Safety and immunogenicity of mRNA-based mpox vaccine candidate BNT166a: an open-label, dose-escalation,...

Recent mpox outbreaks highlight the need for novel, effective, and scalable vaccines against monkeypox virus (MPXV). The quadrivalent mRNA vaccine candidate BNT166a encoding MPXV antigens A35, B6, M1, and H3 was selected for clinical development based on evidence of immunogenicity and protective efficacy against multiple orthopoxviruses in preclinical models. We aimed to investigate the safety and immunogenicity of BNT166a in healthy adults.

In this open-label, uncontrolled, non-randomised, dose-escalation, first-in-human, phase 1 trial, we included healthy adults with no history of mpox, smallpox, or vaccinia virus (VACV) infection. We assigned VACV-naive participants (ie, individuals with no history of smallpox or mpox vaccination) to receive two intramuscular injections of 10 μg, 30 μg, or 60 μg BNT166a 4 weeks apart, and we assigned VACV-experienced participants (ie, individuals with a history of smallpox vaccination and no other orthopoxvirus vaccination) to receive two 30 μg BNT166a injections 4 weeks apart. The primary endpoints were solicited reactions within 7 days and unsolicited adverse events within 28 days after vaccination in participants who received at least one BNT166a vaccination. Exploratory endpoints of binding and neutralising antibody titres were assessed until 12 months after the second dose in participants who received both BNT166a vaccinations. This trial is registered with ClinicalTrials.gov, NCT05988203, and is ongoing.

Of 159 individuals screened for eligibility between Sept 21, 2023, and March 14, 2024, 48 VACV-naive participants (median age 35 years [IQR 24·0-39·0], 24 [50%] men, and 24 [50%] women) and 16 VACV-experienced participants (median age 58 years [54·5-60·5], five [31%] men, and 11 [69%] women) were enrolled, all of whom received at least one BNT166a vaccination. Among VACV-naive participants, local reactions (grade ≥1) were reported in eight (50%) of 16 participants in the 10-μg group, 13 (81%) of 16 in the 30-μg group, and 14 (88%) of 16 in the 60-μg group after the first dose, and in nine (60%) of 15 participants in the 10-μg group, 12 (86%) of 14 in the 30-μg group, and 13 (93%) of 14 in the 60-μg group after the second dose. Local reactions were reported in 11 (69%) of 16 VACV-experienced participants after the first dose and 14 (88%) of 16 after the second dose. Among VACV-naive participants, systemic events were reported in ten (63%) of 16 participants in the 10-μg group, seven (44%) of 16 in the 30-μg group, and 11 (69%) of 16 in the 60-μg group after the first dose, and in 11 (73%) of 15 participants in the 10-μg group, 13 (93%) of 14 in the 30-μg group, and 14 (100%) of 14 in the 60-μg group after the second dose. Systemic adverse events were reported in seven (44%) of 16 VACV-experienced participants after the first dose and in 13 (81%) of 16 after the second. Most events were mild to moderate in severity; two participants in the 60-μg group reported systemic events of grade 3 or worse after the second dose (one reported grade 3 fatigue and grade 3 fever and the other reported grade 4 fever). Adverse events considered BNT166a-related within 28 days of either vaccination were experienced by 18 (28%) participants; all but one (grade 3 neutropenia in a 60-μg dose recipient) were mild to moderate in severity. Three participants (two 10-μg dose recipients and one VACV-experienced participant) had serious adverse events, none of which were considered related to vaccination. BNT166a induced binding antibodies against all four mRNA-encoded antigens in all participants, with a 100% seroresponse rate 2 weeks after the second dose; titres persisted until 12 months after the second dose. MPXV clade IIb neutralising antibodies were detected in eight (62%) of 13 VACV-naive participants in the 10-μg group, ten (71%) of 14 in the 30-μg group, and 11 (92%) of 12 in the 60-μg group, and in 14 (93%) of 15 VACV-experienced participants. VACV neutralising antibodies were detected in six (46%) of 13 VACV-naive participants in the 10-μg group, 11 (79%) of 14 in the 30-μg group, and 12 (100%) of 12 in the 60-μg group, and in 14 (93%) of 15 VACV-experienced participants. MPXV and VACV neutralising titres peaked at 2 weeks after the second dose in the VACV-naive groups and at 1 month after the second dose in the VACV-experienced group and declined towards baseline concentrations in all groups over 12 months after the second dose.

In both VACV-naive and VACV-experienced participants, BNT166a was well tolerated, with local and systemic reactogenicity events occurring more frequently after the second dose than the first. BNT166a efficiently induced multiantigen-directed MPXV antibodies, which persisted until 12 months. MPXV clade IIb and VACV neutralising capacity was shown but with waning long-term responses. The overall safety and immunogenicity profile supported BNT166a's advancement to phase 2 trials.

BioNTech and the Coalition for Epidemic Preparedness Innovations.