A Study Looking at the Effectiveness, Immune Response, and Safety of a COVID-19 Vaccine in Adults in the United Kingdom

Study Overview
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Brief Summary
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This is a study to evaluate the efficacy, immune response, and safety of a coronavirus disease 2019 (COVID-19) vaccine called SARS-CoV-2 rS with Matrix-M1 adjuvant in adults aged 18-84 years in the United Kingdom. A vaccine causes the body to have an immune response that may help prevent the infection or reduce the severity of symptoms. An adjuvant is something that can make a vaccine work better. This study will look at the protective effect, body's immune response, and safety of SARS-CoV-2 rS with Matrix-M1 adjuvant in the study population. Participants in the study will randomly be assigned to receive SARS-CoV-2 rS with Matrix-M1 adjuvant or placebo. Each participant in the study will receive a total of 2 intramuscular injections over the course of the study. Approximately 15,000 participants will take part in the study. The first approximately 400 participants who meet additional criteria will receive a flu vaccine, in addition to the SARS-CoV-2 rS vaccine or placebo, as part of a sub-study. An effort will be made to enroll a target of at least 25% of participants who are ≥ 65 years of age, as well as prioritizing other groups that are most affected by COVID-19, including racial and ethnic minorities. Unblinding of treatment assignment may occur in order to allow a participant to make an informed decision regarding receipt of an already approved or deployed SARS-CoV-2 vaccine. Participants who choose to receive an approved or deployed SARS-CoV-2 vaccine as per UK government guidance will be encouraged to remain in the study for scheduled safety assessments.

Official Title
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A Phase 3, Randomised, Observer-Blinded, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of a SARS-CoV-2 Recombinant Spike Protein Nanoparticle Vaccine (SARS-CoV-2 rS) With Matrix-M1™ Adjuvant in Adult Participants 18-84 Years of Age in the United Kingdom

Conditions
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COVID-19, SARS-CoV-2 Infection

Intervention / Treatment
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* Biological: SARS-CoV-2 rS/Matrix M1-Adjuvant
* Other: Placebo
* Biological: Licensed seasonal influenza vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able and willing to comply with all study requirements. Willing to allow investigators to discuss medical history with their General Practitioner and access all relevant medical records. Willing and able to give informed consent. Women of child-bearing potential must agree not to have sexual intercourse with men, or must consistently use an agreed method of contraception, from at least 28 days prior to enrolment in the study, through 3 months after the last vaccination. Room air oxygen saturation > 95% at Screening/Day 0. Seasonal Flu Vaccine Co-Administration Sub-Study only: Participant should not have received a current season flu vaccine, should have no reason why the specific sub-study flu vaccine cannot be administered, and should not have any prior history of allergy or severe reaction to seasonal flu vaccines. Exclusion Criteria: Participation in other COVID-19 vaccine or preventative drug trials for the duration of the study. Future participation in any blood tests for the duration of the study where participants are informed of their levels of COVID-19 antibodies or antigens. Participation in any trial involving an investigational drug, biologic or device within 45 days prior to the first study vaccination. History of laboratory-confirmed COVID-19 infection any time prior to first study vaccination. Receipt of any immunoglobulins and/or any blood products within 3 months prior to planned administration of study vaccine. Any confirmed or suspected immunosuppressive or immunodeficient state. Chronic administration (defined as more than 14 continuous days) of immunosuppressant medication within the past 3 months, except topical steroids or short-term oral steroids (course lasting ≤ 14 days). Note: An immunosuppressant dose of glucocorticoid is defined as a systemic dose ≥ 10 mg of prednisone per day or equivalent. The use of topical, inhaled, and nasal glucocorticoids will be permitted if other chronic disease conditions do not exclude a participant from the study. History of allergic disease or reactions likely to be made worse by any component of the study vaccines. History of anaphylaxis to any prior vaccine. Pregnancy, breast-feeding or willingness/intention to become pregnant within 3 months following the last study vaccination. Current diagnosis of or treatment for cancer (except basal cell carcinoma of the skin and cervical carcinoma in situ. Bleeding disorder, or prior history of significant bleeding or bruising following intramuscular injections or venepuncture (e.g. to draw blood for tests). Continuous use of anticoagulants or anti-platelet agents. Note: The preventative use of ≤ 325 mg of aspirin per day is permitted. Suspected or known current alcohol or drug dependency. Study team member or first-degree relative of any study team member (inclusive of sponsor, contract research organization (CRO), and site personnel involved in the study). Participants having any current workup of undiagnosed illness within 8 weeks prior to start of study which could lead to new condition or diagnosis. Received any live vaccine within 4 weeks or any vaccine (excluding flu) within 2 weeks prior to first study vaccination; or any licensed flu vaccine within 1 week prior to first study vaccination or plans to receive any vaccine from these time periods until 28 days after the second study vaccination. Have clinically significant chronic cardiovascular, endocrine (hormones), gastrointestinal, hepatic (including hepatitis B and C), renal (kidney), neurological, respiratory, psychiatric or other medical disorders not excluded by other exclusion criteria, that are assessed by the investigator as being clinically unstable within the prior 4 weeks as evidenced by: a) Hospitalisation for the condition, including day surgical interventions; b) New significant organ function deterioration; or c) Needing addition of new treatments or major dose adjustments of current treatments (mild or moderate well-controlled comorbidities are allowed). History of chronic neurological disorders that have required prior specialist physician review for diagnosis and management (such as multiple sclerosis, dementia, transient ischemic attacks, Parkinson's disease, degenerative neurological conditions, and neuropathy) or a history of stroke or previous neurological disorder within 12 months with residual symptoms. Participants with a history of migraine or chronic headaches or nerve root compression that have been stable on treatment for the last 4 weeks are not excluded. Any autoimmune disease/condition (iatrogenic or congenital). Any other significant disease, disorder or finding that, in the opinion of the investigator, may significantly increase the risk to the volunteer because of participation in the study, affect the ability of the volunteer to participate in the study, or impair interpretation of the study data. Participant requires the use of continuous oxygen therapy or any oxygen therapy while awake or is anticipated to require daytime oxygen therapy during the course of the study. Other protocol-defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 84 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: SARS-CoV-2 rS/Matrix-M1 Adjuvant<br>2 doses of 5 µg SARS-CoV-2 rS + 50 µg Matrix-M1 adjuvant (co-formulated), 1 dose each on Days 0 and 21. | Biological: SARS-CoV-2 rS/Matrix M1-Adjuvant<br>* Alternating intramuscular (deltoid) injections of SARS-CoV-2 rS co-formulated with Matrix-M1 adjuvant (0.5 mL) on Days 0 and 21.<br>* Other names: NVX-CoV2373;|
| Placebo Comparator: Cohort 1: Placebo<br>2 doses of Placebo (Saline), 1 dose each on Days 0 and 21. | Other: Placebo<br>* Alternating intramuscular (deltoid) injections of placebo (0.5 mL) on Days 0 and 21.<br>* Other names: Sodium chloride 0.9% (BP, sterile);|
| Experimental: Cohort 2: SARS-CoV-2 rS/Matrix-M1 Adjuvant Plus Licensed Seasonal Flu Vaccine<br>2 doses of 5 µg SARS-CoV-2 rS + 50 µg Matrix-M1 adjuvant (co-formulated), 1 dose each on Days 0 and 21. 1 dose of licensed seasonal flu vaccine on Day 0. | Biological: SARS-CoV-2 rS/Matrix M1-Adjuvant<br>* Alternating intramuscular (deltoid) injections of SARS-CoV-2 rS co-formulated with Matrix-M1 adjuvant (0.5 mL) on Days 0 and 21.<br>* Other names: NVX-CoV2373;Biological: Licensed seasonal influenza vaccine<br>* Single intramuscular injection of licensed seasonal flu vaccine, administered ideally in opposite deltoid to SARS-CoV-2 rS with Matrix-M1 adjuvant or placebo injection on Day 0.<br>|
| Placebo Comparator: Cohort 2: Placebo Plus Licensed Seasonal Flu Vaccine<br>2 doses of Placebo (Saline), 1 dose each on Days 0 and 21. 1 dose of licensed seasonal flu vaccine on Day 0. | Other: Placebo<br>* Alternating intramuscular (deltoid) injections of placebo (0.5 mL) on Days 0 and 21.<br>* Other names: Sodium chloride 0.9% (BP, sterile);Biological: Licensed seasonal influenza vaccine<br>* Single intramuscular injection of licensed seasonal flu vaccine, administered ideally in opposite deltoid to SARS-CoV-2 rS with Matrix-M1 adjuvant or placebo injection on Day 0.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants with Symptomatic Mild, Moderate, or Severe Coronavirus Disease 2019 (COVID-19) | Number of participants, testing serologically negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at baseline, with first occurrence of positive (+) polymerase chain reaction (PCR)-confirmed SARS-CoV-2 illness with symptomatic mild, moderate, or severe COVID-19 with onset from Day 28 through the length of the study. | From Day 28 to Day 386 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants with Symptomatic Moderate or Severe COVID-19 | Number of participants, testing serologically negative for SARS-CoV-2 at baseline with first occurrence of (+) PCR-confirmed, SARS-CoV-2 illness with symptomatic moderate or severe COVID-19 with onset from Day 28 through the length of the study. | From Day 28 to Day 386 | 
| Participants with Symptomatic Severe COVID-19 | Number of participants, testing serologically negative for SARS-CoV-2 at baseline with first occurrence of (+) PCR-confirmed, SARS-CoV-2 illness with symptomatic severe COVID-19 with onset from Day 28 through the length of the study. | From Day 28 to Day 386 | 
| Participants with Symptomatic Mild, Moderate, or Severe COVID-19 Regardless of Baseline Serostatus | Number of participants, regardless of serostatus at baseline, with first occurrence of (+) PCR-confirmed, SARS-CoV-2 illness with symptomatic mild, moderate, or severe COVID-19 assessed from Day 28 through the length of the study. | From Day 28 to Day 386 | 
| Participants with Asymptomatic or Symptomatic COVID-19 | Number of participants, regardless of serostatus at baseline, with first occurrence of (+) PCR-confirmed, or nucleocapsid protein serologically confirmed, SARS-CoV-2 illness with asymptomatic or symptomatic COVID-19 with onset from Day 28 through the length of the study. | From Day 28 to Day 386 | 
| Participants with COVID-19 requiring Hospitalization, Intensive Care Unit (ICU), or Mechanical Ventilation | Number of participants, regardless of serostatus at baseline, with first occurrence of (+) PCR-confirmed, SARS-CoV-2 illness with COVID-19 with onset from Day 28 through the length of the study. | From Day 28 to Day 386 | 
| Participants with Symptomatic Mild COVID-19 | Number of participants, regardless of serostatus at baseline, with first occurrence of (+) PCR-confirmed, SARS-CoV-2 illness with symptomatic mild COVID-19 (with no progression to moderate or severe COVID-19 during the course of the COVID-19 episode) with onset from Day 28 through the length of the study. | From Day 28 to Day 386 | 
| Serum IgG Antibody Levels at Multiple Time Points Expressed as Geometric Mean ELISA Units (GMEUs) | Serum IgG antibody levels specific for the SARS-CoV-2 rS protein antigen(s) as detected by enzyme-linked immunosorbent assay (ELISA) expressed as GMEUs at Day 0 and Day 35. | Day 0 to Day 35 | 
| Participants with Serious Adverse Events (SAEs) | Number of participants with SAEs through the length of the study by Medical Dictionary for Regulatory Activities (MedDRA) classification and relationship to study vaccination. | 386 days | 
| Participants with Medically Attended Adverse Events (MAAEs) Related to Study Vaccination | Number of participants with MAAEs related to study vaccination through the length of the study by MedDRA classification. | 386 days | 
| Participants with Adverse Events of Special Interest (AESIs) | Number of participants with AESIs, which include potential immune-mediated medical conditions (PIMMCs) and AESIs relevant to COVID-19 such as possible vaccine-enhanced disease by MedDRA classification through the length of the study. | 386 days | 
| Participants with Solicited Local and Systemic Adverse Events (AEs) | Number of participants with solicited local and systemic AEs for 7 days after each study vaccination. | 28 days | 
| Participants with All MAAEs Through Day 35 | Number of participants with all MAAEs through Day 35 by MedDRA classification and relationship to study vaccination. | 35 days | 
| Participants with Unsolicited AEs Through Day 49 | Number of participants with unsolicited AEs through Day 49 by MedDRA classification and relationship to study vaccination. | 49 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Coronavirus