Development of a vaccine against Salmonella Paratyphi A
| ISRCTN | ISRCTN15485902 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN15485902 |
| EudraCT/CTIS number | 2021-003259-41 |
| IRAS number | 249094 |
| Secondary identifying numbers | CPMS 50702, MR/R025347/1, IRAS 249094 |
- Submission date
- 14/02/2022
- Registration date
- 14/02/2022
- Last edited
- 20/12/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Infections and Infestations
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data
Record updated in last year
Plain English Summary
Background and study aims
Typhoid and Paratyphoid fever are both forms of an illness called enteric fever. Their names come from the bacteria that cause them: Salmonella Typhi (typhoid) and Salmonella Paratyphi A (paratyphoid). They both cause high fevers, headache, muscle and joint aches, abdominal pain, constipation and feeling generally unwell. If severe or left untreated, it can result in complications, long-term carriage of the bacteria or death.
There are approximately 14.3 million cases of enteric fever every year, with 3.3 million of these due to paratyphoid. It is spread by the faeces of an infected person, typically via contaminated water or food. It is found in parts of the world where people have inadequate access to clean water and sanitation.
Effective vaccines against typhoid fever already exist but there are no licensed vaccines against paratyphoid fever yet. The University of Maryland have developed an oral paratyphoid vaccine. It has already been given to humans and was shown to be safe. It now needs testing to see if it might prevent disease.
The Oxford Vaccine Group has developed a method of testing enteric fever vaccines called controlled infection or “challenge” studies whereby participants are given the vaccine and later a dose of the bacteria which can cause disease. Participants are then monitored closely to see if they become unwell and then treated with effective antibiotics. This model of studying vaccines has been undertaken by participants in previous Oxford Vaccine Group studies since 2011.
This study aims to assess the efficacy of a new oral paratyphoid vaccine using a human challenge study. It will also extend our knowledge on the immune response to paratyphoid infection and oral vaccination against paratyphoid.
Who can participate?
Healthy adult volunteers aged 18 - 55 years
What does the study involve?
In this study we will give participants either two doses of the oral paratyphoid vaccine that is being tested (CVD 1902) or a placebo, 14 days apart. Twenty-eight days after the second vaccine or placebo dose all participants will then be given the “challenge”(a dose of Salmonella Paratyphi A). We will be looking to see if the vaccine prevents disease.
Following challenge, all participants are monitored closely and are treated with antibiotics if they become unwell, or 14 days after drinking the bacteria, whichever is sooner.
The planned study visits will take place over a period of 14 months and during this period participants will be seen multiple times, including daily for 2 weeks during the period of challenge. Participants will also be asked to keep an online diary of their symptoms during both the vaccination and challenge period.
What are the possible benefits and risks of participating?
The risks to participants in this study are low but are associated with the potential side effects of the vaccine, symptomatic infection following challenge and the risk of subsequent complications, for example chronic carriage of S. Paratyphi A. These risks are all minimised by strict inclusion and exclusion criteria to the trial, recording of symptoms by participants in a daily e-diary, presence of an on-call 24-hour team, regular in-person reviews by the study team including daily during challenge and prompt treatment of all cases of infection. In addition, there is a very small risk of onward transmission of paratyphoid to close contacts of participants. Again, this is minimised by strict inclusion and exclusion criteria and by emphasising the importance of good hand hygiene to the participants throughout the trial.
There is no direct benefit to participants taking part in this study. Participants may benefit from being informed about their general health status, for example from study tests such as blood tests.
Where is the study run from?
Oxford Vaccine Group at the Centre for Clinical Vaccinology and Tropical Medicine (CCTVM) at the Churchill Hospital in Oxford (UK)
When is the study starting and how long is it expected to run for?
June 2021 to February 2025
Who is funding the study?
Medical Research Council (UK)
Who is the main contact?
1. Miss Sophie Vernon, sophie.vernon@paediatrics.ox.ac.uk
2. Dr Margaret Paganotti Vicentine, margarete.paganottivicentine@paediatrics.ox.ac.uk
3. Dr Naina McCann, naina.mccann@paediatrics.ox.ac.uk
Contact information
Miss Sophie Vernon
Scientific
Scientific
CCVTM
University of Oxford
Churchill Hospital
Oxford
OX3 7LE
United Kingdom
| sophie.vernon@paediatrics.ox.ac.uk |
Dr Margaret Paganotti Vicentine
Scientific
Scientific
CCVTM
University of Oxford
Churchill Hospital
Oxford
OX3 7LE
United Kingdom
| margarete.paganottivicentine@paediatrics.ox.ac.uk |
Dr Naina McCann
Scientific
Scientific
CCVTM
University of Oxford
Churchill Hospital
Oxford
OX3 7LE
United Kingdom
| naina.mccann@paediatrics.ox.ac.uk |
Study information
| Study design | Interventional randomized controlled trial (multi-centre) |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details to request a participant information sheet |
| Scientific title | Development of a live attenuated vaccine against Salmonella Paratyphi A |
| Study acronym | VASP |
| Study hypothesis | The purpose of this study is to assess the efficacy of the orally-administered live-attenuated vaccine CVD 1902 and extend our knowledge of the immune response both to S. Paratyphi A infection and vaccination. |
| Ethics approval(s) | Approved 19/11/2021, South Central - Berkshire Research Ethics Committee (Level 3, Block B, Whitefriars, Lewins Mead, Bristol, BS1 2NT, UK; +44 207 104 8121; berkshire.rec@hra.nhs.uk), ref: 21/SC/0330 |
| Condition | Development of a live attenuated vaccine against Salmonella Paratyphi A |
| Intervention | Vaccination days and post vaccination visits Vaccine randomisation will be completed on the 1st vaccination day. We will also complete an interim medical assessment; check vital signs, urine test for participants of childbearing potential, and collect blood, saliva and stool samples. We will take blood and stool samples on all visits whilst saliva samples will only be taken on selected visits. We ask that all participants drink a solution of sodium bicarbonate to neutralise their stomach acid. Then, one minute later the CVD 1902 vaccine (or placebo) will be given to participants to drink. We would also give participants access to a web-based electronic diary (e-diary), and a thermometer to take daily temperatures. We ask participants to record their temperature twice daily and any symptoms every day for one week after each vaccination. After receiving the first vaccine (day -42), we will see participants after a week (day-35). A second vaccination will be given 14 days after the first vaccine (day -28). Participants will then have a further follow up visits prior to challenge (Day -21). During these post-vaccination visits we would review the e-diary for symptoms, ask if any medications have been taken, and obtain further blood and stool samples to make sure the bacteria has been cleared. At some visits saliva samples will also be taken (both vaccination days, day 0 (challenge), day 1 and day 2, at day 28, day 90, day 180, day 365). Challenge day (day 0) Start of the intense monitoring period Participants are asked to provide stool samples and blood is collected from all participants. Participants of childbearing potential will have a urinary pregnancy test performed. We would perform a mood assessment and set up the electronic diary for the challenge period. Participants will be asked to fast for 90 minutes before the visit. They will be given a solution of sodium bicarbonate (to neutralise stomach acid) followed by a drink containing Salmonella Paratyphi A bacteria. At follow up visits e-diary entries will be reviewed, observations will be taken plus blood and stool samples. Participants will be seen daily until one of two outcomes: 1. We anticipate some participants will not develop infection (anticipated one third in the placebo arm). They will be seen daily for 14 days. On day 14 post challenge they will be given a treatment course of antibiotics. Participants of childbearing potential will have a urine pregnancy test before they start antibiotics. They will then be telephoned on day 21 after challenge to check on their progress and reviewed in person at day 28 post challenge. 2. For the remaining participants (anticipated two thirds in the placebo arm) they will be seen daily, until 14 days post challenge until the point at which they receive a diagnosis of paratyphoid infection (either from the result of a blood test result or reaching the diagnostic criteria by symptoms). At this point they will be asked to come back for a diagnostic visit where blood and stool samples will be taken. They will be started on a course of antibiotics at this visit. Participants of childbearing potential will have a urine pregnancy test before they start antibiotics. For safety reasons, participants are seen at approximately 12, 24, 48, 72 and 96 hours after their diagnostic visit. If no other visit is scheduled for day 14 post challenge date they will also be seen (this would only occur in those diagnosed before day 10). They will then be telephoned on day 21 after challenge to check on their progress and reviewed in person at day 28 post challenge. For safety reason pregnancy tests will be performed on participants of childbearing potential before both vaccinations, prior to challenge, prior to starting antibiotics ie at day 14 if not diagnosed, or at the diagnostic visit if participants are diagnosed. Long term follow up All participants will have follow up visits at day 90, day 180, day 365 where blood, saliva and stool samples will be taken. Mood assessment will be performed at baseline (-42), at challenge visit (day 0), at day 7 post challenge and at day 14 post challenge or at paratyphoid diagnosis. Vital signs, physical examination, blood and urine sampling, ECG, and mood assessment can be performed at any stage in the study if felt to be clinically indicated. From these procedures we will collect data including: - proportion of participants diagnosed with infection following challenge in the vaccine and placebo groups - safety and tolerability of the CVD 1902 - the immune response to the vaccine alone and following challenge which may correlate with protection from disease. 1. Vaccine: CVD 1902 CVD 1902 is a live attenuated strain of Salmonella Paratyphi A, an unlicensed, experimental oral vaccine for Salmonella Paratyphi A infection developed by the Center for Vaccine Development at the University of Maryland in Baltimore. A dose contains not less than 2 x 10^10 CFU and vaccine recipients in this trial will receive 2 doses delivered in 30 mL carrier sodium bicarbonate solution, 14 days apart. 2. Placebo: The vaccine placebo is 30 mL 1.3% w/v sodium bicarbonate solution made up using BP sodium bicarbonate powder with sterile water. 3. Pre-treatment: Sodium bicarbonate solution for both vaccine and placebo arms. Both groups will receive 120 mL of sodium bicarbonate solution prior to vaccine or placebo. Sodium bicarbonate solution will be reconstituted from pharmaceutical grade sodium bicarbonate powder and sterile water at a concentration of 1.3% w/v. Sodium bicarbonate powder and sterile water for the pre-treatment bicarbonate solution prior to vaccine and challenge administration will be stored in a secure drug cupboard within a temperature-controlled room. 4. S. Paratyphi A challenge strain. A parent seed lot, S888P5SP01, was established in March 2010 after serial colony selections on Luria Broth PTK agar plates and stored in the Novartis Vaccines and Diagnostics bacterial seed bank (Siena, Italy). This lot was used to establish the GMP Master Cell Bank, SA-13-002. Under GMP conditions in GenIbet BioPharmaceuticals, Portugal, 3 dose levels of the challenge agent were produced in chemically-defined media, using sucrose as the carbon source, to prepare a bulk bacterial suspension (Active Substance, 00513). Prepared vials containing the challenge agent were stored at -80°C ± 5°C and transferred to the Oxford Vaccine Group Laboratory in 2013. 5.. Antibiotics. Antibiotics are used to treat diagnosed Salmonella Paratyphi A infection or at day 14 post challenge for those who have not been diagnosed. 6. Other medications These will be used, if required, to treat symptoms that may occur during symptomatic Salmonella Paratyphi A infection (for example, paracetamol, etc). Updated 12/09/2023: Female participants changed to participants of childbearing potential. |
| Intervention type | Biological/Vaccine |
| Pharmaceutical study type(s) | Not Applicable |
| Phase | Not Applicable |
| Drug / device / biological / vaccine name(s) | - |
| Primary outcome measure | Development of clinical or microbiologically proven paratyphoid infection following oral challenge with 1-5x10^3 S. Paratyphi A (strain NVGH308) delivered in a sodium bicarbonate solution at 14 days after the administration of the challenge agent: Paratyphoid fever is diagnosed if ANY of the following apply: 1. A positive blood culture for S. Paratyphi A from 72 h post-challenge 2. A positive blood culture for S. Paratyphi A within 72 h post-challenge, with one or more signs/symptoms of paratyphoid infection (such as recorded temperature ≥38.0°C) 3. Persistent positive blood cultures (two or more blood cultures taken at least 4 h apart) for S. Paratyphi A within 72 h post-challenge. 4. Oral temperature ≥38.0°C persisting for 12 h |
| Secondary outcome measures | Current secondary outcome measures as of 12/02/2024: 1. Clinical course of paratyphoid infection after challenge between placebo and CVD 1902 groups, in particular: 1.1. time to onset of symptoms 1.2. duration of illness 1.3. symptom severity 1.4. time to onset of bacteraemia 1.5. time to onset of stool shedding 1.6. inflammatory response Evaluated using clinical reporting, physical examination findings, microbiological assays to detect S. Paratyphi A in blood and stool, and laboratory assays to monitor inflammatory responses. 2. Innate, humoral, cell-mediated and mucosal responses to vaccination at baseline (Day -42) and post-vaccination time points (D-35, D-28, D-21 and D0) measured using immunological laboratory assays. These may include: 2.1. S. Paratyphi A antigen specific antibodies and serum bactericidal antibody titres 2.2. Cell-mediated responses (including antigen specific cell frequencies, description of lymphocyte populations, B and T cell repertoire) 2.3. Cytokine and acute phase reactant profile and kinetics 3. Immunological laboratory assays to assess innate, humoral, cell-mediated and mucosal responses to challenge will be taken at various time points following challenge. Baseline samples will be taken on D0 and post-challenge samples will be taken on D1, D2, D4, D7, D14, D28, D90, D180 and D365. Post-diagnosis samples will be taken on day of paratyphoid diagnosis, 12-24 hours following diagnosis and 96 hours following diagnosis. A variety of sample types will be taken, these may include: 3.1. Cell-mediated responses (including antigen specific cell frequencies, description of lymphocyte populations, B and T cell repertoire) 3.2. Cytokine and acute phase reactant profile and kinetics 3.3. S. Paratyphi A antigen-specific IgA, IgM and IgG antibodies 4. Clinical observation and participant recording of symptoms, both solicited and unsolicited plus safety laboratory data. This will be evaluated using vaccination e-diaries completed by the participant daily for 7 days following each vaccine and then with any additional symptoms. Laboratory data will be taken at post-vaccination visits (D-35, D-28, D-21, D0). 5.Immunological response data post-vaccination (including S. Paratyphi A specific antibody titres, cell-mediated responses) will be combined with vaccine efficacy data following S. Paratyphi A challenge to investigate if particular immunological markers could be used to predict protection from paratyphoid infection. _____ Previous secondary outcome measures: 1. Clinical course of paratyphoid infection after challenge between placebo and CVD 1902 groups, in particular: 1.1. time to onset of symptoms 1.2. duration of illness 1.3. symptom severity 1.4. time to onset of bacteraemia 1.5. time to onset of stool shedding 1.6. inflammatory response Evaluated using clinical reporting, physical examination findings, microbiological assays to detect S. Paratyphi A in blood and stool, and laboratory assays to monitor inflammatory responses. 2. Innate, humoral, cell-mediated and mucosal responses to vaccination at baseline (Day -42) and post-vaccination time points (D-35, D-28, D-21 and D0) measured using immunological laboratory assays. These may include: 2.1. S. Paratyphi A antigen specific antibodies and serum bactericidal antibody titres 2.2. Cell-mediated responses (including antigen specific cell frequencies, description of lymphocyte populations, B and T cell repertoire) 2.3. Cytokine and acute phase reactant profile and kinetics 3. Immunological laboratory assays to assess innate, humoral, cell-mediated and mucosal responses to challenge will be taken at various time points following challenge. Baseline samples will be taken on D0 and post-challenge samples will be taken on D1, D2, D4, D7, D14, D28, D90, D180 and D365. Post-diagnosis samples will be taken on day of paratyphoid diagnosis, 12-24 hours following diagnosis and 96 hours following diagnosis. A variety of sample types will be taken, these may include: 3.1. Cell-mediated responses (including antigen specific cell frequencies, description of lymphocyte populations, B and T cell repertoire) 3.2. Cytokine and acute phase reactant profile and kinetics 3.3. S. Paratyphi A antigen-specific IgA, IgM and IgG antibodies 4. Clinical observation and participant recording of symptoms, both solicited and unsolicited plus safety laboratory data and microbiological data from blood and stool cultures following vaccination. This will be evaluated using vaccination e-diaries completed by the participant daily for 7 days following each vaccine and then with any additional symptoms. Laboratory and microbiological data will be taken at post-vaccination visits (D-35, D-28, D-21, D0). 5.Immunological response data post-vaccination (including S. Paratyphi A specific antibody titres, cell-mediated responses) will be combined with vaccine efficacy data following S. Paratyphi A challenge to investigate if particular immunological markers could be used to predict protection from paratyphoid infection. |
| Overall study start date | 01/06/2021 |
| Overall study end date | 28/02/2025 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Upper age limit | 55 Years |
| Sex | Both |
| Target number of participants | UK Sample Size: Up to 76 participants |
| Total final enrolment | 72 |
| Participant inclusion criteria | Current inclusion criteria as of 23/03/2023: 1. Willing and able to give informed consent for participation in the study 2. Aged between 18 and 55 years inclusive at time of vaccination 3. In good health as determined by medical history, physical examination and clinical judgment of the study team 4. Willing to be available for all required appointments and if applicable to travel to vaccination and challenge site 5. 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 6. Agree to allow study staff to contact his or her GP or equivalent NHS databases to access the participant’s vaccination records, medical history and have their opinion solicited as to the participant’s appropriateness for inclusion 7. Agree to allow study staff to access NHS health records and participant identifiable data as required for study purposes 8. Agree to allow his or her GP (and/or Consultant if appropriate), to be notified of participation in the study 9. Agree to allow Public Health England to be informed of their participation in the study 10. Agree to give his or her close household contacts written information informing them of the participant's involvement in the study and offering them voluntary screening for S. Paratyphi A carriage 11. Agree to have 24-hour contact with study staff during the 4 weeks post-challenge and are able to ensure that they are contactable by mobile phone for the duration of the vaccination and challenge period until antibiotic completion 12. Have internet access to allow completion of the e-diary and real-time safety monitoring 13. Agree to avoid antipyretic/anti-inflammatory treatment from challenge until advised by a study doctor or until 14 days after challenge 14. Agree to refrain from donating blood for the duration of the study 15. Agree to provide their National Insurance/Passport number for the purposes of TOPS registration and for payment of reimbursement expenses 16. Participants must have received at least one dose of a SARS-CoV-2 vaccine that has been approved for use by the MHRA (or other national regulatory authority) >4 weeks prior to enrollment 17. Agree to not receive other vaccinations (eg Covid-19 vaccines) during the 7 days before and after study vaccination and during the 21 days post-challenge _____ Previous inclusion criteria as of 14/04/2022: 1. Willing and able to give informed consent for participation in the study 2. Aged between 18 and 55 years inclusive at time of vaccination 3. In good health as determined by medical history, physical examination and clinical judgment of the study team 4. Willing to be available in Oxford for all required appointments 5. 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 6. Agree to allow study staff to contact his or her GP to access the participant’s vaccination records, medical history and have their opinion solicited as to the participant’s appropriateness for inclusion 7. Agree to allow study staff to access NHS health records as required for study purposes 8. Agree to allow his or her GP (and/or Consultant if appropriate), to be notified of participation in the study 9. Agree to allow Public Health England to be informed of their participation in the study 10. Agree to give his or her close household contacts written information informing them of the participant's involvement in the study and offering them voluntary screening for S. Paratyphi A carriage 11. Agree to have 24-hour contact with study staff during the 4 weeks post-challenge and are able to ensure that they are contactable by mobile phone for the duration of the vaccination and challenge period until antibiotic completion 12. Have internet access to allow completion of the e-diary and real-time safety monitoring 13. Agree to avoid antipyretic/anti-inflammatory treatment from challenge until advised by a study doctor or until 14 days after challenge 14. Agree to refrain from donating blood for the duration of the study 15. Agree to provide their National Insurance/Passport number for the purposes of TOPS registration and for payment of reimbursement expenses 16. Participants must have received at least one dose of a SARS-CoV-2 vaccine that has been approved for use by the MHRA (or other national regulatory authority) >4 weeks prior to enrollment 17. Agree to not receive other vaccinations (eg Covid-19 vaccines) during the 7 days before and after study vaccination and during the 21 days post-challenge _____ Previous inclusion criteria: 1. Willing and able to give informed consent for participation in the study. 2. Aged between 18 and 55 years inclusive at time of vaccination. 3. In good health as determined by medical history, physical examination and clinical judgment of the study team. 4. Live or reside within the Thames Valley Area. 5. 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. 6. Agree to allow study staff to contact his or her GP to access the participant’s vaccination records, medical history and have their opinion solicited as to the participant’s appropriateness for inclusion. 7. Agree to allow study staff to access NHS health records as required for study purposes. 8. Agree to allow his or her GP (and/or Consultant if appropriate), to be notified of participation in the study. 9. Agree to allow Public Health England to be informed of their participation in the study. 10. Agree to give his or her close household contacts written information informing them of the participants’ involvement in the study and offering them voluntary screening for S. Paratyphi A carriage. 11. Agree to have 24-hour contact with study staff during the four weeks post challenge and are able to ensure that they are contactable by mobile phone for the duration of the vaccination and challenge period until antibiotic completion. 12. Have internet access to allow completion of the e-diary and real-time safety monitoring. 13. Agree to avoid antipyretic/anti-inflammatory treatment from challenge until advised by a study doctor or until 14 days after challenge. 14. Agree to refrain from donating blood for the duration of the study. 15. Agree to provide their National Insurance/Passport number for the purposes of TOPS registration and for payment of reimbursement expenses. 16. Participants must have received at least one dose of a SARS-CoV-2 vaccine that has been approved for use by the MHRA (or other national regulatory authority) > four weeks prior to enrollment. 17. Agree to not receive other vaccinations (eg Covid-19 vaccines) during the 7 days before and after study vaccination and during the 21 days post-challenge. |
| Participant exclusion criteria | Updated 12/09/2023: Female participants changed to participants of childbearing potential. Current exclusion criteria as of 23/03/2023: 1. History of significant organ/system disease that could interfere with trial conduct or completion. Including, for example, but not restricted to: 1.1. Cardiovascular disease including a diagnosis of hypertension 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 previous cholecystectomy 1.7. Gastro-intestinal disease including requirement for antacids, H2-receptor antagonists, proton pump inhibitors or laxatives 1.8. Neurological disease 1.9. Metabolic disease 1.10. Autoimmune disease 1.11. Psychiatric illness requiring hospitalisation 1.12. Known or suspected drug misuse 1.13. Known or suspected alcohol misuse (alcohol misuse defined as an intake exceeding 42 units per week) 1.14. Infectious disease 2. Have any known or suspected impairment of immune function, alteration of immune function, or prior immune exposure that may alter immune function to typhoid resulting from, for example: 2.1. Congenital or acquired immunodeficiency, including IgA deficiency 2.2. Human Immunodeficiency Virus infection or symptoms/signs suggestive of an HIV-associated condition 2.3. Receipt of immunosuppressive therapy such as anti-cancer chemotherapy or radiation therapy within the preceding 12 months or long-term systemic corticosteroid therapy. 2.4. Receipt of immunoglobulin or any blood product transfusion within 3 months of study start 2.5. 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 deemed clinically significant by the study doctors 5. Weight less than 50kg 6. Presence of implants or prosthesis 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 fluoroquinolones, macrolide antibiotics, co-trimoxazole or ceftriaxone 9. Family history of aneurysmal disease 10. Participants of childbearing potential who are pregnant, lactating or who are unwilling to ensure that they or their partner use effective contraception 30 days prior to vaccination and continue to do so until three negative stool samples have been obtained at least one week after completion of antibiotic treatment 11. Full-time, part-time or voluntary occupations involving: 11.1. Clinical or social work with direct contact with young children (defined as those attending pre-school groups or nursery or aged under 2 years), or 11.2. Clinical or social work with direct contact with highly susceptible patients or persons in whom typhoid infection would have particularly serious consequences 11.3. Commercial food handling (involving preparing or serving unwrapped foods not subjected to further heating) 11.4. (unless willing to avoid work from vaccination until demonstrated not to be infected with S. Paratyphi A after challenge by clearance samples in accordance with guidance from Public Health England and willing to allow study staff to inform their employer) 12. Close household contact with: 12.1. Young children (defined as those attending pre-school groups, nursery or those aged less than 2 years) 12.2. Individuals who are immunocompromised (including pregnancy) 13. Scheduled elective surgery or other procedures requiring general anaesthesia during the study period 14. Participants who have participated in another research study involving an investigational product that might affect risk of paratyphoid 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) 15. Detection of any abnormal results from screening investigations (at the clinical discretion of the study team) 16. Inability to comply with any of the study requirements (at the discretion of the study staff and the participant’s General Practitioner) 17. Any other social, psychological or health issues which, in the opinion of the study staff, may 17.1. put the participant or their contacts at risk because of participation in the study, 17.2. adversely affect the interpretation of the primary endpoint data, 17.3. Impair the participant’s ability to participate in the study 18. Have any history of allergy to vaccine components 19. Having been resident in an enteric fever endemic country for 6 months or more 20. Have previously been diagnosed with laboratory-confirmed typhoid or paratyphoid infection or been given a diagnosis compatible with enteric fever 21. Have participated in previous typhoid or paratyphoid challenge studies (with ingestion of challenge agent) 22. Have received any oral typhoid vaccination (eg Ty21a or M01ZH09) at any time 23. Have a prolonged corrected QT interval (> 450 milliseconds) on ECG screening 24. Significant blood donation or planned blood donation within 3 months of enrollment ______ Previous exclusion criteria: 1. History of significant organ/system disease that could interfere with trial conduct or completion. Including, for example, but not restricted to: 1.1. Cardiovascular disease including a diagnosis of hypertension 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 previous cholecystectomy 1.7. Gastro-intestinal disease including requirement for antacids, H2-receptor antagonists, proton pump inhibitors or laxatives 1.8. Neurological disease 1.9. Metabolic disease 1.10. Autoimmune disease 1.11. Psychiatric illness requiring hospitalisation 1.12. Known or suspected drug misuse 1.13. Known or suspected alcohol misuse (alcohol misuse defined as an intake exceeding 42 units per week) 1.14. Infectious disease 2. Have any known or suspected impairment of immune function, alteration of immune function, or prior immune exposure that may alter immune function to typhoid resulting from, for example: 2.1. Congenital or acquired immunodeficiency, including IgA deficiency 2.2. Human Immunodeficiency Virus infection or symptoms/signs suggestive of an HIV-associated condition 2.3. Receipt of immunosuppressive therapy such as anti-cancer chemotherapy or radiation therapy within the preceding 12 months or long-term systemic corticosteroid therapy. 2.4. Receipt of immunoglobulin or any blood product transfusion within 3 months of study start 2.5. 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 deemed clinically significant by the study doctors 5. Weight less than 50kg 6. Presence of implants or prosthesis 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 fluoroquinolones, macrolide antibiotics, co-trimoxazole or ceftriaxone 9. Family history of aneurysmal disease 10. Female participants who are pregnant, lactating or who are unwilling to ensure that they or their partner use effective contraception 30 days prior to vaccination and continue to do so until three negative stool samples have been obtained after completion of antibiotic treatment 11. Full-time, part-time or voluntary occupations involving: 11.1. Clinical or social work with direct contact with young children (defined as those attending pre-school groups or nursery or aged under 2 years), or 11.2. Clinical or social work with direct contact with highly susceptible patients or persons in whom typhoid infection would have particularly serious consequences 11.3. Commercial food handling (involving preparing or serving unwrapped foods not subjected to further heating) 11.4. (unless willing to avoid work from vaccination until demonstrated not to be infected with S. Paratyphi A after challenge by clearance samples in accordance with guidance from Public Health England and willing to allow study staff to inform their employer) 12. Close household contact with: 12.1. Young children (defined as those attending pre-school groups, nursery or those aged less than 2 years) 12.2. Individuals who are immunocompromised (including pregnancy) 13. Scheduled elective surgery or other procedures requiring general anaesthesia during the study period 14. Participants who have participated in another research study involving an investigational product that might affect risk of paratyphoid 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) 15. Detection of any abnormal results from screening investigations (at the clinical discretion of the study team) 16. Inability to comply with any of the study requirements (at the discretion of the study staff and the participant’s General Practitioner) 17. Any other social, psychological or health issues which, in the opinion of the study staff, may 17.1. put the participant or their contacts at risk because of participation in the study, 17.2. adversely affect the interpretation of the primary endpoint data, 17.3. Impair the participant’s ability to participate in the study 18. Have any history of allergy to vaccine components 19. Having been resident in an enteric fever endemic country for 6 months or more 20. Have previously been diagnosed with laboratory-confirmed typhoid or paratyphoid infection or been given a diagnosis compatible with enteric fever 21. Have participated in previous typhoid or paratyphoid challenge studies (with ingestion of challenge agent) 22. Have received any oral typhoid vaccination (eg Ty21a or M01ZH09) at any time 23. Have a prolonged corrected QT interval (> 450 milliseconds) on ECG screening 24. Significant blood donation or planned blood donation within 3 months of enrollment |
| Recruitment start date | 25/02/2022 |
| Recruitment end date | 20/11/2023 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centres
Churchill Hospital
Churchill Hospital
Old Road
Headington
Oxford
OX3 7LE
United Kingdom
Old Road
Headington
Oxford
OX3 7LE
United Kingdom
John Radcliffe Hospital
Headley Way
Headington
Oxford
OX3 9DU
United Kingdom
Headington
Oxford
OX3 9DU
United Kingdom
University Hospital Southampton NHS Foundation Trust
Southampton General Hospital
Tremona Road
Southampton
SO16 6YD
United Kingdom
Tremona Road
Southampton
SO16 6YD
United Kingdom
University Hospitals Bristol and Weston NHS Foundation Trust
Trust Headquarters
Marlborough Street
Bristol
BS1 3NU
United Kingdom
Marlborough Street
Bristol
BS1 3NU
United Kingdom
Sheffield Teaching Hospitals NHS Foundation Trust
Northern General Hospital
Herries Road
Sheffield
S5 7AU
United Kingdom
Herries Road
Sheffield
S5 7AU
United Kingdom
Liverpool School of Tropical Medicine
Pembroke Place
Liverpool
L3 5QA
United Kingdom
Liverpool
L3 5QA
United Kingdom
University Hospitals Birmingham NHS Foundation Trust
Queen Elizabeth Hospital
Mindelsohn Way
Edgbaston
Birmingham
B15 2GW
United Kingdom
Mindelsohn Way
Edgbaston
Birmingham
B15 2GW
United Kingdom
Sponsor information
University of Oxford
University/education
University/education
Research Governance, Ethics and Assurance (RGEA)
Joint Research Office
1st floor, Boundary Brook House
Churchill Drive
Headington
Oxford
OX3 7GB
England
United Kingdom
| RGEA.Sponsor@admin.ox.ac.uk | |
| Website | http://www.ox.ac.uk/ |
"ROR" |
https://ror.org/052gg0110 |
Funders
Funder type
Research council
Medical Research Council
Government organisation / National government
Government organisation / National government
- Alternative name(s)
- Medical Research Council (United Kingdom), UK Medical Research Council, MRC
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 01/03/2025 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | Planned publication in a high-impact peer-reviewed journal |
| IPD sharing plan | The datasets generated during and/or analysed during the current study will be available upon request directed to Professor Sir Andrew J Pollard (andrew.pollard@paediatrics.ox.ac.uk) or upon written approval of the sponsor. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol file | version 2.1 | 30/11/2021 | 14/02/2022 | No | No |
| Protocol file | version 3.1 | 11/04/2022 | 14/04/2022 | No | No |
| Protocol file | version 3.0 | 07/03/2022 | 14/04/2022 | No | No |
| Protocol article | 24/05/2023 | 25/05/2023 | Yes | No | |
| Protocol file | version 4.0 | 04/11/2022 | 12/06/2023 | No | No |
| HRA research summary | 28/06/2023 | No | No | ||
| Protocol file | version 4.1 | 03/07/2023 | 12/09/2023 | No | No |
| Protocol file | version 5.0 | 12/10/2023 | 12/02/2024 | No | No |
| Protocol file | version 5.1 | 23/02/2024 | 07/03/2024 | No | No |
| Protocol file | version 5.2 | 26/04/2024 | 20/05/2024 | No | No |
Additional files
- 41154_Protocol V2.1_30Nov2021.pdf
- ISRCTN15485902_Protocol_v3.1_11Apr2022.pdf
- ISRCTN15485902_Protocol_V3.0_07Mar2022.pdf
- ISRCTN15485902 VASP Protocol V4.0 04Nov2022.pdf
- ISRCTN15485902_PROTOCOL_V4.1_03Jul23.pdf
- ISRCTN15485902 VASP Protocol V5.0 12Oct 2023_clean.pdf
- ISRCTN15485902_Protocol_V5.1_23Feb2024.pdf
- ISRCTN15485902_Protocol_V5.2_26April2024.pdf
Editorial Notes
20/12/2024: The intention to publish date was changed from 31/12/2024 to 01/03/2025.
19/12/2024: The following changes were made to the study record:
1. Contact details updated.
2. Total final enrolment added.
3. The overall study end date was changed from 30/04/2025 to 28/02/2025.
20/05/2024: Uploaded protocol v5.2 (not peer-reviewed) as an additional file.
07/03/2024: The following changes were made:
1. The recruitment end date was changed from 30/04/2024 to 20/11/2023.
2. The target number of participants was changed from "Planned Sample Size: 74-76; UK Sample Size: 74-76" to "UK Sample Size: Up to 76 participants".
3. The study website link was removed.
4. The participant information sheet was changed from "http://trials.ovg.ox.ac.uk/trials/VASP";.
5. Uploaded protocol v5.1 (not peer-reviewed) as an additional file.
12/02/2024: The following changes were made to the trial record:
1. Uploaded protocol v5.0 (not peer-reviewed) as an additional file.
2. The secondary outcome measures were changed.
3. The overall end date was changed from 31/12/2024 to 30/04/2025.
4. The recruitment end date was changed from 31/10/2023 to 30/04/2024.
5. The study participating centre Imperial College Healthcare NHS Trust was removed.
6. The plain English summary was updated to reflect these changes.
21/09/2023: Contact details updated.
12/09/2023: The following changes were made to the study record:
1. Uploaded protocol v4.1 (not peer-reviewed).
2. Contact details, interventions and exclusion criteria updated.
12/06/2023: Uploaded protocol v4.0 (not peer-reviewed).
25/05/2023: Publication reference added.
18/04/2023: The IPD sharing statement has been added.
23/03/2023: The following changes were made to the trial record:
1. The contacts were changed.
2. The study design was changed from "Interventional randomized controlled trial" to "Interventional randomized controlled trial (multi-centre)".
3. The target number of participants was changed from 76 to 74 - 76.
4. The inclusion criteria were changed.
5. The exclusion criteria were changed.
6. The trial participating centres University Hospital Southampton NHS Foundation Trust, University Hospitals Bristol and Weston NHS Foundation Trust, Sheffield Teaching Hospitals NHS Foundation Trust, Liverpool School of Tropical Medicine, Imperial College Healthcare NHS Trust, University Hospitals Birmingham NHS Foundation Trust were added.
29/07/2022: The primary contact was updated.
14/04/2022: The following changes have been made:
1. The participant inclusion criteria have been changed.
2. Two protocol files have been uploaded.
14/02/2022: Trial's existence confirmed by the National Institute for Health Research (NIHR) (UK).
