Salmonella Paratyphi A controlled human infection model in an endemic setting: determining safety, dose escalation, and correlates of protection
Salmonella Paratyphoid A
This is an inpatient dose-finding controlled human infection model (CHIM) study of Salmonella Paratyphi A infection in healthy adult participants in Pakistan. In total, up to 60 participants will be recruited. Participants will be challenged with S. Paratyphi A (strain NVGH 308) beginning at a dose of 1-5 x 103 CFU/30 ml, the dose previously established to give a desired ‘attack’ rate of approximately 66% (as per prior Oxford Vaccine Group S. Paratyphi A studies: OVG 2013/07, REC Ref: 14/SC/0004; OVG 2014/01, REC Ref: 14/SC/1204, OVG 2018/07, REC Ref: 21/SC/0330). Because of pre-existing immunity in an endemic country, we anticipate that a higher dose of challenge may be required to successfully reach the target attack rate; the programme will therefore run as a dose-escalation study, increasing a log of the dose at a time for each cohort of 3-5 participants enrolled. Given this study is the first SPA CHIM in Pakistan, we will start with a cohort of 3 participants. The first cohort will be further split into two groups (1+2 participants with an interval of at least 7 days to monitor the safety closely. The first dose review by the Data Safety Monitoring Board (DSMB) will be conducted after the first 3 participants have been challenged and followed up for 14 days. The second cohort will be another 3 participants. After we challenged the first 6 participants (cohorts 1 and 2), the DSMB will review the safety data and if there are no safety concerns, we will increase the cohort size to 5 participants. A dose review will be done after each of the cohorts reaching the 14 days of follow-up. To ensure safety of the participants and also because of the lower reliability of closed-sanitation systems in Karachi, the study will be run on an inpatient basis at Aga Khan University (AKU) to ensure that volunteers are managed in a containment environment that avoids risk of onward transmission of paratyphoid A in the community (and conversely infection of the volunteers from cont
1. Willing and able to give informed consent. 2. Aged 18 -55yrs. 3. In good health as determined by medical history, physical examination and clinical judgment of the study team. 4. Available for all required appointments (agree to being residential in Karachi until confirmed clearance). 5. Able to comply with all study requirements, including infection control precautions. 6. Agree to medical record review. 7. Agree to avoid antipyretic/anti-inflammatory treatment from challenge until advised by a study doctor or until 14 days after challenge. 8. Agree to refrain from donating blood for the duration of the study. 9. Agree to avoid vaccination during the study period. 10. For participants of childbearing potential, they should be willing to ensure that they or their partner use effective contraception until confirmed clearance. 11. Agree to remaining admitted in the hospital and take leave from work for a period of 10-20 days
1. History of significant organ/system disease that could interfere with study conduct or completion, in the opinion of the study team. Including, for example, but not restricted to: 1.1 Cardiovascular disease 1.2 Respiratory disease 1.3 Haematological disease 1.4 Endocrine disorders 1.5 Renal or bladder disease, including history of renal calculi 1.6 Biliary tract disease, including biliary colic, asymptomatic gallstones or polyps or previous cholecystectomy 1.7 Gastro-intestinal disease including chronic diarrhoea, inflammatory bowel disease, irritable bowel syndrome or diseases requiring use of regular antacids, H2-receptor antagonists, proton pump inhibitors, laxatives or prokinetic agents 1.8 Neurological disease 1.9 Metabolic disease 1.10 Psychiatric illness requiring hospitalisation, or other mental health condition 1.11 Known or suspected drug abuse 1.12 Known or suspected alcohol misuse 1.13 Infectious disease 1.14 Coagulation disorder 2. Known or suspected impairment of immune function, alteration of immune function, or prior immune exposure that may alter immune function to paratyphoid, resulting from, for example: 2.1 Congenital or acquired immunodeficiency, including IgA deficiency 2.2 History of auto-immune disease 2.3 Human Immunodeficiency Virus or symptoms/signs suggestive of an HIV-associated condition 2.4 Receipt of immunosuppressive therapy such as anti-cancer chemotherapy or radiation therapy within the preceding 12 months or long-term systemic corticosteroid therapy 2.5 Receipt of immunoglobulin or any blood product transfusion within 3 months of study start 2.6 History of cancer (except squamous cell or basal cell carcinoma of the skin and cervical carcinoma in situ) 3. HLA-B27 positive. 4. Moderate or severe depression or anxiety as classified by the Hospital Anxiety and Depression Score at screening or challenge that is dee