High-Dose Moderna mRNA-1273 Booster Study for Lung Transplant Recipients

Lung transplant recipients have poor outcomes after COVID-19 infection with mortality. Due to the immunosuppression, they have had poor responses to SARS-CoV-2 vaccine and remain at high risk of poor outcomes. This is a Phase I/II clinical trial to evaluate the safety and immune response from a higher dose mRNA-1273 vaccine among lung transplant recipients who have already received three or four doses of the COVID-19 vaccine.

This is a Phase I/II open-label dose-finding trial among lung transplant recipients who received three or four mRNA vaccine doses (mRNA-1273 or BNT162b2) after lung transplantation to: standard-dose (50 ug), mid-dose (100 ug) or high-dose (200 ug) mRNA-1273 booster vaccine. Sixty participants will be enrolled into three dose groups: 1) Standard-dose - 20 participants, 2) Mid-dose - 20 participants, 3) High-dose - 20 participants. The first 2 participants in both the mid-dose and high dose groups will be considered the 'sentinel' group. Participants in the sentinel group will receive the vaccine and undergo a 7-day observation period for safety and reactogenicity before additional participants are enrolled into that dose group.

Overall study enrollment will begin with the mid-dose sentinel group (n=2). During the observation period for the mid-dose sentinel group, we will enroll two participants into the standard-dose group. Once the mid-dose sentinel group completes their 7-day observation period without triggering halting rules and is approved to proceed by the DSMB, we will enroll the next 27 participants (Cohort 1) with a 2:1 randomization into the mid-dose (n=18) and standard-dose (n=9) groups.

Once all 20 participants have received their mid-dose vaccine without triggering halting rules and is approved to proceed by the DSMB, we will enroll the high-dose sentinel group (n=2). Once the high-dose sentinel group completes their 7-day observation period without triggering halting rules and is approved to proceed by the DSMB, we will enroll the next 27 participants (Cohort 2) with a 2:1 randomization into the high-dose (n=18) and standard-dose (n=9) groups. All 20 participants in the mid-dose group will be enrolled prior to the enrollment of the high-dose group.

We will perform stratified randomization for the two cohorts based on: 1) the number of prior doses, and 2) prior receipt of any BNT162b2 vaccines. Randomization with be done by the UCLA Clinical and Translational Science Institute (CTSI) statistics team based on scheduled participants prior to the study visit. The 6 participants in the sentinel (n=4) and initial (n=2) groups (Table 1) will be assigned into the 3 groups based on their scheduled visit day.

Eligibility Criteria:
1. All adult lung transplant recipients (age ≥ 18 at the time of consent) who received all of their COVID-19 vaccines after lung transplantation.
2. Received three or four doses of either the Moderna mRNA-1273 or Pfizer BNT162b2 vaccine with the last dose received at least 4 months prior to study enrollment.
3. Currently receiving standard regimen of three drug immunosuppression with prednisone, tacrolimus and mycophenolate mofetil (cellcept, minimum 250 mg bid) or mycophenolate sodium (myfortic, minimum 180 mg bid).
4. Agrees not to receive other investigational agents for prophylaxis against COVID-19 including Evusheld monoclonal antibodies for at least 30 days after the study vaccine.
5. Understands and agrees to comply with the study procedures and provides written informed consent.
6. Is in stable health without any new or worsening medical conditions in the opinion of the Investigator.
7. Female participants of childbearing potential (\<1 year since start of menopause) may be enrolled in the study if the participant fulfills all the following criteria:

   1. Has a negative pregnancy test at Visit 1 Day 1.
   2. Has practiced adequate contraception or has abstained from all activities that could result in pregnancy for at least 28 days prior to the first injection (Day 1).
   3. Has agreed to continue adequate contraception or practice abstinence through 3 months following the booster injection (Day 90).
   4. Is not currently breastfeeding.
   5. Adequate female contraception is defined as consistent and correct use of a Food and Drug Administration (FDA) approved contraceptive method in accordance with the product label. For example:

   i. Barrier method (such as condoms, diaphragm, or cervical cap) used in conjunction with spermicide ii. Intrauterine device iii. Prescription hormonal contraceptive taken or administered via oral (pill), transdermal (patch), subdermal, or IM route iv. Sterilization of a female participant's monogamous male partner prior to entry into the study v. Note: periodic abstinence (e.g., calendar, ovulation methods) and withdrawal are not acceptable methods of contraception.

Exclusion Criteria:

1. Previous documented COVID-19 infection.
2. Use of investigational agents for prophylaxis against COVID-19 within 90 days of the start of the study, including Evusheld monoclonal antibodies.
3. Ongoing therapy for acute cellular or antibody mediated rejection.
4. Intravenous immunoglobulins (IVIG) administration within the prior 3 months or ongoing IVIG therapy.
5. Anaphylaxis or allergic reaction to any prior vaccines.
6. History of anaphylaxis or other significant adverse reaction requiring medical intervention after receipt of a vaccine.
7. Is acutely ill or febrile 24 hours prior to or at the Day 1 visit. Fever is defined as a body temperature ≥ 38.0°C/100.4°F. Participants meeting this criterion may be rescheduled within the relevant window periods. Afebrile participants with minor illnesses can be enrolled at the discretion of the investigator.
8. Pregnant or breastfeeding.
9. Has a medical, psychiatric, or occupational condition that may pose additional risk as a result of participation, or that could interfere with safety assessments or interpretation of results according to the investigator's judgment.
10. Known history of hypertension (HTN) with systolic blood pressure (BP) \> 180 mm Hg at the Day 1 visit.
11. Known history of hypotension with systolic blood pressure \< 85 mm Hg at the Day 1 visit.
12. Bleeding disorder considered a contraindication to IM injection or phlebotomy.
13. Active malignancy diagnosed within previous 4 years (excluding non-melanoma skin cancer).
14. Received a major surgery including lung transplantation in the past 3 months.