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

NCT ID: NCT05541861

Last Updated: 2026-01-13

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 383 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-11-08
• Study Completion Date: 2024-11-22

Brief Summary

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.

Conditions

SARS-CoV-2 Infection; COVID-19

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: TRIPLE

Study Groups

Cohort 1: BNT162b2 Bivalent 30 mcg + BNT162b4 5 mcg (Aged 18-55 Years)

Participants aged 18-55 years received an intramuscular injection of BNT162b2 Bivalent 30 mcg along with BNT162b4 5 mcg at Day 1.

Group Type: EXPERIMENTAL

BNT162b4 5 mcg

Intervention Type: BIOLOGICAL

Anti-viral RNA vaccine for active immunization against COVID-19 administered as intramuscular injection.

BNT162b2 Bivalent (original/Omicron BA.4/BA.5) 30 mcg

Intervention Type: BIOLOGICAL

Anti-viral RNA vaccine for active immunization against COVID-19 administered as intramuscular injection.

Cohort 2: BNT162b2 Bivalent 30 mcg + BNT162b4 10 mcg (Aged 18-55 Years)

Participants aged 18-55 years received an intramuscular injection of BNT162b2 Bivalent 30 mcg along with BNT162b4 10 mcg at Day 1. Participants who consented to receive a second dose of the study drugs received BNT162b2 Bivalent 30 mcg along with BNT162b4 10 mcg again as Dose 2 at 6 to 7 months after Dose 1.

Group Type: EXPERIMENTAL

BNT162b4 10 mcg

Intervention Type: BIOLOGICAL

Anti-viral RNA vaccine for active immunization against COVID-19 administered as intramuscular injection.

BNT162b2 Bivalent (original/Omicron BA.4/BA.5) 30 mcg

Intervention Type: BIOLOGICAL

Anti-viral RNA vaccine for active immunization against COVID-19 administered as intramuscular injection.

Cohort 3a: BNT162b2 Bivalent/Monovalent 30 mcg + BNT162b4 15 mcg (Aged 18-55 Years)

Participants aged 18-55 years received a dose of BNT162b2 Bivalent 30 mcg (Omicron BA.4/BA.5) along with BNT162b4 15 mcg at Day 1, Participants who consented to receive a second dose of the study drugs received BNT162b2 Monovalent (OMI XBB.1.5) 30 mcg along with BNT162b4 15 mcg again as Dose 2 at 6 to 7 months after Dose 1.

Group Type: EXPERIMENTAL

BNT162b4 15 mcg

Intervention Type: BIOLOGICAL

Anti-viral RNA vaccine for active immunization against COVID-19 administered as intramuscular injection.

BNT162b2 Monovalent (OMI XBB.1.5) 30 mcg

Intervention Type: BIOLOGICAL

Anti-viral RNA vaccine for active immunization against COVID-19 administered as intramuscular injection.

BNT162b2 Bivalent (original/Omicron BA.4/BA.5) 30 mcg

Intervention Type: BIOLOGICAL

Anti-viral RNA vaccine for active immunization against COVID-19 administered as intramuscular injection.

Cohort 3b: BNT162b2 Bivalent/Monovalent 30 mcg + BNT162b4 15 mcg (Aged >55 Years)

Participants aged \>55 years received a dose of BNT162b2 Bivalent 30 mcg (Omicron BA.4/BA.5) along with BNT162b4 15 mcg at Day 1. Participants who consented to receive a second dose of the study drugs received BNT162b2 Monovalent (OMI XBB.1.5) 30 mcg along with BNT162b4 15 mcg again as Dose 2 at 6 to 7 months after Dose 1.

Group Type: EXPERIMENTAL

BNT162b4 15 mcg

Intervention Type: BIOLOGICAL

Anti-viral RNA vaccine for active immunization against COVID-19 administered as intramuscular injection.

BNT162b2 Monovalent (OMI XBB.1.5) 30 mcg

Intervention Type: BIOLOGICAL

Anti-viral RNA vaccine for active immunization against COVID-19 administered as intramuscular injection.

BNT162b2 Bivalent (original/Omicron BA.4/BA.5) 30 mcg

Intervention Type: BIOLOGICAL

Anti-viral RNA vaccine for active immunization against COVID-19 administered as intramuscular injection.

Cohort 4a: BNT162b2 Bivalent/Monovalent 30 mcg + BNT162b4 30 mcg (Aged 18-55 Years)

Participants aged 18-55 years received a dose of BNT162b2 Bivalent 30 mcg (Omicron BA.4/BA.5) along with BNT162b4 30 mcg at Day 1. Participants who consented to receive a second dose of the study drugs received BNT162b2 Monovalent (OMI XBB.1.5) 30 mcg along with BNT162b4 30 mcg again as Dose 2 at 6 to 7 months after Dose 1.

Group Type: EXPERIMENTAL

BNT162b4 30 mcg

Intervention Type: BIOLOGICAL

Anti-viral RNA vaccine for active immunization against COVID-19 administered as intramuscular injection.

BNT162b2 Monovalent (OMI XBB.1.5) 30 mcg

Intervention Type: BIOLOGICAL

Anti-viral RNA vaccine for active immunization against COVID-19 administered as intramuscular injection.

BNT162b2 Bivalent (original/Omicron BA.4/BA.5) 30 mcg

Intervention Type: BIOLOGICAL

Anti-viral RNA vaccine for active immunization against COVID-19 administered as intramuscular injection.

Cohort 4b: BNT162b2 Bivalent/Monovalent 30 mcg + BNT162b4 30 mcg (Aged >55 Years)

Participants aged \>55 years received a dose of BNT162b2 Bivalent 30 mcg (Omicron BA.4/BA.5) along with BNT162b4 30 mcg at Day 1. Participants who consented to receive a second dose of the study drugs received BNT162b2 Monovalent (OMI XBB.1.5) 30 mcg along with BNT162b4 30 mcg again as Dose 2 at 6 to 7 months after Dose 1.

Group Type: EXPERIMENTAL

BNT162b4 30 mcg

Intervention Type: BIOLOGICAL

Anti-viral RNA vaccine for active immunization against COVID-19 administered as intramuscular injection.

BNT162b2 Monovalent (OMI XBB.1.5) 30 mcg

Intervention Type: BIOLOGICAL

Anti-viral RNA vaccine for active immunization against COVID-19 administered as intramuscular injection.

BNT162b2 Bivalent (original/Omicron BA.4/BA.5) 30 mcg

Intervention Type: BIOLOGICAL

Anti-viral RNA vaccine for active immunization against COVID-19 administered as intramuscular injection.

Comparator A: BNT162b2 Bivalent 30 mcg (Aged 18-55 Years)

Participants aged 18-55 years received one intramuscular injection of BNT162b2 30 mcg at Day 1.

Group Type: ACTIVE_COMPARATOR

BNT162b2 Bivalent (original/Omicron BA.4/BA.5) 30 mcg

Intervention Type: BIOLOGICAL

Anti-viral RNA vaccine for active immunization against COVID-19 administered as intramuscular injection.

Comparator B: BNT162b2 Bivalent 30 mcg (Aged >55 Years)

Participants aged \>55 years received one intramuscular injection of BNT162b2 30 mcg at Day 1.

Group Type: ACTIVE_COMPARATOR

BNT162b2 Bivalent (original/Omicron BA.4/BA.5) 30 mcg

Intervention Type: BIOLOGICAL

Anti-viral RNA vaccine for active immunization against COVID-19 administered as intramuscular injection.

Cohort 5: BNT162b4 30 mcg (Aged 18-55 Years)

Participants aged 18-55 years received two intramuscular injections of BNT162b4 30 mcg at Day 1 and 2 months post-Dose 1, respectively.

Group Type: EXPERIMENTAL

BNT162b4 30 mcg

Intervention Type: BIOLOGICAL

Anti-viral RNA vaccine for active immunization against COVID-19 administered as intramuscular injection.

Interventions

BNT162b4 10 mcg

Anti-viral RNA vaccine for active immunization against COVID-19 administered as intramuscular injection.

Intervention Type: BIOLOGICAL

BNT162b4 15 mcg

Anti-viral RNA vaccine for active immunization against COVID-19 administered as intramuscular injection.

Intervention Type: BIOLOGICAL

BNT162b4 30 mcg

Anti-viral RNA vaccine for active immunization against COVID-19 administered as intramuscular injection.

Intervention Type: BIOLOGICAL

BNT162b2 Monovalent (OMI XBB.1.5) 30 mcg

Anti-viral RNA vaccine for active immunization against COVID-19 administered as intramuscular injection.

Intervention Type: BIOLOGICAL

BNT162b4 5 mcg

Anti-viral RNA vaccine for active immunization against COVID-19 administered as intramuscular injection.

Intervention Type: BIOLOGICAL

BNT162b2 Bivalent (original/Omicron BA.4/BA.5) 30 mcg

Anti-viral RNA vaccine for active immunization against COVID-19 administered as intramuscular injection.

Intervention Type: BIOLOGICAL

Eligibility Criteria

Inclusion Criteria

• 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 be vaccinated with:

• 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.

• 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

• 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).
• 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Pfizer

INDUSTRY

Sponsor Role: collaborator

BioNTech SE

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

BioNTech Responsible Person

Role: STUDY_DIRECTOR

BioNTech SE

Locations

Alliance for Multispecialty Research, LLC

Tempe, Arizona, United States

Hoag Hospital

Newport Beach, California, United States

California Research Foundation

San Diego, California, United States

Diablo Clinical Research, Inc.

Walnut Creek, California, United States

Clinical Research Consulting, LLC

Milford, Connecticut, United States

Cenexel RCA (Research Centers of America)

Hollywood, Florida, United States

Research Institute of South Florida, Inc.

Miami, Florida, United States

Great Lakes Clinical Trials LLC - Andersonville

Chicago, Illinois, United States

Johnson County Clin-Trials, Inc. (JCCT)

Lenexa, Kansas, United States

University of Kentucky Center for Clinical and Translational Science (outpatient clinic)

Lexington, Kentucky, United States

Alliance for Multispecialty Research, LLC (Kansas)

Kansas City, Missouri, United States

Finger Lakes Clinical Research

Rochester, New York, United States

CTI Clinical Research Center

Cincinnati, Ohio, United States

Alliance for Multispecialty Research, LLC

Knoxville, Tennessee, United States

Clinical Trials of Texas, LLC / Flourish Research

San Antonio, Texas, United States

Endeavor Clinical Trials, LLC

San Antonio, Texas, United States

DM Clinical Research

Tomball, Texas, United States

Countries

United States

References

Arieta CM, Xie YJ, Rothenberg DA, Diao H, Harjanto D, Meda S, Marquart K, Koenitzer B, Sciuto TE, Lobo A, Zuiani A, Krumm SA, Cadima Couto CI, Hein S, Heinen AP, Ziegenhals T, Liu-Lupo Y, Vogel AB, Srouji JR, Fesser S, Thanki K, Walzer K, Addona TA, Tureci O, Sahin U, Gaynor RB, Poran A. The T-cell-directed vaccine BNT162b4 encoding conserved non-spike antigens protects animals from severe SARS-CoV-2 infection. Cell. 2023 May 25;186(11):2392-2409.e21. doi: 10.1016/j.cell.2023.04.007. Epub 2023 Apr 13.

Reference Type: DERIVED

PMID: 37164012 (View on PubMed)

Wang CY, Peng WJ, Kuo BS, Ho YH, Wang MS, Yang YT, Chang PY, Shen YH, Hwang KP. Toward a pan-SARS-CoV-2 vaccine targeting conserved epitopes on spike and non-spike proteins for potent, broad and durable immune responses. PLoS Pathog. 2023 Apr 20;19(4):e1010870. doi: 10.1371/journal.ppat.1010870. eCollection 2023 Apr.

Reference Type: DERIVED

PMID: 37079651 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

BNT162-21

Identifier Type: -

Identifier Source: org_study_id