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.

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.