Coronavirus
Conditions
Keywords
Covid-19, SARS-CoV-2, Controlled human infection model, Infection study
Brief summary
A phase I, experimental dose finding, open label, clinical infection, safety and viral detection optimisation in previously SARS-CoV-2 infected (unvaccinated or vaccinated) or uninfected vaccinated volunteers.
Detailed description
This is a phase I dose escalation challenge study in which increasing titres of wild-type SARS-CoV-2 (1x10\^1 TCID\_50, 1x10\^2TCID\_50, 1x10\^3TCID\_50, 1x10\^4TCID\_50 and 1x10\^5TCID\_50) will be administered intranasally to different groups of volunteers in order to achieve a 50% (+/-10%) attack rate as determined by quantitative live viral detection and/or qPCR detection in naso-pharyngeal secretions at two consecutive 12 hourly time points (at least 24 hours after inoculation). Dose escalation will be capped at 10\^5 TCID50 and we will proceed to dose confirmation, following DSMB safety review, even if we do not meet our target attack rate of 50% +/- 10%, to enable a larger sample size to assess the dynamic range of protection at that dose and ensure confidence in the negative infection rate at that dose. A Data Safety Monitoring Board (DSMB) will review safety and quantitative virology at each dose level and will recommend continuation based on emergent data. Rescue treatment with a single course of oral Paxlovid will commence immediately after any warning symptoms or signs of COVID-19 disease beyond mild disease. Once the optimal dose of wildtype SARS-CoV-2 has been identified for previously infected volunteers and uninfected vaccinated volunteers (dose escalation groups 1 and 3), further challenge infections in groups 2 and 4 may proceed. Volunteers will remain in isolation rooms within the clinical trials unit for a minimum of 14 days post inoculation and until demonstration of the absence of live virus in two sequential samples. All 4 groups will together enrol up to 132 volunteers. This study will be funded by the Wellcome Trust and Department of Health and Social Care (DHSC).
Interventions
BIOLOGICALSARS-CoV-2 virus
The SARS-COV-2 challenge virus strain was originally obtained from a nose/throat swab taken from a patient who developed respiratory symptoms consistent with COVID-19. The isolate was plaque purified to obtain a 'single' virus entity. The selected plaque, B1, was subsequently manufactured in accordance with GMP at the Great Ormond Street manufacturing suite.
Sponsors
University of Oxford
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
OTHER
Masking
NONE
Masking description
This is an open-label trial, however in order to minimise volunteer adverse event reporting bias by volunteers, study participants will be kept blinded to swab results for as long as possible.
Eligibility
Sex/Gender
ALL
Age
18 Years to 30 Years
Healthy volunteers
Yes
Inclusion criteria
1. Aged 18-30 years on proposed date of enrolment. 2. Body Mass Index (BMI) ≥18.5 kg/m2and ≤28 kg/m2. 3. In good health with no history of clinically significant medical conditions (as described in
Exclusion criteria
) that would interfere with subject safety, as defined by medical history, physical examination, routine laboratory tests, cardiovascular magnetic resonance imaging or echocardiogram, ECG, pulmonary function tests and Chest X-Ray as determined by the Investigator at a screening evaluation. 4. Volunteer is willing and able to give written informed consent for participation in the study 5. Willing to allow the investigators to discuss the volunteer's medical history with their General Practitioner or any relevant health authority 6. Allow the investigator to register volunteer details with a confidential database (The Over-volunteering Prevention Service) to prevent concurrent entry into clinical studies/trials 7. Agreement to refrain from blood donation during the course of the study 8. a. For women of child bearing potential (WOCBP), a willingness to practice continuous effective contraception during the study and, a negative pregnancy test on the day(s) of screening and challenge b. b. For women of child bearing potential (WOCBP) taking the combined oral contraceptive pill, a willingness to use barrier contraception with spermicide during treatment with Paxlovid and for 30 days after completing Paxlovid treatment (should they receive it). 9. Able and willing (in the investigator's opinion) to comply with all study requirements 10. No clinically relevant findings in medical history or on physical examination in the opinion of a clinically qualified investigator, in discussion with the CI if needed 11. For Groups 1 & 2: Previous microbiological confirmation of SARS-CoV-2 infection \> 3 months prior to enrolment (Proof of positive PCR or lateral flow antigen test confirmed via medical notes/ or UK HSA or a history from a volunteer consistent with SARS-CoV-2 infection with other evidence of this infection such as a photograph of a positive lateral flow test on the volunteer's phone or similar) OR serological confirmation such as positive anti-nucleocapsid IgG serology (unless this is explainable by prior vaccination) with the most recent history of symptoms or exposure likely to represent SARS-CoV-2 infection having occurred \> 3 months prior to enrolment. 12. For Groups 3 & 4: Written or electronic evidence of at least one vaccination against SARS- CoV-2 \>21 days prior to enrolment (proof required would include written or electronic evidence from GP/ medical records or electronic NHS COVID pass) where no history of symptoms or exposure can be identified to determine the timing of SARS-CoV-2 infection, volunteers may be enrolled \>7 weeks from the identification of anti-nucleocapsid positivity and \>3 months from their last negative anti-nucleocapsid antibody test.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Occurrence of solicited and unsolicited adverse events | Day 84 | To assess safety and human clinical response to wild type SARS-CoV-2 intranasal challenge in both previously SARS- CoV-2 infected (unvaccinated or vaccinated) and uninfected vaccinated participants via occurrence of adverse events (solicited and unsolicited) collected in e-diaries |
| Occurrence of adverse events as determined by medical assessment | Day 365 | Collection of AE data at each visit time point after SARS-CoV-2 inoculation (Graded 0-3) |
| Selection of optimal dose(s) | Day 14 or until discharge criteria is met | The SARS-CoV-2 dose required to induce upper respiratory tract infection in 50% (+/-10%) of previously SARS-CoV-2 infected healthy volunteers following intranasal challenge. Defined by laboratory identification of SARS-CoV-2 from nasal and pharyngeal swab, using qPCR and/or quantitative live viral detection at two consecutive 12- hourly time points starting 24 hours post-inoculation and up to discharge from quarantine. Optimal dose to be defined in previously SARS-CoV-2 infected (vaccinated or unvaccinated) and uninfected vaccinated healthy volunteers |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Determination of SARS-CoV-2 viral dynamics | Day 365 | Assess the SARS-CoV-2 viral dynamics in upper respiratory samples from previously infected (vaccinated or unvaccinated) or uninfected vaccinated individuals including: determination of the incubation period, peak viral load and the mean duration of infectious viral shedding from quantitative virology measured using qPCR and/or live viral detection on naso-oropharyngeal samples. |
| Exploratory Immunology: Identification of laboratory markers | Day 365 | Ex-vivo ELISpot to SARS-CoV-2 peptide (sfc/1x10\^6 PBMC) |
Countries
United Kingdom
Contacts
Primary ContactVolunteer Recruitment Co-ordinator
Outcome results
None listed