A Study to Evaluate the Efficacy, Immune Response, and Safety of a COVID-19 Vaccine in Adults ≥ 18 Years With a Pediatric Expansion in Adolescents (12 to<18 Years) at Risk for SARS-CoV-2

Inclusion Criteria: Adult Participants : Each participant in the Adult Main Study and/or the Booster Amendment must meet all of thefollowing criteria to be enrolled in this study:

1. Adults ≥ 18 years of age at screening who, by virtue of age, race, ethnicity or lifecircumstances, are considered at substantial risk of exposure to and infection withSARS CoV-2.
2. Willing and able to give informed consent prior to study enrollment and to comply withstudy procedures.
3. Participants of childbearing potential (defined as any participant who has experiencedmenarche and who is NOT surgically sterile [i.e., hysterectomy, bilateral tuballigation, or bilateral oophorectomy] or postmenopausal [defined as amenorrhea at least 12 consecutive months]) must agree to be heterosexually inactive from at least 28 daysprior to enrollment and through 3 months after the last vaccination OR agree toconsistently use a medically acceptable method of contraception from at least 28 daysprior to enrollment and through 3 months after the last vaccination.
4. Is medically stable, as determined by the investigator (based on review of healthstatus, vital signs [to include body temperature], medical history, and targetedphysical examination [to include body weight]). Vital signs must be within medicallyacceptable ranges prior to the first vaccination.
5. Agree to not participate in any other SARS-CoV-2 prevention trial during the studyfollow-up.
6. For the Booster Amendment only, active participants who received a full dose regimenof active vaccine (SARS-CoV-2 rS with Matrix-M1 adjuvant) or any authorized/approvedCOVID-19 vaccine are eligible for participation. Such participants must demonstratereceipt by producing valid documentation of vaccination at the booster visit. Pediatric Participants : Each participant in the Pediatric Expansion and/or the Booster Amendment must meet all ofthe following criteria to be enrolled in this study:
7. Pediatric participants 12 to < 18 years of age at screening, determined to be healthyor medically stable by the investigator (based on review of health status, vital signs [to include body temperature], medical history, and targeted physical examination [toinclude body weight]). Vital signs must be within medically acceptable ranges prior tothe first vaccination.
8. Participant and parent(s)/caregiver(s) or legally acceptable representative willingand able to give informed consent and assent, as required, prior to study enrollmentand to comply with study procedures.
9. Participants of childbearing potential (defined as any participant who has experiencedmenarche and who is NOT surgically sterile [ie, hysterectomy, bilateral tuballigation, or bilateral oophorectomy] must agree to be heterosexually inactive from atleast 28 days prior to enrollment and through 3 months after the last vaccination ORagree to consistently use a medically acceptable method of contraception from at least 28 days prior to enrollment and through 3 months after the last vaccination.
10. Agree to not participate in another SARS-CoV-2 prevention trial during the studyfollow-up.
11. For the Booster Amendment only, active participants who received a full dose regimenof active vaccine (SARS-CoV-2 rS with Matrix-M1 adjuvant) or any authorized/approvedCOVID-19 vaccine are eligible for participation. Such participants must demonstratereceipt by producing valid documentation of vaccination. Site-Specific Sub Study: Each participant in the Substudy must meet all of the following criteria to be enrolled inthis study:
12. Be an active, enrolled participant in the 2019nCoV-301 study.
13. Adults 18 years of age or older or adolescents 12 to < 18 years of age at initialscreening for the parent study.
14. Willing and able to give informed consent prior to substudy enrollment and to complywith extra study procedures.
15. Documented receipt of the 2 doses of the primary series of NVX-CoV2373 and the booster (third dose) of NVX-CoV2373 in the parent protocol. The booster dose must have beenadministered at least 6 months prior to entering the substudy.
16. Participants of childbearing potential (defined as any participant who has experiencedmenarche and who is NOT surgically sterile or postmenopausal) must agree to beheterosexually inactive from at least 28 days prior to entering and through the end ofthe substudy OR agree to consistently use a medically acceptable method ofcontraception for the 28 days of follow-up for the substudy.
17. Is medically stable, as determined by the investigator (based on review of healthstatus, vital signs (to include body temperature) and targeted physical examination (if medically indicated by reported symptoms). Vital signs must be within medicallyacceptable ranges prior to administration of study vaccination.
18. Agree to not participate in any other non-NVX-CoV2373 study during the substudy. Note: For participants who develop COVID-19, anti-SARS-CoV-2 therapy (approved, authorizedor investigational) is permitted.

Exclusion Criteria: Adult and adolescent participants meeting any of the following criteria will be excludedfrom the study:

1. Unstable acute or chronic illness. Criteria for unstable medical conditions include:
2. Substantive changes in chronic prescribed medication (change in class orsignificant change in dose) in the past 2 months.
3. Currently undergoing workup of undiagnosed illness that could lead to diagnosisof a new condition. Note: Well-controlled human immunodeficiency virus [HIV] with undetectable HIV RNA [< 50 copies/mL] and CD4 count > 200 cells/µL for at least 1 year, documented within thelast 6 months, is NOT considered an unstable chronic illness. Participant's orparent's/caregiver's verbal report will suffice as documentation.
4. Participation in research involving an investigational product (drug/biologic/device)administered within 45 days prior to first study vaccination.
5. History of a previous laboratory-confirmed diagnosis of SARS-CoV-2 infection orCOVID-19. A previous diagnosis of COVID-19 during participation in this trial is notexclusionary for the Booster Amendment.
6. Received any vaccine within 4 days prior to first study vaccination or planned receiptof any vaccine before Day 49 (i.e., 28 days after second vaccination), except forinfluenza vaccination, which may be received ≥ 4 days prior to or ≥ 7 days aftereither study vaccination. Rabies vaccine, at any time it is medically indicated, isnot exclusionary. Prior receipt of another approved or authorized COVID-19 vaccineprior to booster injection is not exclusionary in the Booster Amendment. Suchparticipants must provide documentation of vaccine and date(s) of administration.
7. Autoimmune or immunodeficiency disease/condition (iatrogenic or congenital) or therapythat causes clinically significant immunosuppression. NOTE: Stable endocrine disorders (eg, thyroiditis, pancreatitis, including stable diabetes mellitus) are NOT excluded.
8. Chronic administration (defined as > 14 continuous days) of immunosuppressant orsystemic glucocorticoids causing clinically significant immunocompromise, within 90days prior to first study vaccination and/or third (booster) vaccination. NOTE: Animmunosuppressant dose of glucocorticoid is defined as a systemic dose ≥ 20 mg ofprednisone per day or equivalent. The use of topical, inhaled, and nasalglucocorticoids is permitted. Topical tacrolimus and ocular cyclosporin are permitted.
9. Received immunoglobulin or blood-derived products, within 90 days prior to first studyvaccination and/or third (booster) vaccination.
10. Active cancer (malignancy) on chemotherapy that is judged to cause clinicallysignificant immunocompromise within 1 year prior to first study vaccination (with theexception of malignancy cured via excision, at the discretion of the investigator).This criterion is not applicable to participants diagnosed during participation inthis trial who accept participation in the Booster Amendment.
11. Any known allergies to products contained in the investigational product.
12. Participants who are breastfeeding, pregnant, or who plan to become pregnant within 3months following last study vaccination.
13. Any other condition that, in the opinion of the investigator, would pose a health riskto the participant if enrolled or could interfere with evaluation of the trial vaccineor interpretation of study results.
14. Study team member or first-degree relative of any study team member (inclusive ofSponsor, and study site personnel involved in the study).
15. Current participation in any other COVID-19 prevention clinical trial.
16. Adult participants who have not received a full dose of any authorized/approvedCOVID-19 vaccine and are unable to provide valid documentation of vaccination will beexcluded from the Booster Amendment. Adult and adolescent participants meeting any of the following criteria will be excludedfrom the substudy:
17. History of laboratory-confirmed (by PCR or other antigen testing) COVID-19 infection ≤ 4 months prior to entering the substudy.
18. Known to be clinically significantly immunocompromised.
19. Received immunoglobulin, blood-derived products, or immunosuppressant drugs within 90days prior to entering substudy.
20. Participants who are breastfeeding, pregnant, or who plan to become pregnant prior tothe end of substudy.
21. History of confirmed myocarditis and/or pericarditis since enrollment to the parentstudy.
22. Any condition that, in the opinion of the investigator, might pose a health risk tothe participant, interfere with protocol compliance or interfere with evaluation ofthe trial vaccine.
23. Study team member or immediate family member of any study team member (inclusive ofSponsor, CRO, and study site personnel involved in the conduct or planning of thesubstudy).