A Randomized Clinical Trial Investigating the Safety, Reactogenicity, and Immunogenicity After Immunization With an mRNA-based Mpox Vaccine Candidate in Africa

Safety, Reactogenicity, and Immunogenicity of an Mpox mRNA Vaccine Candidate, BNT166a, in Healthy Participants Aged 18 Years and Older in African Countries: A Randomized, Double-blind, Placebo-controlled Phase II Trial

This is a randomized, double-blind, placebo-controlled study which aims to assess the safety, reactogenicity, and immunogenicity after one and two doses of BNT166a or placebo in healthy participants.

Study Overview

• Status: Recruiting
• Conditions: Smallpox; Mpox (Monkeypox); Orthopoxvirus Infection
• Intervention / Treatment: Biological: BNT166a; Other: Placebo

Detailed Description

This study will include the following cohorts:

• Cohort 1: healthy adults aged 18 to 45 years inclusive who are Orthopoxvirus-naïve.
• Cohort 2: healthy adults aged 18 to 64 years inclusive who are Orthopoxvirus-experienced.

All participants will receive two doses of BNT166a or placebo at least 28 days apart.

The planned study duration per participant is ~14 months.

• Study Type: Interventional
• Enrollment (Estimated): 310
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: BioNTech clinical trials patient information; Phone Number: +49 6131 9084; Email: patients@biontech.de

Study Locations

• Democratic Republic of the Congo
  • Kinshasa, Democratic Republic of the Congo, 01306
    • Not yet recruiting
    • University of Kinshasa UNIKIN
  • Kinshasa, Democratic Republic of the Congo, 5345
    • Not yet recruiting
    • Institute National de Recherche Biomedicale
• South Africa
  • Cape Town, South Africa, 7405
    • Not yet recruiting
    • TASK Applied Science
  • Cape Town, South Africa, 7530
    • Recruiting
    • TREAD Research Pty Ltd
  • Cape Town, South Africa, 7975
    • Not yet recruiting
    • Desmond Tutu Health Foundation Masiphumelele Clinic
  • Johannesburg, South Africa, 1864
    • Recruiting
    • Perinatal HIV Research Unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Key Inclusion Criteria (applicable to all participants unless otherwise specified):

• Are male or female individuals ≥18 years of age at the time of giving informed consent:

  • Cohort 1: ≥18 to ≤45 years of age
  • Cohort 2: ≥18 to ≤64 years of age
• Cohort 1: Participants must be Orthopoxvirus-naïve (have no history of smallpox or mpox vaccination or mpox infection).
• Cohort 2: Participants must be Orthopoxvirus-experienced (have evidence of mpox or smallpox vaccination or mpox infection at least 2 years prior to consent).

Key Exclusion Criteria (applicable to all participants unless otherwise specified):

• Have had recent exposure to mpox (defined as close contact with a probable or confirmed case of mpox within the past 28 days, or have evidence of mpox infection or mpox vaccination within 2 years prior to consent).
• Have a contraindication, warning and/or precaution to vaccination with a messenger ribonucleic acid (mRNA) Coronavirus disease 2019 (COVID-19) vaccine as specified in the Summary of Product Characteristics for BNT162b2 (COMIRNATY United States Prescribing Information/European Union Summary of Product Characteristics) and BNT166 Investigator Brochure.
• Have a history of allergies, hypersensitivities, or intolerance to the study treatments including any excipients thereof.
• Have a current or history of cardiovascular diseases, e.g., myocarditis, pericarditis, myocardial infarction, congestive heart failure, cardiomyopathy, or clinically significant arrhythmias.
• Have any known bleeding diathesis or condition associated with prolonged bleeding that would, in the opinion of the investigator, contraindicate intramuscular injection.
• Have a body mass index ≤18.5 kg/m^2 or ≥35 kg/m^2.

NOTE: Other protocol defined Inclusion/Exclusion criteria apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1 - BNT166a Dose Level (DL) 1 (Orthopoxvirus-naïve participants, aged 18-45 years); Two doses of investigational medicinal product (IMP).	Biological: BNT166a; Intramuscular injection. Injections should be given in the deltoid muscle, using the same non-dominant arm for all IMP doses.
Experimental: Cohort 1 - BNT166a DL 2 (Orthopoxvirus-naïve participants, aged 18-45 years); Two doses of IMP.	Biological: BNT166a; Intramuscular injection. Injections should be given in the deltoid muscle, using the same non-dominant arm for all IMP doses.
Placebo Comparator: Cohort 1 - Placebo (Orthopoxvirus-naïve participants, aged 18-45 years); 0.9% sodium chloride solution. Two doses of IMP.	Other: Placebo; Intramuscular injection. Injections should be given in the deltoid muscle, using the same non-dominant arm for all IMP doses.
Experimental: Cohort 2 - BNT166a DL 1 (Orthopoxvirus-experienced participants, aged 18-64 years); Two doses of IMP.	Biological: BNT166a; Intramuscular injection. Injections should be given in the deltoid muscle, using the same non-dominant arm for all IMP doses.
Experimental: Cohort 2 - BNT166a DL 2 (Orthopoxvirus-experienced participants, aged 18-64 years); Two doses of IMP.	Biological: BNT166a; Intramuscular injection. Injections should be given in the deltoid muscle, using the same non-dominant arm for all IMP doses.
Placebo Comparator: Cohort 2 - Placebo (Orthopoxvirus-experienced participants, aged 18-64 years); 0.9% sodium chloride solution. Two doses of IMP.	Other: Placebo; Intramuscular injection. Injections should be given in the deltoid muscle, using the same non-dominant arm for all IMP doses.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number (and percentage) of participants with at least one solicited local reaction (pain, erythema/redness, induration/swelling)	At each dose level of BNT166a in Orthopoxvirus-naïve (Cohort 1) and Orthopoxvirus-experienced (Cohort 2) adults.	For up to 7 days following each dose
Number (and percentage) of participants with at least one solicited systemic reaction (fever, headache, fatigue/tiredness, muscle pain/myalgia, joint pain/arthralgia, chills, diarrhea, vomiting)	At each dose level of BNT166a in Orthopoxvirus-naïve (Cohort 1) and Orthopoxvirus-experienced (Cohort 2) adults.	For up to 7 days following each dose
Number (and percentage) of participants with at least one use of antipyretics/analgesics	At each dose level of BNT166a in Orthopoxvirus-naïve (Cohort 1) and Orthopoxvirus-experienced (Cohort 2) adults.	For up to 7 days following each dose
Number (and percentage) of participants with at least one unsolicited adverse event (AE) (post-Dose 1)	At each dose level of BNT166a in Orthopoxvirus-naïve (Cohort 1) and Orthopoxvirus-experienced (Cohort 2) adults.	From Dose 1 to 28 days post-Dose 1
Number (and percentage) of participants with at least one unsolicited AE (post-Dose 2)	At each dose level of BNT166a in Orthopoxvirus-naïve (Cohort 1) and Orthopoxvirus-experienced (Cohort 2) adults.	From Dose 2 to 28 days post-Dose 2
Number (and percentage) of participants with at least one serious adverse event	At each dose level of BNT166a in Orthopoxvirus-naïve (Cohort 1) and Orthopoxvirus-experienced (Cohort 2) adults.	From Dose 1 until the end of study, i.e., up to ~14 months
Number (and percentage) of participants with at least one AE of special interest	At each dose level of BNT166a in Orthopoxvirus-naïve (Cohort 1) and Orthopoxvirus-experienced (Cohort 2) adults.	From Dose 1 until the end of study, i.e., up to ~14 months
Number (and percentage) of participants with at least one medically attended AE	At each dose level of BNT166a in Orthopoxvirus-naïve (Cohort 1) and Orthopoxvirus-experienced (Cohort 2) adults.	From Dose 1 until the end of study, i.e., up to ~14 months
Number (and percentage) of participants with at least one AE leading to a participant's withdrawal from the study	At each dose level of BNT166a in Orthopoxvirus-naïve (Cohort 1) and Orthopoxvirus-experienced (Cohort 2) adults.	From Dose 1 until the end of study, i.e., up to ~14 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Geometric mean titers (GMT) of BNT166a antigen-specific (A35, B6, H3, and M1) binding antibody titers	At each dose level of BNT166a in Orthopoxvirus-naïve (Cohort 1) and Orthopoxvirus-experienced (Cohort 2) adults, at the defined timepoints.	At baseline, 1 month post-Dose 1, and 1 month post- Dose 2
Geometric mean fold rise (GMFR) of BNT166a antigen-specific (A35, B6, H3, and M1) binding antibody titers	At each dose level of BNT166a in Orthopoxvirus-naïve (Cohort 1) and Orthopoxvirus-experienced (Cohort 2) adults. Ratio post-baseline/baseline at the defined timepoints.	At 1 month post-Dose 1 and 1 month post-Dose 2
GMT of MPXV-specific neutralizing antibody titers	At each dose level of BNT166a in Orthopoxvirus-naïve (Cohort 1) and Orthopoxvirus-experienced (Cohort 2) adults, at the defined timepoints.	At baseline, 1 month post-Dose 1, and 1 month post-Dose 2
GMFR of MPXV-specific neutralizing antibody titers	At each dose level of BNT166a in Orthopoxvirus-naïve (Cohort 1) and Orthopoxvirus-experienced (Cohort 2) adults. Ratio post-baseline/baseline at the defined timepoints.	At 1 month post-Dose 1 and 1 month post-Dose 2
GMT of vaccinia virus (VACV)-specific neutralizing antibody titers	At each dose level of BNT166a in Orthopoxvirus-naïve (Cohort 1) and Orthopoxvirus-experienced (Cohort 2) adults, at the defined timepoints.	At baseline, 1 month post-Dose 1, and 1 month post-Dose 2
GMFR of VACV-specific neutralizing antibody titers	At each dose level of BNT166a in Orthopoxvirus-naïve (Cohort 1) and Orthopoxvirus-experienced (Cohort 2) adults. Ratio post-baseline/baseline at the defined timepoints.	At 1 month post-Dose 1 and 1 month post-Dose 2

Collaborators and Investigators

• Sponsor: BioNTech SE
• Collaborators: Coalition for Epidemic Preparedness Innovations
• Investigators: Study Director: BioNTech Responsible Person, BioNTech SE

Study record dates

Study Major Dates

• Study Start (Actual): February 20, 2026
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): June 1, 2027

Study Registration Dates

• First Submitted: January 23, 2026
• First Submitted That Met QC Criteria: January 23, 2026
• First Posted (Actual): January 30, 2026

Study Record Updates

• Last Update Posted (Actual): March 4, 2026
• Last Update Submitted That Met QC Criteria: March 2, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Ribonucleic acid (RNA) vaccine; Active immunization; Monkeypox virus (MPXV)
• Additional Relevant MeSH Terms: Infections; Virus Diseases; DNA Virus Infections; Animal Diseases; Primate Diseases; Rodent Diseases; Smallpox; Poxviridae Infections; Mpox, Monkeypox
• Other Study ID Numbers: BNT166-02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No