This study evaluates the safety and immunogenicity of the mRNA-1273 vaccine in older adults. The vaccine, which encodes the stabilized prefusion SARS-CoV-2 spike protein (S-2P), was tested in a phase 1, dose-escalation, open-label trial. The trial was expanded to include 40 older adults (56 to 70 years or ≥71 years) who received two doses of either 25 μg or 100 μg of the vaccine administered 28 days apart. Solicited adverse events were predominantly mild or moderate, including fatigue, chills, headache, myalgia, and injection site pain. Binding-antibody responses increased rapidly after the first immunization, with higher titers observed in the 100-μg dose group compared to the 25-μg dose group. Neutralizing activity was detected in all participants after the second immunization. The vaccine elicited a strong CD4 cytokine response involving type 1 helper T cells. The 100-μg dose induced higher binding- and neutralizing-antibody titers than the 25-μg dose, supporting its use in a phase 3 trial. The study concludes that the mRNA-1273 vaccine is safe and immunogenic in older adults, with the 100-μg dose showing promise for future trials.This study evaluates the safety and immunogenicity of the mRNA-1273 vaccine in older adults. The vaccine, which encodes the stabilized prefusion SARS-CoV-2 spike protein (S-2P), was tested in a phase 1, dose-escalation, open-label trial. The trial was expanded to include 40 older adults (56 to 70 years or ≥71 years) who received two doses of either 25 μg or 100 μg of the vaccine administered 28 days apart. Solicited adverse events were predominantly mild or moderate, including fatigue, chills, headache, myalgia, and injection site pain. Binding-antibody responses increased rapidly after the first immunization, with higher titers observed in the 100-μg dose group compared to the 25-μg dose group. Neutralizing activity was detected in all participants after the second immunization. The vaccine elicited a strong CD4 cytokine response involving type 1 helper T cells. The 100-μg dose induced higher binding- and neutralizing-antibody titers than the 25-μg dose, supporting its use in a phase 3 trial. The study concludes that the mRNA-1273 vaccine is safe and immunogenic in older adults, with the 100-μg dose showing promise for future trials.