Safety and Effects of an Investigational COVID-19 Vaccine as Booster in Healthy People

An Exploratory Phase I, Randomized, Observer-blind, Active-controlled, Dose-escalation Trial Evaluating the Safety, Tolerability, and Immunogenicity of an Investigational RNA-based SARS-CoV-2 Vaccine in COVID-19 Vaccine Experienced Healthy Adults

This was an exploratory Phase I, randomized, observer-blind, active-controlled, dose-escalation trial to evaluate four dose levels (DLs) of BNT162b4 given in combination with BNT162b2 Bivalent (original/Omicron BA.4/BA.5) to select a safe and tolerable dose and to evaluate BNT162b4 + BNT162b2 Bivalent (original/Omicron BA.4/BA.5) when given as Dose 1 and Dose 2 (booster) in Cohorts 1 and 2 and BNT162b4 + BNT162b2 Monovalent (OMI XBB.1.5) when given as Dose 2 (booster) in Cohorts 3a, 3b, 4a, and 4b, and 30 microgram (mcg) BNT162b4 when given alone as Dose 1 and Dose 2 in Cohort 5.

The trial used a staggered dosing process schema, i.e., enrollment into the next higher dose level was done sequentially and subject to safety data from the previous dose levels, with sentinel participants in Cohorts 1, 2, 3a, and 4a. Cohort 3b investigating the same dose level as cohort 3a but in participants aged >55 years was opened after safety data for participants aged 18-55 years in Cohort 3a had been reviewed. Enrollment into Cohorts 4a and 4b was opened after safety data for Cohort 3a and 3b had been reviewed. Cohort 5 participants were not randomized and received two doses of BNT162b4 alone after which a safety review was performed after all participants received Dose 2 in this cohort.

BNT162b4 plus BNT162b2 Bivalent (original/Omicron BA.4/BA.5)/Monovalent (OMI XBB.1.5) was co-administered (as a single injection).

BNT162b4 alone was administered as a single injection.

Inclusion Criteria (applicable to all dose groups unless specified otherwise):

• Had given informed consent by signing and dating the informed consent form (ICF) before initiation of any trial-specific procedures.

• Were willing and able to comply with scheduled visits, treatment schedule, laboratory tests, lifestyle restrictions, e.g., to follow good practices to reduce their chances of being infected or spreading COVID-19, and other requirements of the trial. This included that they were able to understand and follow trial-related instructions.

• Were aged 18 years and older at randomization (Cohorts 1-4) or 18 to 55 years (Cohort 5), had a body mass index over 18.5 kg/m^2 and under 35 kg/m^2 (Cohorts 1-4) and under 30 kg/m^2 (Cohort 5), and weighed at least 50 kg at Visit 0.

• Were healthy, in the clinical judgment of the investigator based on participant-reported medical history data, and physical examination, 12-lead ECG, vital signs, and clinical laboratory test outcomes at Visit 0.

  • Note: Healthy participants with pre-existing stable disease (e.g., obesity), defined as disease not requiring significant change in therapy or hospitalization for worsening disease during the 84 days before Visit 0, could be included.

• Agreed not to enroll in another trial with an IMP starting from Visit 0 and until 168 days (Cohorts 1-4) and 90 days (Cohort 5) after receiving the last IMP dose. Inclusion criteria pertaining to Dose 2 (Cohorts 1-4 only): If 168 days after the participant's first IMP dose had passed before they consented to Dose 2, they should have agreed to not enroll in another trial from the time of consent to Dose 2 until 168 days after receiving Dose 2 of the IMP.

• Agreed not to be vaccinated with:

  • Non-trial vaccines (except COVID-19 vaccines, as per next sub-bullet) starting 28 days prior to the Dose 1 and until 28 days after receiving of the last IMP dose. Seasonal influenza vaccine is allowed; however, it should be given at least 14 days before or after any administration of IMP. Inclusion criteria pertaining to Dose 2 (Cohorts 1-4 only): If 28 days after the participant's first IMP dose had passed before they consented to continue Dose 2, they should not have been vaccinated with non-trial vaccines starting from the time of consent to Dose 2 and until 168 days after receiving the Dose 2 of the IMP.
  • Non-trial COVID-19 vaccines starting at least 90 days prior to the Visit 1 and until completion of the participant's last trial visit (Cohorts 1-4) and until 28 days post-Dose 2 (Cohort 5 only).

• Had been vaccinated with at least three doses of an RNA-based COVID-19 vaccine authorized in the United States (US) before Visit 0. The last COVID-19 RNA vaccine dose must have been administered at least 90 days before Visit 1.

  • Note: Documented confirmation of prior COVID-19 vaccine receipt must be obtained prior to randomization (Cohorts 1-4) or prior to Visit 1 (Cohort 5 only).

• Had negative human immunodeficiency virus (HIV) -1 and HIV-2 test results at Visit 0.

• Had negative Hepatitis B surface antigen test results at Visit 0.

• Had negative anti-Hepatitis C virus (HCV) antibodies, or negative HCV polymerase chain reaction test results if the anti-HCV was positive at Visit 0.

• Participants of childbearing potential (POCBP) that had a negative serum beta human chorionic gonadotropin (β-HCG) pregnancy test result at Visit 0 and negative urine pregnancy test results prior to receiving Dose 1, additionally for Cohort 5 only, a negative urine pregnancy test result prior to receiving Dose 2. Participants born female that were postmenopausal or permanently sterilized (verified by medical records) were not considered POCBP. Inclusion criteria pertaining to Dose 2 (Cohorts 1-4 only): POCBP that had a negative urine pregnancy test results prior to receiving Dose 2.

• POCBP who agreed to practice a highly effective form of contraception and required their male sexual partners to use condoms with a spermicidal agent, starting at Visit 0 and continuously until 28 days after receiving the last IMP dose. Inclusion criteria pertaining to Dose 2 (Cohorts 1-4 only) : If 28 days after the participant's first IMP dose had passed before they consent to continue Dose 2, they should have a negative urine β-HCG pregnancy test result at Visit 7 and agree to practice a highly effective form of contraception and required their male sexual partners to use condoms with a spermicidal agent, starting from the time they consent to Dose 2 and continuously until 28 days after receiving Dose 2 of IMP.

• POCBP who agreed not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during trial, starting at Visit 0 and continuously until 28 days after receiving the last IMP dose. Inclusion criteria pertaining to Dose 2 (Cohorts 1-4 only): If 28 days after the participant's first IMP dose had passed before they consented to continue Dose 2, they should have agreed not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during trial, starting from the time they consented to Dose 2 and continuously until 28 days after receiving Dose 2 of IMP.

• Men who were sexually active with partners of childbearing potential and who had not had a verified vasectomy (documented in medical records) that agreed to use condoms with a spermicidal agent and to practice a highly effective form of contraception with their sexual partners born female starting at Visit 0 and continuously until 28 days after receiving the last IMP dose. Inclusion criteria pertaining to Dose 2 (Cohorts 1-4 only): If 28 days after the participant's first IMP dose had passed before they consent to continue Dose 2, they should have agreed to use condoms with a spermicidal agent and to practice a highly effective form of contraception with their sexual partners born female starting from the time they consent to Dose 2 and continuously until 28 days after receiving Dose 2 of IMP.

• Men who were willing to refrain from sperm donation, starting at Visit 0 and continuously until 28 days after receiving the last IMP dose. Inclusion criteria pertaining to Dose 2 (Cohorts 1-4 only): If 28 days after the participant's first IMP dose had passed before they consent to continue Dose 2, they should have agreed to refrain from sperm donation, starting from the time they consent to Dose 2 and continuously until 28 days after receiving Dose 2 of IMP.

Inclusion Criteria (Dose 2 groups, Cohorts 1-4 only):

Participants were eligible to receive Dose 2 if all of the following criteria (in addition to inclusion criteria above) apply:

• Had given informed consent by signing and dating the ICF reflecting the respective protocol version before administration of Dose 2.
• Had enrolled in a dose cohort and received Dose 1 of BNT162b4 + BNT162b2 Bivalent (original/Omicron BA.4/BA.5) in this trial.
• Were healthy in the opinion of the investigator based on a brief (symptom-directed) physical examination.

Exclusion Criteria (applicable to all dose groups unless specified otherwise):

• Breastfeeding or intending to become pregnant starting with Visit 0 until 28 days after receiving the last dose of trial IMP or intending to father children starting with Visit 0 until 28 days after receiving the last trial IMP dose.

• History of any severe adverse reactions to vaccines or to vaccine components and including history of anaphylaxis and related symptoms such as hives, respiratory difficulty, angioedema, and/or abdominal pain. (Not excluded from participation: a participant who had an anaphylactic adverse reaction to pertussis vaccine as a child).

• Current or history of the following medical conditions:

  1. Uncontrolled or moderate or severe respiratory diseases (e.g., asthma, chronic obstructive pulmonary disease); symptoms of asthma severity as defined in the most recent US National Heart, Lung, and Blood Institute asthma management guidelines.

  2. Diabetes mellitus type 1 or type 2, or new onset of Diabetes mellitus type 1 or 2 from the administration of Dose 1, including cases controlled with diet alone (Not excluded: history of isolated gestational diabetes).

  3. Hypertension:

     • If a person had been found to have elevated blood pressure or hypertension during screening or previously, excluded for blood pressure that is not well controlled. Well controlled blood pressure was defined as consistently <=140 mm Hg systolic and <= 90 mm Hg diastolic, with or without medication, with only isolated, brief instances of higher readings, which must be ≤150 mm Hg systolic and ≤90 mm Hg diastolic at Visit 0.
     • If a person did not have a history of elevated blood pressure or hypertension previously or during screening, also excluded for systolic blood pressure ≥150 mm Hg at Visit 0 or diastolic blood pressure ≥100 mm Hg at Visit 0. Exclusion pertaining to Dose 2 (all cohorts): Participants who had new onset of worsening hypertension since enrollment, that, in the opinion of the investigator would constitute an increased risk to the individual's participation in Dose 2 would not receive Dose 2.

  4. Any current or history of cardiovascular diseases such as myocarditis, pericarditis, myocardial infarction, symptomatic congestive heart failure, cardiomyopathy or clinically significant arrhythmias. Exclusion pertaining to Dose 2 (all cohorts): Participants who had new onset of cardiovascular disease since enrollment, that, in the opinion of the investigator would constitute an increased risk to the individual's participation in Dose 2 would not receive Dose 2.

  5. A diagnosed bleeding disorder (e.g., factor deficiency, coagulopathy, or platelet disorder requiring special precautions). Exclusion pertaining to Dose 2 (all cohorts): Participants who had new onset of a bleeding disorder since enrollment, that, in the opinion of the investigator, would constitute an increased risk to the individual's participation in Dose 2 would not receive Dose 2.

  6. Seizure disorders: History of seizure(s) within the past 3 years. Also excluded if participant had used medications in order to prevent or treat seizure(s) at any time within the past 3 years.

  7. Screening 12-lead ECG that was consistent with probable or possible myocarditis or pericarditis, or demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of the trial results. Exclusion pertaining to Dose 2 (all cohorts): Only symptomatic participants or whose clinical picture, in the opinion of the investigator, warrant ECG will have a repeat 12-lead ECG prior to Dose 2.

     • Note: ECG changes including but not limited to: paroxysmal or sustained atrial or ventricular arrhythmias, atrioventricular block (grade 2-3) or bundle branch block, diffuse ST-segment elevation or PR-segment inversion, QTcF interval (QT interval corrected by the Fridericia formula) >450 ms in men and >460 ms in women, changes supporting myocardial infarction and/or myocardial ischemia. Exclusion pertaining to Dose 2 (all cohorts): Subjects who had a repeat ECG prior to Dose 2 and had a change or new onset that, in the opinion of the investigator, will not receive Dose 2.

• Current or history of major psychiatric illness, including but not limited to bipolar disorder, major depressive disorder, schizophrenia, autism, and attention deficit-hyperactivity disorder that could interfere with participation and follow-up as required by the trial protocol. Exclusion pertaining to Dose 2 (Cohorts 1-4): Participants who had a change or new onset psychiatric illness.

• Current or history of the following diseases associated with immune dysregulation:

  • Primary immunodeficiencies.
  • History of solid organ or bone marrow transplantation.
  • Asplenia: any condition resulting in the absence of a functional spleen.
  • Currently existing or history of autoimmune disease including and not limited to thyroid autoimmune disease, multiple sclerosis, or psoriasis. Exclusion pertaining to Dose 2 (Cohorts 1-4): Participants who had a change or new onset immunodeficiency.

• Received any non-trial IMP within 28 days before Visit 0 or Visit 7 (Cohorts 1-4) and (Cohort 5) within 28 days before Dose 1 and Dose 2 (except seasonal influenza vaccine, which should be given at least 14 days before or after any administration of IMP).

• Received or planned treatment throughout the entire trial with radiotherapy or immunosuppressive therapy, including cytotoxic agents or systemic corticosteroids (if systemic corticosteroids are administered for >=14 days at a dose of >=20 mg/day of prednisone or equivalent), e.g., for cancer or an autoimmune disease, or planned receipt throughout this trial. Inhaled/nebulized (except high doses as per exclusion criteria above), intraarticular, intrabursal, or topical (skin or eyes) corticosteroids were permitted.

• Blood/plasma products and/or immunoglobulin containing therapy (including monoclonal antibodies) received:

  • Cohorts 1-4: within 120 days before Visit 1 or Visit 7 or administration was planned starting at Visit 0 or prior to Visit 7 until 120 days after the last IMP administration in this trial.
  • Cohort 5: within 120 days before dosing and prior to Dose 2 or administration is planned starting at Visit 0 or prior to Dose 2 until 90 days after the last IMP administration in this trial.
  • Exclusion pertaining to Dose 2 (Cohorts 1-4): if 28 days after the participant's last IMP dose had passed before they consent to continue Dose 2, blood/plasma products and/or immunoglobulin containing therapy (including monoclonal antibodies) received within 120 days before Dose 2 of IMP (Visit 7) continuously until 120 days after receiving Dose 2 of IMP.

• Received allergy treatment with antigen injections within 28 days before Visit 1 or Visit 7 (Cohorts 1-4) and within 28 days before dosing (Cohort 5) or where allergy treatment with antigen injections were scheduled within 14 days after any visit with IMP administration in this trial.

• Participants with a history of SARS-CoV-2 infection (symptomatic or asymptomatic) <60 days prior to randomization.

• Have received any non-RNA or unauthorized COVID-19 vaccine, aside from Dose 1 of the current trial.

• Any existing condition which may affect IMP administration and/or assessment of local reactions assessment at the injection site, e.g., tattoos, severe scars, etc.

• Were vulnerable individuals as per International Council for Harmonisation (ICH) E6 definition, i.e., are individuals whose willingness to participate in a clinical trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate.

• Any screening hematology and/or blood chemistry laboratory value that meets the definition of a Grade >=1 abnormality at Visit 0, or an abnormal C-reactive protein (identified by any method) or troponin I value.

  • Note: Participants with any stable Grade 1 abnormalities (according to the toxicity grading scale) may be considered eligible at the discretion of the investigator. Gilberts disease, in and of itself, is not considered exclusionary. Exclusion pertaining to Dose 2: Only symptomatic participants or whose clinical picture, in the opinion of the investigator, warrant laboratory investigation, would have a repeat lab(s) prior to Dose 2.

• History of alcohol abuse or drug addiction within 1 year before Visit 0, or 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 wellbeing if they participate as participants in the trial, or that could prevent, limit, or confound the protocol-specified assessments.