Safety and Immunogenicity Study of a SARS-CoV-2 (COVID-19) Variant Vaccine (mRNA-1273.351) in Naïve and Previously Vaccinated Adults
Condition: COVID-19; COVID-19 Immunisation
MeSH terms: COVID-19
Intervention: mRNA-1273; mRNA-1273.351
Intervention description: Lipid nanoparticle (LNP) dispersion containing an mRNA that encodes for the pre fusion stabilized spike protein of the Wuhan-Hu-1 strain of SARS-CoV-2. mRNA-1273 consists of an mRNA Drug Substance that is manufactured into LNPs composed of the proprietary ionizable lipid, SM-102, and 3 commercially available lipids, cholesterol, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), and PEG2000 DMG.; Lipid nanoparticle (LNP) dispersion containing an mRNA that encodes for the pre fusion stabilized spike protein of the B.1.351 variant SARS-CoV-2 strain. mRNA-1273.351 consists of an mRNA Drug Substance that is manufactured into LNPs composed of the proprietary ionizable lipid, SM-102, and 3 commercially available lipids, cholesterol, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), and PEG2000 DMG.
Phase: Phase 1
Study type: Interventional
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 135.0
Sex: All
Minimum age: 18 Years
Maximum age: 99 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Coronavirus; COVID-19; Immunogenicity; mRNA-1273; mRNA-1273.351; SARS-CoV-2; SARS-CoV-2 B.1.351; vaccine

Summary:

      This is a phase 1, open-label, randomized clinical trial in males and non-pregnant females,
      18 years of age and older, who are in good health, have no known history of COVID-19 or
      SARS-CoV-2 infection, and meet all other eligibility criteria. This clinical trial is
      designed to assess the safety, reactogenicity and immunogenicity of mRNA-1273.351
      manufactured by ModernaTX, Inc, given in vaccination schedules alone, sequentially, or
      coadministered with mRNA-1273. mRNA-1273.351 is a novel lipid nanoparticle (LNP)-encapsulated
      mRNA-based vaccine that encodes for a full-length, prefusion stabilized S protein of the
      SARS-CoV-2 B.1.351 variant. Enrollment will occur at approximately five domestic clinical
      research sites.

      This study includes two cohorts. Cohort 1 will provide rapid information about the
      immunogenicity of mRNA-1273.351 in a previously vaccinated group. This cohort can inform near
      term public health decisions if the variant virus becomes more widespread. Cohort 2 will
      evaluate different strategies for generation of cross protective immune responses in a naïve
      population. This cohort will take longer to provide information on the immunogenicity of
      mRNA-1273.351, but is important to inform future public health strategies. Cohort 1 will
      include approximately 60 subjects 18 years of age and older who received two vaccinations of
      mRNA-1273 at dosages of 50 mcg, 100 mcg, or 250 mcg in the Phase 1 clinical trial (DMID
      20-0003). Subjects in Cohort 1 will receive a single intramuscular (IM) injection of the
      designated vaccine and will be followed through 12 months after vaccination. Follow-up visits
      will occur on Days 8, 15, and 29, as well as 3, 6, and 12 months after the vaccination.
      Cohort 2 will include approximately 150 participants 18 through 55 years of age who have not
      received a COVID-19 vaccine, have no known history of COVID-19 or SARS-CoV-2 infection, and
      do not have underlying conditions that are associated with an increased risk of severe
      illness from SARS-CoV-2 infection. Enrollment may close before the full 150 participants
      based on estimates on the timing of immunogenicity results and the need to inform public
      health decisions. They will be randomly assigned to one of 8 treatment arms and will receive
      2 or 3 IM injections of the vaccine and followed through 12 months after the last
      vaccination. Follow-up visits will occur 7, 14, and 28 days after each vaccination, as well
      as 3, 6 and 12 months post the last vaccination.

      The primary objective is to evaluate the safety and reactogenicity of mRNA-1273 and
      mRNA-1273.351 vaccines, in naïve and previously vaccinated individuals.
    

Eligibility criteria:

        Inclusion Criteria:

          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. Cohort 1: previously received 2 doses of mRNA-1273 intramuscular (IM) as part of DMID
             20-0003.

          5. Cohort 1: Male or non-pregnant female, >/= 18 years of age at time of enrollment.
             Cohort 2: Male or non-pregnant female, 18 through 55 years of age at time of
             enrollment.

          6. Women of childbearing potential* must agree to practice 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).

             ** 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. 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, 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 or for dose
             optimization, as determined by the participating site 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.

          8. Oral temperature is less than 100.0 degrees Fahrenheit (37.8 degrees Celsius).

          9. Must agree to have samples stored for secondary research.

         10. Agrees to adhere to Lifestyle Considerations throughout study duration.

         11. Must agree to refrain from donating blood or plasma during the study (outside of this
             study).

        Exclusion Criteria:

          1. Positive pregnancy test prior to each vaccine administration.

          2. BMI > 40.0 kg / m^2.

          3. Female subject who is breastfeeding.

          4. Has any medical disease or condition that, in the opinion of the participating site 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.

          5. 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.

             Type 2 diabetes mellitus, not including prediabetes.

          6. 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.

          7. Has participated in another investigational study involving any investigational
             product* within 5 half-lives 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.

             ** Up to 15 months after the first vaccination.

          9. Has a history of hypersensitivity or severe allergic reaction (e.g., anaphylaxis,
             generalized urticaria, angioedema, other significant reaction) to drugs or any
             previous licensed or unlicensed vaccines or to polyethylene glycol (PEG) or a
             PEG-containing product.

         10. 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.

         11. Anticipating the need for immunosuppressive treatment within the next 6 months.

         12. 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.

         13. Has any blood dyscrasias or significant disorder of coagulation.

         14. Received or plans to receive a licensed, live vaccine within 4 weeks before or after
             each vaccination.

         15. Received or plans to receive a licensed, inactivated vaccine within 2 weeks before or
             after each vaccination.

         16. Receipt of any other SARS-CoV-2 vaccine or any experimental coronavirus vaccine at any
             time prior to or during the study, except Cohort 1 subjects who received mRNA-1273 in
             DMID 20-0003.

         17. Close contact of anyone known to have SARS-CoV-2 infection within 14 days prior to
             vaccine administration.

         18. History of COVID-19 diagnosis, positive SARS-CoV-2 PCR test, or, for Cohort 2 only, a
             known positive SARS-CoV-2 serologic test.

         19. On current treatment with investigational agents for prophylaxis of COVID-19.