This is a Multi-Part, Phase 3, randomized, observer-blinded study to evaluate the safety and immunogenicity of booster doses of Omicron subvariant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) recombinant (r) spike (S) protein nanoparticle vaccines (SARS-CoV-2 rS) adjuvanted with Matrix-M™ adjuvant (NVX-CoV2515 [BA.1] and NVX-CoV2540 [BA.5]) and bivalent (NVX-CoV2373 [prototype] + Omicron subvariant) SARS-CoV-2 rS vaccines (NVX-CoV2373 + NVX CoV2515 and NVX CoV2373 + NVX CoV2540) in previously vaccinated adults 18 years of age and older.

Part 1

Inclusion Criteria:

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

1. Adults ≥ 18 and ≤ 64 years of age at screening.
2. Willing and able to give informed consent prior to study enrollment and to comply with study procedures.
3. Female 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] or postmenopausal [defined as amenorrhea ≥ 12 consecutive months]) must agree to be heterosexually inactive from at least 28 days prior to enrollment and through the end of the study OR agree to consistently use a medically acceptable method of contraception listed below from ≥ 28 days prior to and through the end of the study.
4. Is medically stable, as determined by the investigator (based on a 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 medically acceptable ranges prior to the vaccination.
5. Agrees to not participate in any other SARS-CoV-2 prevention or treatment trials for the duration of the study.
6. Have previously received 2 doses of the Moderna and/or Pfizer-BioNTech COVID-19 prototype vaccines with the last dose having been given ≥ 180 days prior to study vaccination or 3 doses of the Moderna and/or Pfizer-BioNTech COVID-19 prototype vaccines with the last dose having been given ≥ 90 days previously prior to the study vaccination.

Exclusion Criteria:

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

1. Received COVID-19 vaccines other than Moderna and/or Pfizer-BioNTech in the past, inclusive of clinical trial COVID- 19 vaccines.
2. Participation in research involving receipt of investigational products (drug/biologic/device) within 90 days prior to study vaccination.
3. Received any vaccine ≤ 90 days prior to study vaccination, except for influenza vaccination which may be received > 14 days prior to study vaccination, or rabies vaccine which may be given if medically indicated.
4. Any known allergies to products contained in the investigational product.
5. Any history of anaphylaxis to any prior vaccine.
6. Autoimmune or immunodeficiency disease/condition (iatrogenic or congenital) requiring ongoing immunomodulatory therapy.
7. Chronic administration (defined as > 14 continuous days) of immunosuppressant, systemic glucocorticoids, or other immune-modifying drugs within 90 days prior to study vaccination.
8. Received immunoglobulin, blood-derived products, or immunosuppressant drugs within 90 days prior to the first study vaccination, except for rabies immunoglobulin which may be given if medically indicated.
9. Active cancer (malignancy) on therapy within 3 years prior to study vaccination (with the exception of adequately treated non-melanomatous skin carcinoma or lentigo maligna and uterine cervical carcinoma in situ without evidence of disease, at the discretion of the investigator).
10. Participants who are breastfeeding, pregnant, or who plan to become pregnant prior to the end of the study.
11. Suspected or known history of alcohol abuse or drug addiction within 2 years prior to the study vaccine dose that, in the opinion of the investigator, might interfere with protocol compliance.
12. Any other condition that, in the opinion of the investigator, would pose a health risk to the participant if enrolled or could interfere with evaluation of the study vaccine or interpretation of study results (including neurologic or psychiatric conditions likely to impair the quality of safety reporting).
13. Study team member or immediate family member of any study team member (inclusive of Sponsor, clinical research organization (CRO), and study site personnel involved in the conduct or planning of the study).

Part 2

Inclusion Criteria:

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

1. Adults and adolescents ≥ 18 years of age at screening.
2. Willing and able to give informed consent prior to study enrollment and to comply with study procedures.
3. Female 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] or postmenopausal [defined as amenorrhea ≥ 12 consecutive months]) must agree to be heterosexually inactive from at least 28 days prior to enrollment and through the end of the study OR agree to consistently use a medically acceptable method of contraception listed below from ≥ 28 days prior to enrollment and through the end of the study.
4. Is medically stable, as determined 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 medically acceptable ranges prior to the first vaccination.
5. Agrees to not participate in any other SARS-CoV-2 prevention or treatment trials for the duration of the study.
6. Have previously received ≥ 3 doses of the Moderna and/or Pfizer-BioNTech monovalent and/or bivalent COVID-19 vaccines with the last dose having been given ≥ 90 days previously prior to first study booster.

Exclusion Criteria:

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

1. Received COVID-19 vaccines other than Moderna and/or Pfizer-BioNTech in the past, inclusive of clinical trial COVID-19 vaccines.
2. Participation in research involving receipt of investigational products (drug/biologic/device) within 90 days prior to first study vaccination.
3. Received any vaccine ≤ 90 days prior to study vaccination, except for influenza vaccination which may be received > 14 days prior to first study vaccination, or rabies vaccine which may be given if medically indicated.
4. Any known allergies to products contained in the investigational product.
5. Any history of anaphylaxis to any prior vaccine.
6. Autoimmune or immunodeficiency disease/condition (iatrogenic or congenital) requiring ongoing immunomodulatory therapy.
7. Chronic administration (defined as > 14 continuous days) of immunosuppressant, systemic glucocorticoids, or other immune-modifying drugs within 90 days prior to first study vaccination.
8. Received immunoglobulin, blood-derived products, or immunosuppressant drugs within 90 days prior to first study vaccination, except for rabies immunoglobulin which may be given if medically indicated.
9. Active cancer (malignancy) on therapy within 3 years prior to first study vaccination (with the exception of adequately treated non-melanomatous skin carcinoma or lentigo maligna and uterine cervical carcinoma in situ without evidence of disease, at the discretion of the investigator).
10. Participants who are breastfeeding, pregnant, or who plan to become pregnant prior to the end of study.
11. Suspected or known history of alcohol abuse or drug addiction within 2 years prior to the first study vaccine dose that, in the opinion of the investigator, might interfere with protocol compliance.
12. Any other condition that, in the opinion of the investigator, would pose a health risk to the participant if enrolled or could interfere with evaluation of the study vaccine or interpretation of study results (including neurologic or psychiatric conditions likely to impair the quality of safety reporting).
13. Study team member or immediate family member of any study team member (inclusive of Sponsor, clinical research organization [CRO], and study site personnel involved in the conduct or planning of the study).
14. Participants with a history of myocarditis or pericarditis