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.

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.

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.