A Trial Investigating the Safety and Effects of Four BNT162 Vaccines Against COVID-19 in Healthy and Immunocompromised Adults

A Multi-site, Phase I/II, 2-Part, Dose-Escalation Trial Investigating the Safety and Immunogenicity of Four Prophylactic SARS-CoV-2 RNA Vaccines Against COVID-19 Using Different Dosing Regimens in Healthy and Immunocompromised Adults

Originally, the study was planned to include two parts, i.e., Part A and Part B, however Part B was cancelled due to changes in the overall clinical development plan. The objectives originally described for Part B have been implemented in the ongoing development via a pivotal Phase I/II/III trial BNT162-02/C4591001 (ClinicalTrials.gov NCT: 04368728).

The conducted Part A was a dose-finding part to investigate the optimal dose of four different vaccines (BNT162a1, BNT162b1, BNT162b2, and BNT162c2), allowing dose adjustments upwards and downwards in younger participants. Doses tested in older participants and expansion cohorts were chosen based on acceptability of dosing in younger participants.

The vaccines BNT162a1, BNT162b1, BNT162b2, and BNT162c2 were administered using a Prime/Boost (P/B) regimen with two doses given ~21 days apart. The vaccine BNT162c2 was also administered using a Single dose (SD) regimen. Four additional expansion cohorts (cohorts 11, 12, 13, and 14) aged from 18 to 85 years received BNT162b2 using a P/B regimen only. In cohort 11, participants received BNT162b2 using one 3 μg prime dose (Dose 1) and one 30 μg boost dose (Dose 2) of BNT162b2. Participants in cohorts 12, 13, and 14 received two doses of BNT162b2 30 µg, each.

This study was a multi-site, Phase I/II, open-label, dose-escalation study. The study included the first-in-human (FIH) dose and dose ranging groups for all four vaccines in healthy younger participants (aged 18 to 55 years [years]) and older participants (aged 56 to 85 years). The conducted Part A followed a dose escalation design. Discretionary dose de-escalation and refinement was also planned. Study participants with the FIH immunization and any subsequent dose escalation cohorts were immunized using a sentinel dosing/subject staggering. For any dose de-escalation or dose-refinement cohorts in younger adults, i.e., cohorts with doses lower than previously tested, participants were dosed using a subject staggering process. Cohorts in older participants were optional and dependent on acceptability of dosing in younger participants. Part A consisted of a treatment phase and a follow-up phase.

For the BNT162a1 3 µg arm, the Safety Review Committee (SRC) decided to stop dosing after 6 treated participants and to not administer the boost immunization (Dose 2). For the BNT162b1 60 µg arm, the SRC decided to not administer the boost immunization (Dose 2) for the 12 participants.

Inclusion Criteria:

• Have given informed consent by signing the informed consent form (ICF) before initiation of any trial-specific procedures.
• They must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests, lifestyle restrictions (e.g., to practice social distancing and to follow good practices to reduce their chances of being infected or spreading COVID-19), and other requirements of the trial.
• They must be able to understand and follow trial-related instructions.
• For younger adult cohorts, volunteers must be aged 18 to 55 years, have a body mass index (BMI) over 19 kg/m^2 and under 30 kg/m^2, and weigh at least 50 kg at Visit 0. OR For older adult cohorts, volunteers must be aged 56 to 85 years, have a BMI over 19 kg/m^2 and under 30 kg/m^2, and weigh at least 50 kg at Visit 0. OR For the immunocompromised adult cohort (Cohort 13), volunteers must be aged 18 to 85 years, have a BMI over 19 kg/m^2 and under 30 kg/m^2, and weigh at least 50 kg at Visit 0.
• They must be healthy, in the clinical judgment of the investigator, based on medical history, physical examination, 12-lead electrocardiogram (ECG), vital signs (systolic/diastolic blood pressure, pulse rate, body temperature, respiratory rate), and clinical laboratory tests (blood chemistry, hematology, and urine chemistry) at Visit 0. Note: Healthy volunteers with pre-existing stable disease, defined as disease not requiring significant change in therapy or hospitalization for worsening disease during the 6 weeks before enrollment, can be included. OR For the immunocompromised cohort (Cohort 13); volunteers who have previously received solid organ transplant, or peripheral blood stem cell transplantation ≥6 months after transplantation, or individuals with human immunodeficiency virus (HIV) infection with a CD4+ T-cell count of ≥200 x 10^6 /L at Visit 0. Individuals with lower T-cell counts will be excluded from the trial on the basis that this represents a significant medical complication. In the clinical judgment of the investigator, volunteers must be immunocompromised but otherwise healthy. After consultation with the Medical Monitor, this may include individuals receiving immunosuppressant therapy due to another confounding disease at least 2 weeks prior to enrollment and/or at least 6 weeks following immunization with BNT162b2, and/or individuals with immunosuppressive treatment of an autoimmune disease if the disease is stable.
• Women of childbearing potential (WOCBP) must have a negative beta-human chorionic gonadotropin urine test at Visit 0 and Visit 1. Women that are postmenopausal or permanently sterilized will be considered as not having reproductive potential.
• WOCBP must agree to practice a highly effective form of contraception during the trial, starting after Visit 0 and continuously until 60 days after receiving the last immunization. WOCBP must agree to require their male partners to use condoms during sexual contact (unless male partners are sterilized or infertile).
• WOCBP must confirm that they practice at least one highly effective form of contraception for the 14 days prior to Visit 0.
• WOCBP must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during trial, starting after Visit 0 and continuously until 60 days after receiving the last immunization.
• Men who are sexually active with a WOCBP and have not had a vasectomy must agree to practice a highly effective form of contraception with their female partner of childbearing potential during the trial, starting after Visit 0 and continuously until 60 days after receiving the last immunization.
• Men must be willing to refrain from sperm donation, starting after Visit 0 and continuously until 60 days after receiving the last immunization.
• They must have confirmation of their health insurance coverage prior to Visit 0.
• They must agree to not be vaccinated during the trial, starting after Visit 0 and continuously until 28 days after receiving the last immunization.

Exclusion Criteria:

• Have had any acute illness, as determined by the investigator, with or without fever, within 72 hours prior to the first immunization. An acute illness which is nearly resolved with only minor residual symptoms remaining is allowable if, in the opinion of the investigator, the residual symptoms will not compromise their well-being if they participate as trial subjects in the trial, or that could prevent, limit, or confound the protocol-specified assessments.
• Are breastfeeding on the day of Visit 0 or who plan to breastfeed during the trial, starting after Visit 0 and continuously until at least 90 days after receiving the last immunization.
• Have a known allergy, hypersensitivity, or intolerance to the planned investigational medicinal product (IMP) including any excipients of the IMP.
• Had any medical condition or any major surgery (e.g., requiring general anesthesia) within the past 5 years which, in the opinion of the investigator, could compromise their well-being if they participate as trial subjects in the trial, or that could prevent, limit, or confound the protocol-specified assessments.
• Have any surgery planned during the trial, starting after Visit 0 and continuously until at least 90 days after receiving the last immunization.
• Had any chronic use (more than 21 continuous days) of any systemic medications, including immunosuppressant's or other immune-modifying drugs (except for Cohort 13), within the 6 months prior to Visit 0 unless in the opinion of the investigator, the medication would not prevent, limit, or confound the protocol-specified assessments or could compromise subject safety. Note: Healthy volunteers with pre-existing stable disease, defined as disease not requiring significant change in therapy or hospitalization for worsening disease during the 6 weeks before enrollment, can be included.
• Had any vaccination within the 28 days prior to Visit 0.
• Had administration of any immunoglobulins and/or any blood products within the 3 months prior to Visit 0.
• Had administration of another investigational medicinal product including vaccines within 60 days or 5 half-lives (whichever is longer), prior to Visit 0.
• Have a known history of active or ongoing hepatitis B or hepatitis C infection; or except for Cohort 13: HIV-1 or HIV-2 infection within the 30 days prior to Visit 0.
• Have a positive polymerase chain reaction (PCR)-based test for SARS-CoV-2 within the 30 days prior to Visit 1.
• Have a positive drugs of abuse (for amphetamines, benzodiazepines, barbiturates, cocaine, cannabinoids, opiates, methadone, methamphetamines, phencyclidine, and tricyclic antidepressants) result at Visit 0 or Visit 1.
• Have a positive breath alcohol test at Visit 0 or Visit 1.
• Previously participated in an investigational trial involving lipid nanoparticles.
• Are subject to exclusion periods from other investigational trials or simultaneous participation in another clinical trial. When entering the follow-up phase, i.e., after completing the end of treatment (EoT) visit, subjects are allowed to participate in other clinical trials not investigating COVID-19 vaccines or treatments; subjects immunized with BNT162 vaccines in this clinical trial are allowed to participate in other clinical trials involving immunization with BNT162b2.
• Have any affiliation with the trial site (e.g., are close relative of the investigator or dependent person, such as an employee or student of the trial site).
• Have a history (within the past 5 years) of substance abuse or known medical, psychological, or social conditions which, in the opinion of the investigator, could compromise their well-being if they participate as trial subjects in the trial, or that could prevent, limit, or confound the protocol-specified assessments.
• Have a history of hypersensitivity or serious reactions to previous vaccinations.
• Have a history of Guillain-Barré Syndrome within 6 weeks following a previous vaccination.
• Have a history of narcolepsy.
• Have history of alcohol abuse or drug addiction within 1 year before Visit 0.
• (Except for Cohort 13) Have a history of or suspected immunosuppressive condition, acquired or congenital, as determined by medical history and/or physical examination at Visit 0.
• Have any abnormality or permanent body art (e.g., tattoo) that, in the opinion of the investigator, would obstruct the ability to observe local reactions at the injection site.
• Have had any blood loss >450 mL, e.g., due to donation of blood or blood products or injury, within the 7 days prior to Visit 0 or plan to donate blood during the trial, starting after Visit 0 and continuously until at least 7 days after receiving the last immunization.
• Have symptoms of COVID-19, e.g., respiratory symptoms, fever, cough, shortness of breath and breathing difficulties.
• Have had contact with persons diagnosed with COVID-19 or who tested positive for SARS-CoV-2 by any diagnostic test within the 30 days prior to Visit 1.
• Are soldiers, volunteers in detention, contract research organization (CRO) or sponsor staff or their family members.
• Regular receipt of inhaled/nebulized corticosteroids (except for Cohort 13).
• For older volunteers and for Cohort 13 only: Have a condition known to put them at high risk for severe COVID-19, including those with any of the following risk factors:
• Uncontrolled hypertension.
• Diabetes mellitus (HbA1c >8.5% ≥3 months, according to the medical history reported by the subject).
• Chronic obstructive pulmonary disease.
• Asthma.
• Chronic liver disease.
• Known Stage 3 or worse chronic kidney disease (glomerular filtration rate <60 mL/min/1.73 m^2); Except for post-renal transplant patients who should have (estimated) GFR ≥40 mL/min/1.73 m^2.
• Serious heart conditions, such as heart failure, coronary artery disease, or cardiomyopathies.
• Sickle cell disease.
• Cancer (except for Cohort 13).
• Are immune compromised due to stem cell or organ-transplantation with significant medical complications such as acute or chronic graft rejection or graft versus host disease requiring intensive immunosuppressive treatment, transplant failure or infectious complications or other conditions that would be considered a contraindication for vaccination.
• Are immune compromised due to HIV infection with a CD4+ count of < 200 x 10^6 /L at screening or significant medical complications such as opportunistic infections, malignant complications (e.g., lymphoma, Kaposi sarcoma), other organ manifestations consistent with advanced AIDS or other conditions that would be considered a contraindication for vaccination.
• Resident in a long term facility.
• Current vaping or smoking (occasional smoking is acceptable).
• History of chronic smoking within the prior year.