Abstract
Current hemagglutinin (HA)-based seasonal influenza vaccines induce vaccine strain-specific neutralizing antibodies that usually fail to provide protection against mismatched circulating viruses. Inclusion in the vaccine of highly conserved internal proteins such as the nucleoprotein (NP) and the matrix protein 1 (M1) was shown previously to increase vaccine efficacy by eliciting cross-reactive T-cells. However, appropriate delivery systems are required for efficient priming of T-cell responses. In this study, we demonstrated that administration of novel self-amplifying mRNA (SAM®) vectors expressing influenza NP (SAM(NP)), M1 (SAM(M1)), and NP and M1 (SAM(M1-NP)) delivered with lipid nanoparticles (LNP) induced robust polyfunctional CD4 T helper 1 cells, while NP-containing SAM also induced cytotoxic CD8 T cells. Robust expansions of central memory (TCM) and effector memory (TEM) CD4 and CD8 T cells were also measured. An enhanced recruitment of NP-specific cytotoxic CD8 T cells was observed in the lungs of SAM(NP)-immunized mice after influenza infection that paralleled with reduced lung viral titers and pathology, and increased survival after homologous and heterosubtypic influenza challenge. Finally, we demonstrated for the first time that the co-administration of RNA (SAM(M1-NP)) and protein (monovalent inactivated influenza vaccine (MIIV)) was feasible, induced simultaneously NP-, M1- and HA-specific T cells and HA-specific neutralizing antibodies, and enhanced MIIV efficacy against a heterologous challenge. In conclusion, systemic administration of SAM vectors expressing conserved internal influenza antigens induced protective immune responses in mice, supporting the SAM® platform as another promising strategy for the development of broad-spectrum universal influenza vaccines.
Highlights
Influenza virus is a respiratory pathogen responsible for 250,000–500,000 deaths annually worldwide [1], and vaccination is the most cost-effective way to prevent and control influenza outbreaks [2]
All SAM vaccines were immunogenic in BALB/c mice, inducing NP-specific cytotoxic CD8+ T cells and CD4+ Th1 cells and matrix protein 1 (M1)-specific CD4+ but not CD8+ T cells
SAM vaccines induced antigen-specific TEM and TCM cell subsets, both of which are important for long-lasting protection, confirming previous observations obtained with RNA vaccines [51]
Summary
Influenza virus is a respiratory pathogen responsible for 250,000–500,000 deaths annually worldwide [1], and vaccination is the most cost-effective way to prevent and control influenza outbreaks [2]. Licensed inactivated influenza vaccines (IIV) include the hemagglutinin (HA) viral surface protein, inducing strain-specific antibody responses that protect against antigenically matched or closely related viruses. Due to the high mutation rate in HA, yearly update of seasonal vaccines is required to match the circulating viruses. Seasonal vaccines are not effective against newly emerging influenza viruses or pandemic outbreaks [3, 4]. For this reason, a “universal” influenza vaccine that could offer broad-range of protection against all subtypes of influenza A virus has been the focus of research efforts for the last two decades. The addition of adjuvants, such as MF59, increases the breadth of immunity elicited by seasonal and pandemic influenza vaccines [5, 6], but not sufficiently to overcome the limitation of seasonal vaccine strain changes [7]
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