SARS-CoV-2 Infection
Conditions
Keywords
Covid-19, SARS-CoV-2, Controlled human infection model, Infection study, Omicron
Brief summary
A phase 1, dose-finding open label clinical infection, safety and viral detection optimization in healthy volunteers immunologically experienced against SARS-CoV-2.
Detailed description
The aim of this phase 1 dose escalation study is to develop a safe human infection model with SARS-CoV-2 in healthy volunteers who have previously been vaccinated against SARS CoV-2 and either have been infected with SARS-CoV-2 and have evidence of this, or have developed antibodies against SARS-CoV-2. Increasing titres of SARS-CoV-2 Omicron BA.5 subvariant (starting from 1x10\^5 TCID50, up to 1x10\^8 TCID50) will be administered intranasally to different groups of 5-7 volunteers. This is in order to achieve a 50%-75% attack rate as determined by two or more quantifiable qRT-PCR detections at two consecutive timepoints from 2 days post-challenge. A Data Safety Monitoring Board (DSMB) will review safety and quantitative virology data at each dose level and will recommend continuation, dose escalation or de-escalation, based on emergent data. Dose escalation will take place in increments of up to 10 times the previous dose. Once the optimal dose of SARS-CoV-2 Omicron BA.5 subvariant has been identified in group 1, further inoculations in group 2 may proceed following DSMB review of infection rate, viral load and clinical data. Group 1 will enrol up to 28 participants whilst up to 24 participants will be enrolled into Group 2 across several sites. Rescue therapy with Paxlovid or alternative agents subject to local site availability (e.g. Remdesivir) will be administered to infected participants after any warning signs or symptoms of COVID-19 beyond mild disease. Volunteers with PCR positivity from 2 days post-challenge will remain in negative pressure isolation rooms within the clinical trials unit for a minimum of 14 days post-inoculation, and until no viable virus is found in two consecutive samples and a negative or decreasing viral load is demonstrated by qRT-PCR. Volunteers without PCR positivity from 2 days post-challenge will remain in negative pressure isolation rooms within the clinical trials unit for a minimum of 11 days post-inoculation.
Interventions
BIOLOGICALOmicron BA.5 SARS-CoV-2 challenge 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. All manufacturing steps are carried out in accordance with GMP by BioMARC, operating out of Colorado State University.
Sponsors
University of Oxford
Imperial College Healthcare NHS Trust
Chelsea and Westminster Hospital, UK
Royal Free London NHS Trust
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 40 Years
Healthy volunteers
Yes
Inclusion criteria
1. Aged 18-40 years at the time of enrolment. 2. Evidence of having had at least one Covid-19 vaccine, with the last vaccination at least 3 months before enrolment. 3. Positive serology for SARS-CoV-2 at screening OR evidence of prior infection with SARS-CoV-2 (Evidence will be assessed by a clinician and may include evidence of a positive PCR result, a photograph of a positive lateral flow on the volunteer's phone or anti-nucleocapsid positivity at any time). 4. Body Mass Index (BMI) ≥18.5 kg/m2 and ≤28 kg/m2 at admission to the quarantine unit. The upper limit of BMI may be increased to ≤30kg/m2 at the PI's discretion, in the case of a physically fit muscular individual. 5. 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, ECG, spirometry and Chest X-Ray as determined by the Investigator at a screening evaluation. 6. Willing and able to provide written informed consent for participation in the study. 7. Willing to allow the investigators to discuss the volunteer's medical history with their General Practitioner or any relevant health authority. 8. Allow the investigator to register volunteer details with a confidential database (The Over-volunteering Protection Service) to prevent concurrent entry into clinical studies/trials. 9. Agreement to refrain from blood donation during the course of the study. 10. For people of child bearing potential (POCBP): a willingness to practice continuous effective contraception (see below) from 4 weeks before admission to the quarantine unit until discharge from the quarantine unit, and negative pregnancy tests on screening (urine) and pre-enrolment admission days (urine and serum). 11. Agree to abstain from sexual activity or use effective contraception from the start of treatment with Paxlovid until 7 days after completing treatment with Paxlovid should they receive it. For people of child bearing potential (POCBP) taking the combined oral contraceptive pill, a willingness to use barrier contraception during treatment with Paxlovid and until completion of one menstrual cycle after completing Paxlovid treatment. 12. Able and willing (in the investigator's opinion) to comply with all study requirements. 13. No clinically relevant findings in medical history or on physical examination.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Occurrence of solicited and unsolicited adverse events, including severe adverse events | Day 180 | Safety and human clinical response to SARS-CoV-2 Omicron BA.5 subvariant intranasal challenge in participants who are immunologically experienced against SARS-CoV-2 will be measured by solicited and unsolicited adverse events, including severe adverse events, post viral challenge and other objective parameters such as vital signs, physical examination, smell test, spirometry, ECG, and clinical laboratory results. |
| Selection of the optimal SARS-CoV-2 dose(s) | Day 14 or until discharge criteria is met | The optimal dose is the dose required to induce laboratory confirmed upper respiratory tract infection in 50%-75% of immunologically experienced, healthy volunteers following intranasal challenge. Laboratory confirmed infection is defined as two or more quantifiable SARS-CoV-2 qRT-PCR from mid-turbinate or throat swab samples, at two consecutive time points starting from D2 post challenge and up to discharge from quarantine. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Determination of SARS-CoV-2 viral dynamics | Day 14 or until discharge criteria is met | Assessment of the SARS-CoV-2 viral dynamics in upper respiratory samples from immunologically experienced individuals including: determination of the incubation period, peak viral load and the mean duration of infectious viral shedding from quantitative RT-PCR or cell culture. |
| Identification of host immune responses that are associated with SARS-CoV-2 infection status and/or viral load. | Day 180 | Characterisation of humoral immunity markers via blood neutralising antibody titres, blood and mucosal binding antibody titres, and mucosal surrogate neutralising antibody titres. |
Countries
United Kingdom
Contacts
PRINCIPAL_INVESTIGATORHelen McShane, MD PhD
University of Oxford
Outcome results
None listed