Development of multivalent mRNA vaccine candidates for seasonal or pandemic influenza

作者：Sudha V. Chivukula, Timothy Plitnik, Timothy J. Tibbitts, Shrirang Karve, Anusha Dias, Donghui Zhang, Rebecca Goldman, Hardip Gopani, Asad Khanmohammed, Ashish Sarode, Dustin L. Cooper, Heesik Yoon, Younghoon Kim, Yanhua Yan, Sophia T. Mundle, Rachel Groppo, Adrien Beauvais, Jinrong Zhang, Natalie G. Anosova, Charles Pin‐Kuang Lai, Lu Li, Gregory Ulinski, Peter A. Piepenhagen, Joshua M. DiNapoli, Kirill V. Kalnin, Victoria A. Landolfi, Ron Swearingen, Tong‐Ming Fu, Frank DeRosa, Danilo R. Casimiro · 发表于：npj Vaccines · 年份：2021 · DOI：10.1038/s41541-021-00420-6 · 被引用次数：121 · 研究领域：SARS-CoV-2 and COVID-19 Research、Influenza Virus Research Studies、Respiratory viral infections research

Recent approval of mRNA vaccines for emergency use against COVID-19 is likely to promote rapid development of mRNA-based vaccines targeting a wide range of infectious diseases. Compared to conventional approaches, this vaccine modality promises comparable potency while substantially accelerating the pace of development and deployment of vaccine doses. Already demonstrated successfully for single antigen vaccines such as for COVID-19, this technology could be optimized for complex multi-antigen vaccines. Herein, utilizing multiple influenza antigens, we demonstrated the suitability of the mRNA therapeutic (MRT) platform for such applications. Seasonal influenza vaccines have three or four hemagglutinin (HA) antigens of different viral subtypes. In addition, influenza neuraminidase (NA), a tetrameric membrane protein, is identified as an antigen that has been linked to protective immunity against severe viral disease. We detail the efforts in optimizing formulations of influenza candidates that use unmodified mRNA encoding full-length HA or full-length NA encapsulated in lipid nanoparticles (LNPs). HA and NA mRNA-LNP formulations, either as monovalent or as multivalent vaccines, induced strong functional antibody and cellular responses in non-human primates and such antigen-specific antibody responses were associated with protective efficacy against viral challenge in mice.