The purpose of this study is to evaluate the safety, reactogenicity and immune responses of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA-CR-04 vaccine construct when administered in healthy adults previously vaccinated with SARS-CoV-2 mRNA vaccines.

There will be dose-escalation in part A of the study with sentinel dosing strategy implemented in each of 3 dosing levels (Group 1; 2; 3). At start, enrollment in Group 1 and 2 will occur simultaneously with the enrolment of 1st participant in Group 1. Each group will consist of 8 sentinel participants, with 6 receiving the mRNA-CR-04 vaccine and 2 receiving a placebo. The safety data from the sentinel participants in both groups, up to Day 8 post-vaccination, will be reviewed by the Internal Safety Review Committee (iSRC).

If no safety signal is observed, vaccination of the non-sentinel participants in that group will continue. If there are no safety signals observed from the sentinel participants in Group 1 and Group 2, the enrollment and vaccination of the sentinel participants in Group 3 will begin.

Part B of the study will commence only after all Part A participants have completed their Day 15 study visits and the Day 15 interim analysis is completed. In Part B, 2 doses of the mRNA-CR-04 vaccine will be evaluated.

Inclusion Criteria:

1. Written or witnessed informed consent obtained from the participant prior to performance of any study-specific procedure.
2. Participants, who in the opinion of the investigator, can and will comply with the requirements of the protocol (e.g., completion of the eDiary and study procedures).
3. Has received 2 doses of primary series and booster dose(s) of an authorized or licensed mRNA COVID-19 vaccine (only Moderna or Pfizer vaccines) with the last booster dose administered between at least 6 and 18 months or more prior to screening and has provided documentation of receiving the vaccination series (e.g., vaccination card).
4. Negative for SARS-CoV-2 infection by RT-PCR test at screening within 7 days prior to study vaccination.
5. Is a male or nonpregnant female of 18 to 49 years, inclusive, at screening.
6. If the participant is a woman of childbearing potential (WOCBP), the participant agrees to practice true abstinence or use at least 1 highly effective form of contraception for at least 30 days prior to study vaccination up to 1 month after study vaccination.
7. Agrees to refrain from blood or plasma donation from screening and up to 6 months after vaccination.
8. Is healthy or medically stable as determined by investigator judgment based on medical history, clinical laboratory tests, vital sign measurements, and physical examination findings.

Exclusion Criteria:

1. Has a new onset, clinically significant, abnormal biochemistry or hematology finding [defined as greater than or equal to (>=) Grade 1] at screening (participants with Grade 1 laboratory abnormalities that have been stable for at least 6 months before enrollment may be included in the study).

2. Has any medical disease or condition that, in the opinion of the investigator, precludes study participation. This includes any acute, subacute, intermittent, or chronic medical disease or condition that would place the participant at an unacceptable risk of injury, render the participant unable to meet the requirements of the protocol, or may interfere with the evaluation of responses or the participant's successful completion of the trial.

3. Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination (no laboratory testing required).

4. History of myocarditis, pericarditis, second- and third-degree heart block or idiopathic cardiomyopathy, or presence of any medical condition that increases risk of myocarditis or pericarditis, including cocaine abuse, cardiomyopathy, endomyocardial fibrosis, hypereosinophilic syndrome, hypersensitivity myocarditis eosinophilic granulomatosis with polyangiitis, persistent myocardial viral infection (e.g., due to enterovirus or adenovirus).

5. Has an acute febrile illness with a temperature >=38.0 degree Celsius (°C) or >=100.4 degree Fahrenheit (°F) observed by the participant or at the study site within 72 hours prior to study vaccination. Participants with suspected COVID-19 symptoms should be excluded and referred for medical care.

6. Has a history of hypersensitivity or severe allergic reaction, including anaphylaxis, generalized urticaria, angioedema, and other significant reactions to any previous vaccine, or any component of the study vaccine.

7. Has a body mass index greater than (>) 40 Kilograms meter per square (kg/m^2).

8. Has had known close contact with anyone who had a confirmed SARS-CoV-2 infection within 14 days before study vaccination.

9. Has a history of documented SARS-CoV-2 infection or COVID-19 within 6 months before the date of screening visit.

10. Has any self-reported or medically documented clinically significant medical or psychiatric condition. Significant medical conditions include, but are not limited to, the following:

    1. Moderate or severe respiratory disease (e.g., chronic obstructive pulmonary disease, asthma).
    2. Uncontrolled hypertension, defined as an average systolic blood pressure >= 140 millimeters of mercury (mmHg) or an average diastolic blood pressure >= 90 mmHg, based on an average of up to 3 blood pressure measurements.
    3. Clinically significant cardiovascular disease (e.g., congestive heart failure, cardiomyopathy, ischemic heart disease).
    4. Neurological or neurodevelopmental conditions (e.g., Down syndrome, dementia, chronic migraine not controlled by medication, epilepsy, stroke or seizures in the last 3 years, encephalopathy, focal neurologic deficits, Guillain- Barré syndrome, encephalomyelitis, or transverse myelitis).
    5. Ongoing malignancy or recent diagnosis of malignancy in the last 5 years (excluding basal cell and squamous cell carcinoma of the skin).
    6. Tuberculosis or non-tuberculosis mycobacterial infection.
    7. Autoimmune disease, including hypothyroidism without a defined nonautoimmune cause.
    8. Immunodeficiency of any cause, including from solid organ transplant, blood, or bone marrow transplant, or use of other immune-weakening medicine.
    9. Type 1 or 2 diabetes mellitus regardless of disease control.

11. Has any of the following self-reported or medically documented risk factors for severe COVID-19:

    1. Chronic kidney disease
    2. Cerebrovascular disease
    3. Cystic fibrosis
    4. Chronic liver disease
    5. Pulmonary fibrosis

12. Has participated or plans to participate in another investigational study involving any investigational drug or device within 60 days or 5 half-lives, whichever is longer, before study vaccination and throughout the study.

13. Has received a licensed or authorized non-mRNA COVID-19 vaccine (primary series or booster dose).

14. Has received or plans to receive any licensed vaccine within 4 weeks before or after study vaccination. Inactivated vaccines for influenza are permitted during the study if they are administered at least 14 days before or after study vaccination.

15. Is planning to receive an authorized or licensed COVID-19 booster vaccination for the duration of the study (for participants who are not covered by local recommendations to receive booster per current standard of care) OR is planning to receive an authorized or licensed COVID-19 booster vaccination on or before Day 31 of the study (for participants covered by local recommendations to receive booster).

16. Has received or plans to receive immunoglobulins or any blood or blood products within 90 days before study vaccination and throughout the study.

17. Reports chronic use (more than 14 continuous days) of any medication that may be associated with changes in immune function including, but not limited to, systemic corticosteroids exceeding 20 mg/day of prednisone equivalent, allergy injections, immunoglobulins, interferons, immunomodulators, cytotoxic drugs, or other similar or toxic drugs within 6 months of study vaccination. Note: The use of low-dose topical, ophthalmic, inhaled, intra-articular and intranasal steroid preparations is permitted.

18. Pregnant or lactating female.

19. Female participant planning to become pregnant or planning to discontinue contraceptive precautions within 1 month following study vaccination.

20. Participant is an employee or family member of the investigator or study site personnel.

GSK will assess requests from qualified researchers for anonymized individual patient-level data and related study documents. Data sharing is subject to certain criteria, conditions, and exceptions. For further information, refer tohttps://www.gsk-studyregister.com/About_GSK_Patient_Level_Data_Sharing_Final_13July2023.pdf.

IPD will be made available within 6 months of publishing the results of the primary endpoints, a key secondary endpoints and safety data of the study.

Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Data will be collected in an observer-blind manner.