This is a Phase 2/3 randomized, observer-blinded, placebo-controlled, age de-escalation trial to evaluate the safety and immunogenicity of 2 primary doses of SARS-CoV-2 rS with Matrix-M™ adjuvant (NVX-CoV2373) given 21 days apart and NVX CoV2373 or a variant-based vaccine given as a booster dose or at crossover in pediatric participants (3 age cohorts; 6 to < 12 years, 2 to < 6 years, and 6 to < 24 months of age). Each age cohort will be conducted in 2 parts starting with the oldest age cohort (6 to < 12 years of age).

This is a Phase 2/3 randomized, observer-blinded, placebo-controlled, age de-escalation trial to evaluate the safety and immunogenicity of 2 primary doses of SARS-CoV-2 rS with Matrix-M™ adjuvant (NVX-CoV2373) given 21 days apart and NVX CoV2373 or a variant-based vaccine given as a booster dose or at crossover in pediatric participants (3 age cohorts; 6 to < 12 years, 2 to < 6 years, and 6 to < 24 months of age).

Each age cohort will be conducted in 2 parts starting with the oldest age cohort (6 to < 12 years of age).

Part 1 will enroll approximately 120 healthy or medically stable sentinel participants per age cohort (10% of the intended enrollment population per age cohort, for a total of 360 sentinel participants overall) who will be randomized in a 1:1 ratio to receive 2 doses of NVX-CoV2373 or placebo with doses given 21 days apart.

Part 2 will enroll a larger number of healthy or medically stable participants (N= approximately 1,080 per age cohort), for a total of approximately 3,240 pediatric participants enrolled in Part 2, and a total of approximately 3,600 participants enrolled in the entire trial). Initial randomization in Part 2 will be in a 2:1 ratio, and the safety and effectiveness of 2 doses of NVX-CoV2373 given 21 days apart will be assessed.

Inclusion Criteria:

To be included in this study, each individual must satisfy all of the following criteria:

1. Pediatric participants 6 months to < 12 years of age at randomization, determined to be healthy or medically stable by the investigator (based on review of health status, vital signs [to include body temperature], medical history, and targeted physical examination [to include body weight]). Vital signs must be within the normal range prior to the first vaccination, according to the child's age, sex, weight, and height/length.
2. For children from 6 months to < 12 months of age: born at full-term (≥ 37 weeks gestation) with a minimum birth weight of 2.5 kilograms (kg).
3. Participant and parent(s)/caregiver(s) or legally acceptable representative willing and able to give informed consent and assent, as required, prior to study enrollment and to comply with study procedures.
4. Participants of childbearing potential (defined as any participant who has experienced menarche and who is NOT surgically sterile [ie, hysterectomy, bilateral tubal ligation, or bilateral oophorectomy]) must agree to be heterosexually inactive from at least 28 days prior to enrollment and through 3 months after the last vaccination OR agree to consistently use a highly effective contraception method from at least 28 days prior to enrollment and through 3 months after the last vaccination.
5. Agree not to participate in another SARS-CoV-2 prevention trial for the duration of the study.

Exclusion Criteria:

If an individual meets any of the following criteria, he or she is ineligible for this study:

1. Any acute illness/infection (according to investigator judgment) on the day of vaccination or febrile illness (temperature ≥ 100.4°F [≥ 38.0°C]). A prospective subject should not be included in the study until the condition has resolved or the febrile event has subsided.

2. Unstable acute or chronic illness. Criteria for unstable medical conditions include:

   1. Substantive changes in chronic prescribed medication (change in class or significant change in dose) in the past 2 months.
   2. Currently undergoing workup of undiagnosed illness that could lead to a diagnosis of a new condition.

   NOTE: Well-controlled human immunodeficiency virus [HIV] infection with undetectable HIV ribonucleic acid [RNA < 50 copies/mL] and CD4 count > 200 cells/µL for at least 1 year, documented within the last 6 months, is NOT considered an unstable chronic illness. Participant's or parent's/caregiver's verbal report will suffice as documentation.

3. Participation in research involving an investigational product (drug/biologic/device) administered within 45 days prior to the first study vaccination.

4. History of a previous laboratory-confirmed diagnosis of SARS-CoV-2 infection or COVID-19.

5. Prior administration of an investigational, authorized, or approved Coronavirus vaccine (ie, against either SARS-CoV, SARS-CoV-2, or MERS CoV) or expected receipt during the period of study follow-up.

6. Previous or current diagnosis of MIS-C.

7. Receipt of medications intended to prevent or treat COVID-19.

8. Received any vaccine within 14 days prior to first study vaccination or planned receipt of any vaccine before Day 49 (ie, 28 days after the second vaccination), except for influenza vaccination, which may be received > 14 days prior to or > 14 days after any study vaccination.

9. Known or suspected congenital or acquired immunodeficiency or autoimmune disease/condition; or receipt of immunosuppressive therapy, such as anti-cancer chemotherapy or radiation therapy; or long-term systemic corticosteroid therapy (prednisone or equivalent for > 14 continuous days) within 90 days prior to first study vaccination. NOTE: An immunosuppressant dose of glucocorticoid is defined as a systemic dose ≥ 20 mg of prednisone per day or equivalent. The use of topical, inhaled, and nasal glucocorticoids is permitted. Topical tacrolimus and ocular cyclosporin are permitted. Stable autoimmune endocrine disorders (eg, thyroiditis, pancreatitis), including stable diabetes mellitus type 1, or participants with a history of Kawasaki disease are NOT excluded.

10. Received immunoglobulin or blood-derived products within 90 days prior to first study vaccination.

11. Active cancer (malignancy) on chemotherapy within 1 year prior to first study vaccination (with the exception of malignancy cured via excision, at the discretion of the investigator).

12. Any known allergies to products contained in the investigational product.

13. Participants who are breastfeeding a child, pregnant or who plan to become pregnant within 3 months following the last study vaccination.

14. Any other condition that, in the opinion of the investigator, would pose a health risk to the participant if enrolled or could interfere with the evaluation of the trial vaccine or interpretation of study results.

15. Study team member or first-degree relative of any study team member (inclusive of Sponsor, and study site personnel involved in the study).

16. Current participation in any other COVID-19 prevention clinical trial.

17. Participants with a history of myocarditis or pericarditis.