M2SR, a novel live single replication influenza virus vaccine, provides effective heterosubtypic protection in mice

Abstract

Despite the annual public health burden of seasonal influenza and the continuing threat of a global pandemic posed by the emergence of highly pathogenic/pandemic strains, conventional influenza vaccines do not provide universal protection, and exhibit suboptimal efficacy rates, even when they are well matched to circulating strains. To address the need for a highly effective universal influenza vaccine, we have developed a novel M2-deficient single replication vaccine virus (M2SR) that induces strong cross-protective immunity against multiple influenza strains in mice. M2SR is able to infect cells and expresses all viral proteins except M2, but is unable to generate progeny virus. M2SR generated from influenza A/Puerto Rico/8/34 (H1N1) protected mice against lethal challenge with influenza A/Puerto Rico/8/34 (H1N1, homosubtypic) and influenza A/Aichi/2/1968 (H3N2, heterosubtypic). The vaccine induced strong systemic and mucosal antibody responses of both IgA and IgG classes. Strong virus-specific T cell responses were also induced. Following heterologous challenge, significant numbers of IFN-γ–producing CD8 T cells, with effector or effector/memory phenotypes and specific for conserved viral epitopes, were observed in the lungs of vaccinated mice. A substantial proportion of the CD8 T cells expressed Granzyme B, suggesting that they were capable of killing virus-infected cells. Thus, our data suggest that M2-deficient influenza viruses represent a promising new approach for developing a universal influenza vaccine.

M2SR, a novel live influenza vaccine, protects mice and ferrets against highly pathogenic avian influenza

“…Previous studies have also suggested that cross-reactive HA and NA antibodies between H5N1 and H1N1 influenza viruses contribute to heterologous protection [19–22]. In addition, our previous studies demonstrated that M2SR vaccine induced strong T cell responses, including CD8 T cells of an effector or effector/memory phenotype, armed with cytotoxic mediators such as granzyme B [9]. T cells with this phenotype are associated with protection against influenza in humans.…”

“…M2SR virus (an M2-deficient recombinant influenza virus) was generated using a plasmid rescue system described previously [9, 11]. The six internal genes of M2SR are derived from A/Puerto Rico/8/1934 (PR8, H1N1) [9].…”

“…The six internal genes of M2SR are derived from A/Puerto Rico/8/1934 (PR8, H1N1) [9]. M2SR H5N1 is an M2SR virus expressing the avirulent HA and NA of influenza A/Vietnam/1203/2004 (H5N1).…”

“…Additional groups were immunized with 2 doses of 1.5 ug/mouse H5 HA protein (Immune-Technology Corp., New York, NY, USA) intramuscularly or 2 doses intranasally of medium alone, as mock vaccination. Six weeks after boosting, serum and BAL were collected from three mice per group and anti-H5 HA IgG and IgA binding antibody titers and anti-H5N1 HA inhibition titers were determined by ELISA and by HAI assay, respectively, as previously described [9]. Twenty weeks after boosting, mice were challenged by lethal dose (20 MLD50) of VN1203 and body weight and survival were monitored for 16 days.…”

“…We previously described a novel M2-deficient single replication influenza vaccine virus (M2SR), which was able to provide strong cross-protective immunity against seasonal influenza A strains [9]. M2SR is able to infect cells, undergo a single round of replication and express all viral proteins except M2.…”