Inclusion Criteria:
* The study informed consent form has been signed and dated by the participant and the Investigator
* Adults age between 18 and 50 years inclusive (at the time of enrolment)
* Evidence of having had at least one COVID-19 vaccine, with the last vaccination at least 3 months before enrolment
* Positive serology for SARS-CoV-2 at (pre)screening
* Sero-suitable as defined by having serum and/or nasal antibody titres less than a pre-defined cut-off of a defined assay(s) which will be specified in a separate SOP and based on accumulating antibody data
* People of child-bearing potential (POCBP) must be willing and able to use contraception as described in the study protocol from 2 weeks before the scheduled date of viral challenge until the end discharge from quarantine.
Negative urine pregnancy tests will be required at screening and on day 0 prior to inoculation. On admission to the quarantine unit a negative serum beta human chorionic gonadotropin (β-hCG) is required
* Male participants who are willing to use one of the contraception methods described in the study protocol, from the time of the date of viral challenge until the end of quarantine
* 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
* In good health with no history of clinically significant medical conditions (as described in Exclusion criteria) that would interfere with participant safety, as defined by medical history, physical examination and routine laboratory tests, ECG, and Chest X-Ray and determined by the Investigator at an admission evaluation
* Participants will have a documented medical history either prior to entering the study and/or following medical history review with the study physician at screening
* Willing to be registered with The Over-Volunteering Protection Service (TOPS)
* Willing and able to commit to participation in the study.
Exclusion Criteria:
* History or evidence of any clinically significant or currently active cardiovascular, (including thromboembolic events), respiratory, dermatological, gastrointestinal, endocrine, haematological, hepatic, immunological, rheumatological, metabolic, urological, renal, neurological, psychiatric illness
* Any significant abnormality altering the anatomy or function of the nose or nasopharynx in a substantial way (including loss of or alterations in smell or taste), a clinically significant history of epistaxis (large nosebleeds) within the last 3 months, nasal or sinus surgery within 6 months of inoculation
* Clinically-active, symptomatic rhinitis (including hay fever) or history of severe rhinitis, or seasonal allergic rhinitis likely to be active at the time of inclusion into the study and/or requiring regular nasal corticosteroids on an at least weekly basis, within 30 days of admission to quarantine
* History of anaphylaxis and/or a history of severe allergic reaction or significant intolerance to any food or drug, as assessed by the Investigator
* Significant history or presence of drug or alcohol misuse (exceeding \>28 units a week)
* Current use of any drugs taken through the nasal or inhaled route including recreational drugs
* Psychiatric illness including participants with a history of depression and/or anxiety with associated severe psychiatric comorbidities, for example psychosis.
* Current active smokers, equivalent to \>5 cigarettes per week, including use of tobacco in any form (e.g., smoking or chewing) or other nicotine-containing products in any form (e.g., gum, patch) or electronic cigarettes. • Participants who have smoked ≥5 pack years at any time \[5 pack years is equivalent to one pack of 20 cigarettes a day for 5 years\]) or the equivalent amount of nicotine if using alternative forms. • Ex-smokers who have smoked \<5 pack years at any time must not of have regularly smoked in the last 3 months equivalent to \>5 cigarettes per week.
* Family history of 1st degree relative aged 50 years or less with sudden cardiac or unexplained death
* Personal or Family History of unexpectedly severe COVID-19, adverse response to any other viral disease e.g. Guillain-Barré, or a family history (described as a 1st degree relative) with clotting disorders
* A total body weight of ≤ 45kg and a Body Mass Index (BMI) ≤18 kg/m2 and ≥28 kg/m2. The upper limit of BMI may be increased to ≤ 30kg/m2 at the Investigator's discretion, in the case of physically fit muscular individual
* Venous access deemed inadequate for the phlebotomy demands of the study.
* Any clinically significant abnormal finding on screening biochemistry, haematology and microbiology blood tests or urinalysis i.e. grade 1 lab abnormalities or above apart from minor deviations which are clinically acceptable and approved by the Investigator
* A forced expiratory volume in 1 second (FEV1) and a forced vital capacity (FVC) \<80% of predicted value calculated using ATS/ERS guidance. Spirometry will be performed only if the mMRC dyspnoea score ≥1 or if clinically indicated
* Twelve-lead ECG recording with clinically relevant abnormalities as judged by the Investigator
* History of, or currently active symptoms suggestive of upper or lower respiratory tract infection (including reduced sense of taste and smell, raised body temperature and/or persistent cough) within 4 weeks prior to viral challenge
* Presence of cold-like symptoms and/or fever (defined as participant presenting with a temperature reading of \>37.9ºC) on Day -2, Day -1 and/or pre-challenge on Day 0.
* Evidence of any respiratory pathogens (on Respiratory PCR from upper respiratory tract sample) prior to challenge virus inoculation on admission to the quarantine unit
* Evidence of a live vaccine within 60 days prior to the planned date of viral challenge, a non-live vaccine within 30 days prior to the planned date of viral challenge or intention to receive any vaccination(s) before the day 28 follow-up visit. (NB. No travel restrictions applied after the Day 28 Follow-up visit).
* Receipt of blood or blood products, or loss (including blood donations) of 550 mL or more of blood during the 3 months prior to the planned date of viral challenge or planned during the 3 months after the final visit.
* Medications
1. Use of any medication or product (prescription or over-the-counter), for symptoms of hay fever, nasal congestion or respiratory tract infections or dermatitis/eczema including the use of regular nasal or medium-high potency dermal corticosteroids, antibiotics and First Defence™ (or generic equivalents) within 7 days prior to the planned date of viral challenge apart from those described in Table 7, Permitted Medication or agreed by the Investigator.
2. Receipt of any investigational drug within 3 months prior to the planned date of viral challenge.
3. Receipt of three or more investigational drugs within the previous 12 months prior to the planned date of viral challenge.
4. Receipt of systemic (intravenous and/or oral) glucocorticoids or antiviral drugs known to have activity against respiratory viruses within 6 months prior to the planned date of viral challenge (excluding Pre-Exposure Prophylaxis (PrEP)).
5. Over the counter medications (e.g., paracetamol or ibuprofen) where the dose taken over the preceding 7 days prior to the planned date of viral challenge had exceeded the maximum permissible 24-hour dose (e.g., \>4g per day of paracetamol over the preceding week).
6. Chronically used medications, including any medication known to be a moderate/potent inducer or inhibitor of cytochrome P450 enzymes, within 21 days prior to the planned date of viral challenge, except for those agreed by the Investigator.
7. Participants who have received any systemic chemotherapy agent, immunoglobulins, or other cytotoxic or immunosuppressive drugs at any time.
8. Concurrent use of medications strongly contraindicated for use with Paxlovid unless confirmed alternative rescue therapy will be available to the site at the time of enrolment
* Prior participation in another human viral challenge study in the preceding 6 months taken from the date of viral challenge in the previous study to the date of expected viral challenge in this study. The participant must also have completed the follow up visit requirements of the previous viral challenge study
* Any invasive nasal sampling procedure in the month before date of expected viral challenge in this study (excluding study tolerance test or routine tests for COVID-19)
* Participant is mentally or legally incapacitated in the opinion of the Investigator
* POCBP who:
1. Are breastfeeding within 6 months of study commencement, or
2. Had been pregnant within 6 months prior to the study, or
3. Had a positive pregnancy test at any point during screening or prior to inoculation with challenge virus
* Those in close domestic contact (i.e. sharing a household with, caring for, or daily face to face contact) with children under 2 years, the elderly (\>65 years), immunosuppressed persons, or those with chronic respiratory disease
* Anyone who works on the study (e.g. a delegated study nurse) or in close proximity to the study at the sponsor organisation, participating trial sites or any contract research organisations involved in this study.
* Anyone who is first degree related to, or resides with, anyone who is a delegated member of the research team at a study site
* Any other reason that the Investigator considered made the participant unsuitable to participate
* Participants with no knowledge of their family history
