Safety and Immunogenicity Study of 2019-nCoV Vaccine (mRNA-1273) for Prophylaxis of SARS-CoV-2 Infection (COVID-19)

This is a phase I, open-label, dose-ranging clinical trial in males and non-pregnant females, starting at 18 years of age, inclusive, who are in good health and meet all eligibility criteria. This clinical trial is designed to assess the safety, reactogenicity and immunogenicity of mRNA-1273 manufactured by ModernaTX, Inc. mRNA-1273 is a novel lipid nanoparticle (LNP)-encapsulated mRNA-based vaccine that encodes for a full-length, prefusion stabilized spike (S) protein of SARS-CoV-2. Enrollment will occur at up to 3 domestic clinical research sites. Up to one hundred and fifty-five subjects will be enrolled into one of thirteen cohorts (10 micrograms \[mcg\], 25 mcg, 50 mcg, 100 mcg, and 250 mcg). Subjects will receive an intramuscular (IM) injection (0.5 milliliters \[mL\]) of mRNA-1273 on Days 1 and 29 in the deltoid muscle and will be followed through 12 months post second vaccination (Day 394). Follow-up visits will occur 1, 2, and 4 weeks post each vaccination (Days 8, 15, 29, 36, 43, and 57), as well as 3, 6, and 12 months post second vaccination (Days 119, 209, and 394). The primary objective is to evaluate the safety and reactogenicity of a 2-dose vaccination schedule of mRNA-1273, given 28 days apart, across 5 dosages in healthy adults.

Optional Substudy:

This is an optional third mRNA-1273 vaccination substudy, in subjects 18 years of age and older, who received both the first and second mRNA-1273 vaccinations in the main study and meet all other substudy eligibility criteria. This optional third mRNA-1273 vaccination substudy is designed to assess safety, reactogenicity, and immunogenicity through 12 months post third vaccination (Day 731). Subjects who receive the third mRNA-1273 vaccination will exit the Schedule of Activities for the main study and will enter the Schedule of Activities for the optional substudy. Up to one hundred and twenty subject will be enrolled into two cohorts (consisting of participating subjects who received 2 doses of 25 or 50 mcg and participating subjects who received 2 doses of 100 and 250 mcg). Subjects will receive an IM injection (0.5 mL) at a dosage of 100 mcg/0.5 mL. The primary objective is to evaluate the safety and reactogenicity of a third mRNA-1273 vaccination, at a dosage of 100 mcg.

This is a phase I, open-label, dose-ranging clinical trial in males and non-pregnant females, starting at 18 years of age, inclusive, who are in good health and meet all eligibility criteria. This clinical trial is designed to assess the safety, reactogenicity and immunogenicity of mRNA-1273 manufactured by ModernaTX, Inc. mRNA-1273 is a novel lipid nanoparticle (LNP)-encapsulated mRNA-based vaccine that encodes for a full-length, prefusion stabilized spike (S) protein of SARS-CoV-2. Enrollment will occur at up to 3 domestic clinical research sites. Up to one hundred and fifty-five subjects will be enrolled into one of thirteen cohorts (10 micrograms \[mcg\], 25 mcg, 50 mcg, 100 mcg, or 250 mcg). Subjects will receive an intramuscular (IM) injection (0.5 milliliters \[mL\]) of mRNA-1273 on Days 1 and 29 in the deltoid muscle and will be followed through 12 months post second vaccination (Day 394). Follow-up visits will occur 1, 2, and 4 weeks post each vaccination (Days 8, 15, 29, 36, 43, and 57), as well as 3, 6, and 12 months post second vaccination (Days 119, 209, and 394). The primary objective is to evaluate the safety and reactogenicity of a 2-dose vaccination schedule of mRNA-1273, given 28 days apart, across 5 dosages in healthy adults. The secondary objective is to evaluate the immunogenicity as measured by Immunoglobulin G (IgG) enzyme-linked immunosorbent assay (ELISA) to the SARS-CoV-2 S (spike) protein following a 2-dose vaccination schedule of mRNA-1273 at Day 57.

Optional Substudy:

This is an optional third mRNA-1273 vaccination substudy, in subjects 18 years of age and older, who received both the first and second mRNA-1273 vaccinations in the main study and meet all other substudy eligibility criteria. This optional third mRNA-1273 vaccination substudy is designed to assess safety, reactogenicity, and immunogenicity through 12 months post third vaccination (Day 731). Subjects who receive the third mRNA-1273 vaccination will exit the Schedule of Activities for the main study and will enter the Schedule of Activities for the optional substudy. Up to one hundred and twenty subject will be enrolled into two cohorts (consisting of participating subjects who received 2 doses of 25 or 50 mcg and participating subjects who received 2 doses of 100 and 250 mcg). Subjects will receive an IM injection (0.5 mL) at a dosage of 100 mcg/0.5 mL. The primary objective is to evaluate the safety and reactogenicity of a third mRNA-1273 vaccination, at a dosage of 100 mcg. The secondary objective is to evaluate the immunogenicity as measured by IgG ELISA to the SARS-CoV-2 S protein following a third mRNA-1273 vaccination, at a dosage of 100 mcg, at all timepoints after the third mRNA-1273 vaccination.

Eligibility Criteria:
Inclusion Criteria:

A subject must meet all of the following criteria to be eligible to participate in this study:

1. Provides written informed consent prior to initiation of any study procedures.
2. Be able to understand and agrees to comply with planned study procedures and be available for all study visits.
3. Agrees to the collection of venous blood per protocol.
4. Male or non-pregnant female, \>/= to 18 years of age at time of enrollment.
5. Body Mass Index (BMI) 18.0-35.0 kg/m\^2, inclusive (\< 56 years of age), at screening; BMI 18.0-30.0 kg/m\^2, inclusive (\>/= 56 years of age), at screening.
6. Women of childbearing potential\* must agree to use or have practiced true abstinence\*\* or use at least one acceptable primary form of contraception.\*\*\*, \*\*\*\* Note: These criteria are applicable to females in a heterosexual relationship and child-bearing potential (i.e., the criteria do not apply to subjects in a same sex relationship).

   * Not of childbearing potential - post-menopausal females (defined as having a history of amenorrhea for at least one year) or a documented status as being surgically sterile (hysterectomy, bilateral oophorectomy, tubal ligation/salpingectomy, or Essure(R) placement).

     * True abstinence is 100% of time no sexual intercourse (male's penis enters the female's vagina). (Periodic abstinence \[e.g., calendar, ovulation, symptothermal, post-ovulation methods\] and withdrawal are not acceptable methods of contraception).

       * Acceptable forms of primary contraception include monogamous relationship with a vasectomized partner who has been vasectomized for 180 days or more prior to the subject's first vaccination, intrauterine devices, birth control pills, and injectable/implantable/insertable hormonal birth control products.

         * Must use at least one acceptable primary form of contraception for at least 30 days prior to the first vaccination and at least one acceptable primary form of contraception for 60 days after the last vaccination.
7. Women of childbearing potential must have a negative urine or serum pregnancy test within 24 hours prior to each vaccination.
8. Male subjects of childbearing potential\*: use of condoms to ensure effective contraception with a female partner of childbearing potential from first vaccination until 60 days after the last vaccination.

   \*Biological males who are post-pubertal and considered fertile until permanently sterile by bilateral orchiectomy or vasectomy.
9. Male subjects agree to refrain from sperm donation from the time of first vaccination until 60 days after the last vaccination.
10. In good health.\* \*As determined by medical history and physical examination to evaluate acute or ongoing chronic medical diagnoses/conditions that have been present for at least 90 days, which would affect the assessment of safety of subjects. Chronic medical diagnoses/conditions should be stable for the last 60 days (no hospitalizations, emergency room (ER), or urgent care for condition or need for supplemental oxygen). This includes no change in chronic prescription medication, dose, or frequency as a result of deterioration of the chronic medical diagnosis/condition in the 60 days before enrollment. Any prescription change that is due to change of health care provider, insurance company, etc., or done for financial reasons, and in the same class of medication, will not be considered a deviation of this inclusion criterion. Any change in prescription medication due to improvement of a disease outcome, as determined by the participating site principal investigator (PI) or appropriate sub-investigator, will not be considered a deviation of this inclusion criterion. Subjects may be on chronic or as needed (prn) medications if, in the opinion of the participating site PI or appropriate sub-investigator, they pose no additional risk to subject safety or assessment of reactogenicity and immunogenicity, and do not indicate a worsening of medical diagnosis/condition. Similarly, medication changes subsequent to enrollment and study vaccination are acceptable provided the change was not precipitated by deterioration in the chronic medical condition, and there is no anticipated additional risk to the subject or interference with the evaluation of responses to study vaccination.
11. Oral temperature is less than 100.0 degrees Fahrenheit (37.8 degrees Celsius).
12. Pulse no greater than 100 beats per minute.
13. Systolic blood pressure (BP) is 85 to 150 mm Hg, inclusive.
14. Clinical screening laboratory evaluations (white blood cell (WBC), hemoglobin (Hgb), platelets (PLTs), alanine transaminase (ALT), aspartate transaminase (AST), creatinine (Cr), alkaline phosphatase (ALP), total bilirubin (T. Bili), Lipase, prothrombin time (PT), and partial thromboplastin time (PTT)) are within acceptable normal reference ranges at the clinical laboratory being used.
15. Must agree to have samples stored for secondary research.
16. Agrees to adhere to Lifestyle Considerations throughout study duration.
17. Must agree to refrain from donating blood or plasma during the study (outside of this study).

Leukapheresis Inclusion Criteria:

A subject must meet all of the following criteria to be eligible for leukapheresis:

1. Written informed consent for leukapheresis is provided.
2. Weight \>/= 110 pounds.
3. Screening laboratory evaluations are within acceptable ranges at the site where the leukapheresis procedure will be performed.
4. Negative urine or serum pregnancy test within 48 hours of the leukapheresis procedure for women of childbearing potential.
5. Adequate bilateral antecubital venous access.
6. No use of blood thinners, aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) at least 5 days before the leukapheresis procedure.
7. Enrolled in cohorts 2, 3, 5, 10, or 11, and possibly cohort 6, if enrolled, and completed the two-dose vaccination series.

Optional Substudy Inclusion Criteria:

1. Enrolled in the main study and received both the first and second mRNA-1273 vaccinations.
2. Provides written informed consent for the third mRNA-1273 vaccination.
3. Agrees to the collection of venous blood per substudy.
4. Must agree to have samples stored for secondary research.
5. Women of childbearing potential have had a negative urine pregnancy test within 24 hours before the third mRNA-1273 vaccination.
6. Women of childbearing potential\* must agree to use or have practiced true abstinence\*\* or use at least one acceptable primary form of contraception.\*\*\*/\*\*\*\*

   * Not of childbearing potential - post-menopausal females (defined as having a history of amenorrhea for at least one year) or a documented status as being surgically sterile (hysterectomy, bilateral oophorectomy, tubal ligation/salpingectomy, or Essure® placement).

     * True abstinence is 100% of time no sexual intercourse (male's penis enters the female's vagina). (Periodic abstinence \[e.g., calendar, ovulation, symptothermal, post-ovulation methods\] and withdrawal are not acceptable methods of contraception).

       * Acceptable forms of primary contraception include monogamous relationship with a vasectomized partner who has been vasectomized for 180 days or more prior to the subject's first vaccination, intrauterine devices, birth control pills, and injectable/implantable/insertable hormonal birth control products.

         \*\*\*\*Must use at least one acceptable primary form of contraception for at least 30 days prior to the third mRNA-1273 vaccination and for at least 30 days after the third mRNA-1273 vaccination.

Exclusion Criteria:

A subject who meets any of the following criteria will be excluded from participation in this study:

1. Positive pregnancy test either at screening or just prior to each vaccine administration.
2. Female subject who is breastfeeding or plans to breastfeed from the time of the first vaccination through 60 days after the last vaccination.
3. Has any medical disease or condition that, in the opinion of the participating site principal investigator (PI) or appropriate sub-investigator, precludes study participation.\*

   \*Including acute, subacute, intermittent or chronic medical disease or condition that would place the subject at an unacceptable risk of injury, render the subject unable to meet the requirements of the protocol, or may interfere with the evaluation of responses or the subject's successful completion of this trial.
4. Presence of self-reported or medically documented significant medical or psychiatric condition(s).\*

   \*Significant medical or psychiatric conditions include but are not limited to: Respiratory disease (e.g., chronic obstructive pulmonary disease \[COPD\], asthma) requiring daily medications currently or any treatment of respiratory disease exacerbations (e.g., asthma exacerbation) in the last 5 years. Asthma medications: inhaled, oral, or intravenous (IV) corticosteroids, leukotriene modifiers, long and short acting beta agonists, theophylline, ipratropium, biologics.

   Significant cardiovascular disease (e.g., congestive heart failure, cardiomyopathy, ischemic heart disease), history of myocarditis or pericarditis as an adult, myocardial infarction (MI) within past 6 months, coronary artery bypass surgery or stent placement, or uncontrolled cardiac arrhythmia.

   Neurological or neurodevelopmental conditions (e.g., history of migraines in the past 5 years, epilepsy, stroke, seizures in the last 3 years, encephalopathy, focal neurologic deficits, Guillain-Barré syndrome, encephalomyelitis, transverse myelitis, stroke or transient ischemic attack, multiple sclerosis, Parkinson's disease, amyotrophic lateral sclerosis, Creutzfeldt-Jakob disease, or Alzheimer's disease).

   Ongoing malignancy or recent diagnosis of malignancy in the last five years excluding basal cell and squamous cell carcinoma of the skin, which are allowed.

   An autoimmune disease, including hypothyroidism without a defined non-autoimmune cause, localized or history of psoriasis.

   An immunodeficiency of any cause. Chronic kidney disease, estimated glomerular filtration rate (eGFR) \<60 mL/min/1.73m\^2.
5. Has an acute illness\*, as determined by the participating site PI or appropriate sub-investigator, with or without fever \[oral temperature \>/= 38.0 degrees Celsius (100.4 degrees Fahrenheit)\] within 72 hours prior to each vaccination.

   \*An acute illness which is nearly resolved with only minor residual symptoms remaining is allowable if, in the opinion of the participating site PI or appropriate sub-investigator, the residual symptoms will not interfere with the ability to assess safety parameters as required by the protocol.
6. Has a positive test result for hepatitis B surface antigen, hepatitis C virus antibody, or human immunodeficiency virus (HIV) types 1 or 2 antibodies at screening.
7. Has participated in another investigational study involving any investigational product\* within 60 days, or 5 half-lives, whichever is longer, before the first vaccine administration.

   \*study drug, biologic or device
8. Currently enrolled in or plans to participate in another clinical trial with an investigational agent\* that will be received during the study-reporting period.\*\*

   \*Including licensed or unlicensed vaccine, drug, biologic, device, blood product, or medication.

   \*\*13 months after the first vaccination.
9. Has previously participated in an investigational study involving lipid nanoparticles (LNPs) (a component of the investigational vaccine assessed in this trial).
10. Has a history of hypersensitivity or severe allergic reaction (e.g., anaphylaxis, generalized urticaria, angioedema, other significant reaction) to any previous licensed or unlicensed vaccines.
11. Chronic use (more than 14 continuous days) of any medications that may be associated with impaired immune responsiveness.\*

    \*Including, but not limited to, systemic corticosteroids exceeding 10 mg/day of prednisone equivalent, allergy injections, immunoglobulin, interferon, immunomodulators, cytotoxic drugs, or other similar or toxic drugs during the preceding 6-month period prior to vaccine administration (Day 1). The use of low dose topical, ophthalmic, inhaled and intranasal steroid preparations will be permitted.
12. Anticipating the need for immunosuppressive treatment within the next 6 months.
13. Received immunoglobulins and/or any blood or blood products within the 4 months before the first vaccine administration or at any time during the study.
14. Has any blood dyscrasias or significant disorder of coagulation.
15. Has any chronic liver disease, including fatty liver.
16. Has a history of alcohol abuse or other recreational drug (excluding cannabis) use within 6 months before the first vaccine administration.
17. Has a positive test result for drugs of abuse at screening or before the first vaccine administration. If cannabis is the only detected drug, inclusion is permitted.
18. Has any abnormality or permanent body art (e.g., tattoo) that would interfere with the ability to observe local reactions at the injection site (deltoid region).
19. Received or plans to receive a licensed, live vaccine within 4 weeks before or after each vaccination.
20. Received or plans to receive a licensed, inactivated vaccine within 2 weeks before or after each vaccination.
21. Receipt of any other SARS-CoV-2 or other experimental coronavirus vaccine at any time prior to or during the study.
22. Close contact of anyone known to have SARS-CoV-2 infection within 30 days prior to vaccine administration.
23. History of COVID-19 diagnosis.
24. On current treatment with investigational agents for prophylaxis of COVID-19.
25. Current use of any prescription or over-the-counter medications within 7 days prior to vaccination, unless approved by the investigator or necessary to manage a chronic condition.
26. Plan to travel outside the United States (US) (continental US, Hawaii, and Alaska) from enrollment through 28 days after the last vaccination.
27. Reside in a nursing home or other skilled nursing facility or have a requirement for skilled nursing care.
28. Non-ambulatory.
29. For subjects \>/= 56 years of age, history of chronic smoking within the prior year.
30. For subjects \>/= 56 years of age, current smoking or vaping.
31. For subjects \>/= 56 years of age, individuals currently working with high risk of exposure to SARS-CoV-2 (e.g., active health care workers with direct patient contact, emergency response personnel).

Optional Substudy Exclusion Criteria:

1. Anaphylaxis or other systemic hypersensitivity reaction following a mRNA-1273 or any other vaccination.
2. Immediate allergic reaction of any severity after mRNA-1273 or any of its components.\*

   \*Including polyethylene glycol (PEG)
3. Immediate allergic reaction of any severity to polysorbate.\*

   \*Due to potential cross-reactive hypersensitivity with the vaccine ingredient PEG
4. History of an SAE judged related to mRNA-1273 vaccine.
5. Female subject who is breastfeeding or plans to breastfeed from the time of the third mRNA-1273 vaccination through 30 days after the third mRNA-1273 vaccination.
6. Has an acute illness\*, as determined by the participating site PI or appropriate sub-investigator, with or without fever \[oral temperature \>/=38.0°C (100.4°F)\], within 72 hours prior to the third mRNA-1273 vaccination.

   \*An acute illness which is nearly resolved with only minor residual symptoms remaining is allowable if, in the opinion of the participating site PI or appropriate sub-investigator, the residual symptoms will not interfere with the ability to assess safety parameters as required by the substudy.
7. Has received any approved, authorized or investigational COVID-19 vaccine outside of this trial.
8. Any clinically significant medical condition that, in the opinion of the investigator, poses an additional risk to the subject from vaccination.
9. History of documented COVID-19 infection.
10. Has any medical disease or condition that, in the opinion of the participating site PI or appropriate sub-investigator, precludes substudy participation.
11. Received or plans to receive a licensed vaccine, other than a COVID-19 vaccine, within 2 weeks before or after the third mRNA-1273 vaccination.