimated to cause an attack rate of 57.9% (95%CI 37.3-73.8%) using a primary endpoint of fever ≥38°C and/or bacteraemia, when administered with sodium bicarbonate. This study will use the ST313 Lineage D23580 strain of S. Typhimurium. We will use GMP grade frozen batches of challenge stocks used in the CHANTS study. Stability testing has confirmed stable challenge doses over 2 years since manufacture.
Intervention type	Biological/Vaccine
Phase	Phase I
Drug / device / biological / vaccine name(s)	Salmonella Typhimurium
Primary outcome measure(s)	Sustained fever measured using tympanic temperature at daily assessments from day 0 to 7 Salmonella Typhimurium bacteraemia measured using blood culture positive at daily testing from day 0 to 14
Key secondary outcome measure(s)	Salmonella Colonisation measured using stool culture positive at daily testing from day 0 to 90 Salmonella gastroenteritis measured using clinical diagnosis at daily assessments from day 0 to 14 Mild, moderate or severe diarrhoea measured using the Bristol Stool Chart observation at daily assessments from day 0 to 14 Fever ≥38°C on ≥2 occasions ≥12 hours apart measured using tympanic temperature at daily assessments from day 0 to 14 Any fever measured using tympanic temperature at daily assessments from day 0 to 14 Salmonella bacteraemia alone measured using blood culture positive at daily tests from day 0 to 14 Salmonella Typhimurium bacteraemia with or without fever measured using blood culture positive, tympanic temperature at daily assessments from day 0 to 14
Completion date	30/12/2028

Eligibility

Participant type(s)
Age group	Adult
Lower age limit	18 Years
Upper age limit	50 Years
Sex	All
Target sample size at registration	50
Key inclusion criteria	1. Agree to give informed consent for participation in the study. 2. Aged between 18 and 50 years inclusive at time of challenge. 3. In good health as determined by medical history, physical examination, and clinical judgment of the study team. 4. Agree (in the study team’s opinion) to comply with all study requirements, including capacity to adhere to good personal hygiene and infection control precautions. 5. Agree to allow his or her General Practitioner to be contacted regarding participation in the study. 6. Agree to allow study staff to access their medical history and vaccination records via a shared electronic health record and/or to contact their GP to access medical records. 7. Agree to allow UKHSA and the local health protection team to be informed of their participation in the study. 8. Agree to give his or her close contacts written information informing them of the participant’s involvement in the study. 9. Agree to a period of inpatient quarantine in accordance with study protocols. 10. Agree to make every effort to be contactable 24/7 by study staff during the four weeks post challenge and re-challenge. 11. Agree to allow the study team to hold the name and 24-hour emergency contact number of a close friend, relative or housemate. 12. Agree to avoid antipyretic/anti-inflammatory treatment from the time of challenge (Day 0) until advised by a study doctor or until 14 days after challenge and re-challenge. 13. Agree to refrain from donating blood for the duration of the study. 14. Agree to provide their National Insurance/Passport number for the purposes of Trial over-volunteering prevention system (TOPS) registration and for payment of reimbursement expenses. 15. Be able to understand, retain, weigh up and communicate the study details as outlined in the participant information sheet.
Key exclusion criteria	1. History of microbiologically confirmed Salmonella infection prior to the primary challenge. 2. History of significant organ-specific and/or systemic disease that could interfere with trial conduct or completion. Including, but not restricted to: Cardiovascular disease, vascular disease, respiratory disease, haematological disease, endocrine disorders, renal/bladder disease, biliary tract disease, previous cholecystectomy, gastro-intestinal disease (including specifically a current requirement for antacids, H2-receptor antagonists, proton pump inhibitors or laxatives, inflammatory bowel disease and confirmed diagnosis of irritable bowel syndrome), neurological disease, metabolic disease, autoimmune disease, psychiatric illness requiring hospitalisation, known or suspected drug and/or alcohol misuse disorder, chronic/active infectious disease, severe infection requiring hospitalisation for intravenous antibiotics within the last 10 years, history of recent malaria infection, joint replacement, any orthopaedic/osseous implanted prosthesis, other internal implanted devices e.g. permanent pacemaker, any known or suspected impairment/alteration of immune function (including Human Immunodeficiency Virus infection, recent treatment for malignant disease with immunosuppressive chemotherapy or radiotherapy, solid organ or bone marrow transplant, recent high-dose steroid treatment). 3. Receipt of immunoglobulin or any blood product transfusion within 3 months of study start. 4. History of cancer (except squamous cell or basal cell carcinoma of the skin and cervical carcinoma in situ). 5. Moderate or severe depression or anxiety at screening or challenge. 6. Weight less than 50kg. 7. Anyone taking long-term medication (e.g. analgesia, anti-inflammatories or antibiotics) that may affect symptom reporting or interpretation of the study results. 8. Contraindication to cephalosporin, fluroquinolone, or macrolide antibiotics. 9. Female participants who are pregnant, lactating, or unwilling to ensure that they or their partner use effective contraception during the study. 10. Have a full-time, part-time, voluntary occupations or studies involving: Clinical healthcare work, social work with direct contact with young children (attending pre-school groups or nursery or aged under 2 years) or other clinically vulnerable children/adolescents, clinical or social work with direct contact with highly susceptible patients or persons, commercial food handling. 11. Have close household contact with: young children (attending pre-school groups, nursery or those aged less than 2 years), immunocompromised individuals, pregnant women, people over 70 years old. 12. Scheduled elective surgery or other procedures requiring general anaesthesia during the study period. 13. Participants who have participated in another research study involving an investigational product that might affect risk of Salmonella infection or compromise the integrity of the study within the 30 days prior to enrolment (e.g. significant volumes of blood already taken in previous study). 14. Detection of any abnormal results from screening investigations, unless deemed not clinically significant. 15. Any other social, psychological or health issues which, in the opinion of the study staff, may: put the participant or their contacts at risk because of participation in the study, adversely affect the interpretation of the primary endpoint data, impair the participant’s ability to participate in the study. 16. Have previously received any experimental Salmonella vaccine as part of a clinical trial or participated in previous Salmonella challenge studies (with ingestion of challenge agent). 17. Have a prolonged corrected QT interval (>450 milliseconds) on ECG screening. 18. Screening blood test positive for HLA-B27.
Date of first enrolment	14/08/2026
Date of final enrolment	01/08/2027

Locations

Countries of recruitment

United Kingdom
England

Study participating centre

Imperial College Healthcare NHS Trust

The Bays
St Marys Hospital
South Wharf Road
London
W2 1BL
England

Results and Publications

Individual participant data (IPD) Intention to share	Yes
IPD sharing plan	The datasets generated during and/or analysed during the current study will be stored in a non-publicly available repository to be created during the study as part of the program of activities. The datasets generated and/or analysed during the current study will be published as a supplement to the results publication.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Participant information sheet	version 1.1	24/04/2026	09/06/2026	No	Yes
Protocol file	version 1.1	24/04/2026	09/06/2026	No	No

Additional files

ISRCTN69516953_Protocol_V1.1_24Apr2026.pdf: Protocol file
ISRCTN69516953_PIS_V1.1_24Apr2026.pdf: Participant information sheet

Editorial Notes

09/06/2026: The following changes were made:
1. Ethics approval added.
2. Completion date was changed from 01/12/2028 to 30/12/2028.
3. Date of first enrolment was changed from 01/06/2026 to 14/08/2026.
4. Date of final enrolment was changed from 01/03/2027 to 01/08/2027.
10/03/2026: Study’s existence confirmed by the Wellcome Trust, UK.