Background: Respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) are common respiratory pathogens that cause severe illness in young children. Methods: As part of an age-de-escalation clinical development program, a phase 1 trial of mRNA-based RSV (mRNA-1345) and investigational RSV/hMPV combination (mRNA-1365) vaccines was conducted in infants and children. Participants were randomized in equal numbers to mRNA-1345 (encoding RSV preF), mRNA-1365 (encoding RSV PreF and hMPV F), or placebo, in an observer-blind study. In a stepwise fashion, children 8 to 23 months of age (Part A) received a 3-injection series of mRNA-1345 (30 μg), mRNA-1365 (30 μg), or placebo. After Data Safety Monitoring Board (DSMB) review of these data, infants 5 to 7 months of age (Part B) were similarly randomized to a 3-injection series using a dose escalation approach (starting at 15 μg). The primary study objective was to assess safety/reactogenicity; secondary objectives were evaluation of clinical RSV/hMPV infections and measurement of antibody/cell-mediated immune responses. Results: In children 8 to 23 months of age (Part A), both mRNA-1345 and mRNA-1365 were well-tolerated and induced robust RSV-A and -B neutralizing antibodies (nAbs) and preF-biased binding antibodies (bAbs). RSV-specific cellular responses assessed in a participant subset demonstrated higher type 1 T helper (Th1) than type 2 T helper (Th2) responses. No concerns were identified following active surveillance for respiratory disease through a full RSV season, and age de-escalation progressed to Part B (infants 5 to 7 months of age). Most participants (88.3%) in Part B met the criteria for “RSV-naïve,” and vaccination induced robust nAb and preF-biased bAb responses. In Part B, a protocol-defined study pause was triggered by 2 cases of severe RSV-lower respiratory tract illness (LRTI) in the 15 μg vaccine level recipients, all of whom had received 2 vaccine injections; as of October 2024 (the first RSV season post immunization), RSV-LRTI classified as severe/hospitalized was seen in 2/20, 3/20, and 1/20 of mRNA-1345 15 µg, mRNA-1365 15 µg, and placebo recipients, respectively. The respiratory illnesses in these children have resolved. Conclusions: Vaccination with mRNA-1345 (RSV vaccine) or mRNA-1365 (RSV/hMPV vaccine) increased RSV nAbs in children aged 8 to 23 months, and induced de novo nAb responses in RSV-naïve infants 5 to 7 months old. Vaccination induced a preF-biased bAb response in both age groups and induced RSV-specific Th1 responses in older children. Study dosing and enrollment are paused while immunogenicity assessments and surveillance for respiratory infections are ongoing to better understand the increase in severe/hospitalized RSV LRTI observed among vaccinated, RSV-naïve, young children. Trial registration number: NCT05743881