The high variability of the influenza virus and the limited flexibility of inactivated vaccines result in a need to develop new, more effective preventive therapeutics. The RNA platform is among the most promising ones for developing new generation vaccines against respiratory infections. The study aimed to compare the immunogenicity of two experimental therapeutics based on classic mRNA and self-amplifying RNA (saRNA) encoding the hemagglutinin (HA) of the A(H1N1)pdm09 influenza virus. BALB/c mice were immunized twice with the RNA-based therapeutics at a dose of 2 µg at a 21-day interval. Humoral immune responses were assessed using the hemagglutination inhibition (HAI) assay. After the second immunization, the geometric mean titers of antibodies against the homologous strain A/Wisconsin/588/2019 were 1 : 2281 (CI: 1 : 1319 – 1 : 3943) for the mRNA vaccine and 1 : 640 (CI: 1 : 404 – 1 : 1014) for the saRNA vaccine. Titers against the antigenically distant strain A/Victoria/4897/2022 in the mRNA group and saRNA group reached 1 : 1810 (CI: 1 : 844 – 1 : 3882) and 1 : 452 (CI: 1 : 246 – 1 : 832), respectively. These antibody titer values were considerably higher than those in the group that received the Ultrix Quadri inactivated split vaccine, which did not exceed 1 : 56 (CI: 1 : 26 – 1 : 121). Despite the higher antibody titers in the HAI assay after immunization with the classic mRNA-based vaccine compared with the saRNA-based vaccine, the differences were not statistically significant. Thus, the mRNA- and saRNA-based vaccines induce a pronounced humoral immune response, confirming that these platforms are promising for the development of new generation vaccines.