Development of multivalent mRNA vaccine candidates for seasonal or pandemic influenza

Sudha Chivukula,Sophia T Mundle,Anusha Dias,Joshua Dinapoli,Asad Khanmohammed,Ashish Sarode,Peter Piepenhagen,Natalie G Anosova,Shrirang Karve,Dustin L Cooper ,Gregory Ulinski,Charles P Lai ,Heesik Yoon,Frank Derosa,Rachel Groppo,Young-Hoon Kim ,Rebecca Goldman,Kirill Kalnin ,Tong-Ming Fu,Donghui Zhang,Yanhua Yan,Ron Swearingen,Hardip Gopani,Lü Li ,Jinrong Zhang,Victoria Landolfi,Adrien Beauvais,Timothy Tibbitts,Timothy Plitnik,Danilo R Casimiro

doi:10.1038/s41541-021-00420-6

Abstract

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.

Highlights

MRNA vaccines have reached a new milestone with clinical efficacy demonstrated for COVID-19 vaccines[1,2] and dozens more vaccine candidates have entered the clinical stage of development[3,4,5,6,7,8]
All mRNA preparations had > 95% of 5′ Cap[1] and showed a single homogenous peak on capillary electrophoresis (Supplementary Fig. 1a). mRNA-lipid nanoparticles (LNPs) formulations were prepared by mixing the various lipid components with mRNA under controlled conditions and at fixed ratios
Several advancements in the design of mRNA have led to improvements in its translatability, stability, and immunomodulatory activities[32,33,34]

Summary

Introduction

MRNA vaccines have reached a new milestone with clinical efficacy demonstrated for COVID-19 vaccines[1,2] and dozens more vaccine candidates have entered the clinical stage of development[3,4,5,6,7,8]. In vitro transcribed mRNA packaged in LNPs can produce complex antigens in vivo, via engagement of endogenous ribosomal machinery, with proper post-translational modifications including assembly, glycosylation and trafficking resembling the native antigens. This vaccination modality conveys the advantages of live attenuated vaccines by inducing adaptive immune responses of both humoral and T cell-mediated immunity[9]. The unprecedented rapid development and approval of COVID-19 mRNA vaccines under Emergency Use. Authorization, and the growing safety database in millions of human populations, support the exploration of the mRNA platform to address both global pandemic and seasonal viral pathogens. Current seasonal influenza vaccines include two influenza A subtypes (H1N1 and H3N2) and two influenza B lineages (Victoria and Yamagata) as selected bi-annually by the

Methods

Results

Conclusion