A phase 1–2a trial of the Ad26.COV2.S Covid-19 vaccine evaluated safety, reactogenicity, and immunogenicity in healthy adults aged 18–55 and 65 years or older. The vaccine, a replication-incompetent adenovirus serotype 26 vector encoding a stabilized SARS-CoV-2 spike protein, was tested at two doses (5×10¹⁰ and 1×10¹¹ viral particles per mL) and a placebo. The primary endpoints were safety and reactogenicity, with secondary endpoints including humoral and cellular immunity. After the first dose, common adverse events included fatigue, headache, myalgia, and injection-site pain, with fever being the most frequent systemic event. Reactogenicity was lower after the second dose. Neutralizing antibody titers against wild-type virus reached 90% or more in all participants by day 29, increasing further by day 57. A second dose increased titers by 2.6–2.9-fold. Spike-binding and neutralizing antibody responses were similar. CD4+ T-cell responses were predominantly Th1, with 76–83% of participants in the younger group and 60–67% in the older group showing responses. CD8+ T-cell responses were robust but lower in the older group. The vaccine showed an acceptable safety profile, with most adverse events being mild and resolving within 24 hours. No serious adverse events were attributed to the vaccine. Immunogenicity was strong, with high seroconversion rates and durable antibody responses. The vaccine elicited strong humoral and cellular immune responses, with neutralizing antibody titers reaching 100% in some groups. The results support further development of Ad26.COV2.S, with ongoing phase 3 trials evaluating single-dose and two-dose regimens. The vaccine is supported by preclinical data showing protection against SARS-CoV-2 in non-human primates. The study highlights the vaccine's potential as a single-dose option, with a strong immune response and favorable safety profile.A phase 1–2a trial of the Ad26.COV2.S Covid-19 vaccine evaluated safety, reactogenicity, and immunogenicity in healthy adults aged 18–55 and 65 years or older. The vaccine, a replication-incompetent adenovirus serotype 26 vector encoding a stabilized SARS-CoV-2 spike protein, was tested at two doses (5×10¹⁰ and 1×10¹¹ viral particles per mL) and a placebo. The primary endpoints were safety and reactogenicity, with secondary endpoints including humoral and cellular immunity. After the first dose, common adverse events included fatigue, headache, myalgia, and injection-site pain, with fever being the most frequent systemic event. Reactogenicity was lower after the second dose. Neutralizing antibody titers against wild-type virus reached 90% or more in all participants by day 29, increasing further by day 57. A second dose increased titers by 2.6–2.9-fold. Spike-binding and neutralizing antibody responses were similar. CD4+ T-cell responses were predominantly Th1, with 76–83% of participants in the younger group and 60–67% in the older group showing responses. CD8+ T-cell responses were robust but lower in the older group. The vaccine showed an acceptable safety profile, with most adverse events being mild and resolving within 24 hours. No serious adverse events were attributed to the vaccine. Immunogenicity was strong, with high seroconversion rates and durable antibody responses. The vaccine elicited strong humoral and cellular immune responses, with neutralizing antibody titers reaching 100% in some groups. The results support further development of Ad26.COV2.S, with ongoing phase 3 trials evaluating single-dose and two-dose regimens. The vaccine is supported by preclinical data showing protection against SARS-CoV-2 in non-human primates. The study highlights the vaccine's potential as a single-dose option, with a strong immune response and favorable safety profile.