Protocol for a phase 3, randomized, double-blind clinical trial evaluating the safety and immunogenicity of the MVA-BN® vaccine against mpox in children aged 4 to less than 24 months in the Democratic Republic of the Congo: Data to guide future paediatric vaccination strategies.

INTRODUCTION: This article describes the protocol of the PregInPoxVac vaccine trial, evaluating the safety and immunogenicity of two MVA-BN vaccination regimens (full-dose and half- dose) administered subcutaneously with a 28-day interval in infants aged 4 to <24 months old. Non-inferiority of the full dose and half dose regimens will be compared to adults receiving a full dose regimen as part of the POX-MVA-045 study (ClinicalTrials.govIdentifier:NCT06549530). The PregInPoxVac study is being conducted in Boende, Tshuapa Province, Democratic Republic of the Congo (DRC), a mpox-endemic area; the POX-MVA-045 study is being conducted in Kinshasa, DRC, and Entebbe, Uganda. This is a randomized, double-blind, phase 3 trial assessing two dosing regimens in infants, with immunogenicity and safety compared to a predefined adult reference dataset.

METHODS: This is a phase 3, randomized, double-blind vaccine trial. A total of 344 healthy children aged 4 to <24 months will be enrolled at the Boende General Referral Hospital in the DRC. Participants will be randomized in a 1:1 ratio to receive either two full doses (0.5 mL) or two half doses (0.25 mL) of the MVA-BN® vaccine, administered subcutaneously 28 days apart. The primary objective is to evaluate the immunogenicity and safety of the paediatric vaccination regimen compared to the reference adult regimen, as defined in the POX-MVA-045 vaccine trial. Immunogenicity will be assessed through a hierarchical non-inferiority analysis of neutralizing antibody responses comparing full-dose and half-dose regimens in infants with the full-dose adult reference cohort. As a secondary analysis, the immunogenicity and safety observed in full dose infants will be compared to half dose infants. Additionally, total binding antibodies against vaccinia will also be compared between infants and adults as a secondary objective. Solicited adverse events (AEs) will be recorded for 7 days following each injection or until resolution of the event. Unsolicited AEs will be recorded for 28 days following each injection or until resolution of the event. Medically attended AEs (MAAEs), AEs of special interest (AESIs), serious AEs (SAEs) will be recorded from signing of the informed consent through 12 months after the second dose. Participant enrolment was conducted between 29 May and 30 October 2025.

ETHICS AND DISSEMINATION: The protocol was approved by the Antwerp University Hospital Committee for Medical Ethics (Approval No. 2025-7480), the National Health Ethics Committee of the DRC Ministry of Health (CNES) (Approval No. 641/CNES/BN/PMMF/2025) and by the Congolese Pharmaceutical Regulatory Authority (ACOREP:Approval No. 556/ACRP/DG/CAB/D15/2025). The trial has been registered on ClinicalTrials.gov (Identifier: NCT06844487).Written informed consent will be obtained from all parents or legal guardians prior to any study-related procedures being performed. The results will be published in peer-reviewed scientific journals and presented at national and international conferences.