The primary objective of the study is to determine the relative efficacy of the investigational oral severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) vaccine tablet VXA-CoV2-3.3 compared to a currently recommended vaccine for the prevention of symptomatic Coronavirus Disease 2019 (COVID-19).

In order to represent a more recently circulating SARS-CoV-2 variant, the main study endpoints will now evaluate the VXA-CoV2-3.3 (KP.2 strain) vaccine, and not the VXA-CoV2-3.1 (XBB.1.5 strain) vaccine.

Inclusion Criteria:

1. Adults 18 years of age and above, at time of screening.
2. Completed primary approved/authorized COVID-19 vaccination series and have received ≥ 2 mRNA vaccine doses.
3. Last COVID-19 vaccine received ≥6 months prior to study vaccination.
4. Male and female participants of childbearing potential must agree to consistently use a highly effective method of contraception from at least 30 days prior to enrollment and through 3 months after the last study vaccination.
5. Male participants must refrain from sperm donation from the day of study vaccination through the end of the study. Female participants must refrain from egg donation at least 30 days prior to study vaccination through the end of the study.
6. Is medically stable, as determined by the site investigator (based on review of health status, vital signs, medical history, and physical examination) with screening lab values within normal limits or abnormalities assessed as not clinically significant. Screening platelet count must be >140,000/μL.
7. Agree to not participate in any other SARS-CoV-2 infection prevention trials (vaccine, drug, biologic, PReP) during participation in the study.
8. Willing and able to provide informed consent prior to initiation of study procedures.
9. Available for all study visits, willing to participate in all study procedures, and not planning to relocate from the area for the duration of the study.
10. Negative rapid antigen Covid test at the screening visit and on Day 1 prior to vaccine dosing. An indeterminate should be considered as positive for the purposes of screen-failing participants.

Exclusion Criteria:

1. Participant has an acute illness as defined by any of the following (note: assessment may be repeated once during screening period) as determined by the site investigator, within 72 hours prior to vaccination:

   1. An acute illness that is nearly resolved, with only minor residual symptoms remaining, is allowable if, in the opinion of the site investigator, the residual symptoms will not interfere with the ability of study staff to assess safety parameters as required by the protocol.
   2. Presence of a fever ≥ 38.0°C (100.4°F) measured orally at baseline, on Day 1 prior to vaccination.
   3. Receipt of antipyretic/analgesic medications within 24 hours prior to vaccine administration.

2. Participant has had a positive COVID test within 90 days prior to screening.

3. Current or planned participation in any other interventional clinical trial.

4. Participation in research involving any investigational product within 45 days prior to study vaccination.

5. Receipt of any approved or authorized products intended to prevent SARS-CoV2 infection within 6 months prior to study vaccination.

6. Receipt or donation of blood products or immunoglobulins within 60 days prior to enrollment or planned administration during the study.

7. Received influenza vaccination within 14 days prior to study vaccination, or any other vaccine within 30 days prior to study vaccination.

8. Any autoimmune or immunodeficiency disease/condition (including and not limited to untreated or advanced HIV infection with CD4 counts <200 cells/mm^3, history of AIDS defining illness without immune reconstitution, or clinical manifestations of symptomatic HIV, severe combined immunodeficiency (SCID), hypogammaglobulinemia, asplenia or functional asplenia). Gout managed only for elevated uric acid without gout flares would not be exclusionary, provided no prohibited medications were used.

9. Unstable medical or psychiatric illness (acute or chronic illness) requiring significant medical monitoring and intervention during the 90 days prior to enrollment. Note: diabetes mellitus (Types 1 & 2) are not excluded if assessed by the principal investigator (PI) as well-controlled.

10. Administration of immunosuppressants, systemic glucocorticoids, or other immune-modifying drugs within the following timeframes:

    1. B-cell therapies within the 6 months prior to first study vaccination
    2. Prednisone, ≥20 mg for more than 2 weeks, within the 30 days prior to study vaccination
    3. Other medications in this category, including but not limited to high-dose inhaled corticosteroids (>800 mcg/day of beclomethasone dipropionate or equivalent); antimetabolites; transplant immunosuppressive agents; alkylating agents; cell-depleting agents; or cancer chemotherapeutics, within the 90 days prior to study vaccination.
    4. Any medication for any period of time that, in the opinion of the site investigator, could impede immune response to vaccination.
    5. Use of any dose montelukast OR inhaled, intranasal, intra-articular, or systemic corticosteroids within 2 weeks prior to study vaccination.
    6. Planned use of any of the above medications during the study.
    7. Concomitant allergen immunotherapy (AIT) will be allowed only if the participant is stable in the maintenance phase of AIT. Maintenance AIT should not be dosed for at least 7 days before and 7 days after study vaccine dosing, and the PI must document the treating allergist's approval.

11. Known contraindication to IM injection or blood draws (e.g. bleeding diathesis, acquired coagulopathy, significant bleeding or bruising) or to oral route of administration (unable to swallow tablets).

12. Any known allergies to components contained in the investigational product or comparator or latex allergy (including polyethylene glycol [PEG] allergies) and/or history of serious reactions to vaccination such as anaphylaxis, respiratory problems, hives, or abdominal pain.

13. Women who are pregnant (pregnancy tests will be performed at screening and prior to dosing), breastfeeding, or who plan to become pregnant during the study.

14. History of irritable bowel disease or other inflammatory digestive or gastrointestinal condition that could affect the distribution/safety evaluation of an orally administered vaccine targeting the mucosa of the small intestine. Such conditions may include but are not limited to:

    1. Any history of:

       • GI malignancy
       • malabsorption
       • pancreatobiliary disorders
       • inflammatory bowel disease
       • irritable bowel disease
       • hiatal hernia
       • surgical resection

    2. History of diagnosis or treatment in past 5 years of:

       • esophageal or gastric motility disorder
       • gastroesophageal reflux disorder if any of the following is met: History of severe or uncontrolled gastroesophageal reflux disease (GERD) at any point during this period History of complicated GERD at any point during this period Was on treatment for 12 continuous weeks at any point during this period Has been with chronic or frequent GERD symptoms (e.g., more than twice per week) in the past year
       • peptic ulcer if any of the following is met: History of severe or uncontrolled peptic ulcer at any point during this period History of complicated peptic ulcer at any point during this period Was on treatment for 12 continuous weeks at any point during this period Has been with chronic or frequent peptic ulcer symptoms (e.g., more than twice per week) in the past year
       • cholecystectomy, if any of the following is met: Procedure was performed within 1 year of dosing, or The participant has ongoing/unresolved post-cholecystectomy digestive symptoms within 30 days prior to dosing

15. Use of oral or parenterally administered antibiotics, proton pump inhibitors, H2 blockers, or antacids within 7 days prior to study drug administration or planned use from dosing through Day 31.

16. Use of drugs known to affect gastrointestinal motility including glucagon-like peptide 1 (GLP-1) receptor agonists including tirzepatide (Mounjaro) and semaglutide (Wegovy, Ozempic) within 30 days prior to drug administration. The participant may resume GLP-1 receptor agonists only if all solicited symptoms have completely resolved, with the earliest restart date being Day 9.

17. Daily use (2 or more consecutive days) of nonsteroidal anti-inflammatory drugs within 7 days prior to study drug administration through Day 8 (7 days post-vaccination). Low dose daily ASA ≤ 100 mg for cardio-protection is not exclusionary.

18. Personal or familial history of hypercoagulable states to include personal past history of deep vein thrombosis (DVT).

19. Personal history of myocarditis or pericarditis.

20. Positive Hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV) antibody at the screening visit. Confirmation of positive results with molecular testing is not required.

21. History of drug, alcohol, or chemical abuse within 1 year of screening.

22. Positive urine drug screen for drugs of abuse at screening, except in case of occasional marijuana use. Chronic marijuana use (as determined by the investigator's discretion) or a known history of marijuana abuse in the setting of a positive test is exclusionary. Concurrent or planned use of marijuana from dosing through Day 31 is prohibited. Positive urine drug screen (UDS) at screening due to prescribed stimulants will be reviewed on a case by case basis with the Medical Monitor's approval.

23. Cancer, or treatment for cancer, within the past 3 years (excluding fully treated and resolved basal cell carcinoma or squamous cell carcinoma).

24. History of any form of angioedema.

25. History of GI bleeding including hematochezia (blood in stool) or melena (black stool) of unknown etiology or that has not been evaluated.

26. Any history or conditions that may lead to a higher risk of clotting events and/or thrombocytopenia, including:

    1. Familial coagulopathy or personal history of bleeding disorder or thrombosis. A personal history of stroke, myocardial infarction, or similar condition may not be exclusionary if the participant is medically stable and not receiving a prohibited medication such as an anticoagulant or thrombolytic (low dose prophylactic aspirin is permitted)

    2. History of heparin-related thrombotic events, and/or receiving heparin treatments

    3. History of autoimmune or inflammatory disease

    4. Presence of any of the following conditions known to increase the risk of thrombosis within 6 months prior to screening:

       • Recent surgery other than fully healed cesarean delivery, excision/ biopsy of cutaneous lesions or other procedures that do not require general anesthetic and/or prolonged immobility
       • Immobility (confined to bed or wheelchair for 3 or more successive days)
       • Head trauma with loss of consciousness or documented brain injury
       • Receipt of anticoagulants for prophylaxis of thrombosis (low dose aspirin is permitted)
       • Recent clinically significant infection including hospitalization for COVID-19 related illness.

27. 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 investigational product or interpretation of study results.

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