Protection Against Invasive NTS Disease (PAiNTS) - Identifying correlates of protection and thresholds of protective immunity using a Salmonella Typhimurium challenge-rechallenge model
Non-typhoidal Salmonella infection in healthy volunteers.
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.
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.
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,