Hemagglutinin (HA)-specific antibodies directly bind the virus and prevent its entry into host cells, providing narrow immunity from reinfection by closely related strains. CD8 T cell responses to IAV generated against highly conserved viral proteins/epitopes contribute to clearance of virus during primary IAV infection and also confer broad heterosubtypic protection in animal models. Recent evidence links the cross-reactive CD8 T cell response in man to reduced viral replication and protection from severe illness in pandemic H1N1 infections in European populations, and H7N9 infections in China. Because pre-existing T-cell immunity, independent of baseline antibodies, protects against symptoms and viral shedding associated with influenza, influenza vaccines that stimulate broadly reactive CD8 T cell responses may have the capacity to protect against any pandemic influenza A virus. Human infections with H5N1 and H7N9 avian IAV and the 2009 H1N1 pandemic have spurred an interest in the development of vaccines against IAV with pandemic potential. Major challenges to this effort include our inability to predict which virus will emerge and rapid production and deployment of vaccine if the virus spreads rapidly and vaccine yield is not optimal. In addition, the number of doses of vaccine required depends on whether the population is immunologically naive. Under a collaborative research and development agreement with MedImmune, we have previously developed pandemic live attenuated influenza vaccines (pLAIV) against clade 1 H5N1 viruses on an Ann Arbor cold-adapted (ca) backbone and demonstrated that they induce long-term immune memory. In 2015, an increased number of human infections caused by a new clade (2.2.1.1) of goose/Guangdong (gs/GD) lineage H5N1 viruses were reported in Egypt that would require updating of the H5N1 pLAIV. We explored two strategies to generate suitable pLAIVs. The first was to modify the hemagglutinin gene of a highly pathogenic wild-type (wt) clade 2.2.1.1 virus A/Egypt/N03434/2009 (Egy/09) (H5N1) and include its unmodified neuraminidase (NA) gene; this virus was designated Egy/09 ca. The second approach was to select a low pathogenicity avian influenza H5 virus that elicited antibodies that cross-reacted with a broad range of H5 viruses including the Egypt H5N1 viruses and contained a novel NA gene in order to avoid potential restriction of replication of the vaccine virus by pre-existing anti-NA antibody in the human population. We selected the low pathogenicity A/duck/Hokkaido/69/2000 (H5N3) virus (dk/Hok/00) for this purpose. Both candidate vaccines were attenuated and immunogenic in ferrets. The vaccines induced antibodies that neutralized homologous and heterologous H5 viruses with different degrees of cross-reactivity; Egy/09 ca vaccine antisera were more specific to the gs/GD lineage viruses but did not neutralize recent North American isolates (clade 2.3.4.4), whereas antisera from dk/Hok/69 ca vaccinated ferrets cross-reacted with clade 2.3.4.4 and 2.2.1 viruses but not clade 1 or 2.1 viruses. When vaccinated ferrets were challenged with homologous and heterologous H5 viruses, replication of challenge viruses were reduced in the nasal turbinates and lungs. Thus, we developed two H5 pLAIV candidates that are suitable for clinical development to protect humans from infection with different clades of H5 viruses. An outbreak of avian origin H10N7 influenza was reported among seals in Northern Europe and two fatal human infections with an avian H10N8 virus in China demonstrated that H10 viruses can spread between mammals and cause severe disease in humans. To gain insight into the potential for H10 viruses to cross the species barrier and identify a candidate vaccine strain, we evaluated the in vitro and in vivo properties and antibody response in ferrets to 20 diverse H10 viruses. H10 virus infection of ferrets caused variable weight loss and all 20 viruses replicated throughout the respiratory tract; however, replication in the lungs was highly variable. In glycan-binding assays, the H10 viruses preferentially bound avian-like 2,3-linked sialic acids. Importantly, several isolates also displayed strong binding to long-chain human-like 2,6-linked sialic acids, and exhibited comparable or elevated neuraminidase activity relative to human H1N1, H2N2, and H3N2 viruses. In hemagglutination inhibition assays, 12 antisera cross-reacted with 14 of 20 H10 viruses, and 7 viruses induced neutralizing activity against 15 of the 20 viruses. By combining data on weight loss, viral replication, and the cross-reactive antibody response, we identified A/mallard/Portugal/79906/2009 (H10N7) as a suitable virus for vaccine development. Collectively, our findings suggest that H10 viruses may continue to sporadically infect humans and other mammals, underscoring the importance of developing an H10 vaccine for pandemic preparedness. Monoclonal antibodies (MAbs) have received attention as a treatment option for a variety of infections, including influenza. When a novel influenza A virus emerges, the subtype of the infecting virus may not be known early in clinical presentation. Thus, a MAb that is active against a broad range of influenza subtypes would be invaluable for treatment and prophylaxis. Additionally, treatment strategies capable of interrupting the spread of influenza through sustained human-to-human transmission would limit the public health burden during a pandemic response. MEDI8852 is a novel MAb developed by MedImmune, which neutralizes both group I and group II influenza A viruses (IAV) in vitro. Under a cooperative research and development agreement with MedImmune, we evaluated the efficacy of MEDI8852 as a prophylactic and therapeutic agent against representative group I and II avian influenza A viruses with pandemic potential, in mouse and ferret models. We also assessed the ability of MEDI8852 to block transmission of influenza H1N1pdm09 in a ferret model. We showed that MEDI8852 was effective for prophylaxis and treatment of H7N9 and H5N1 infection in mice, with a clear dose-dependent response and treatment with MEDI8852 24, 48 or 72 h post-infection (hpi) was superior to oseltamivir for H5N1. MEDI8852 alone was effective treatment for lethal H5N1 infection in ferrets compared to oseltamivir and R347 and MEDI8852 plus oseltamivir was better than oseltamivir alone. MEDI8852 or oseltamivir alone early in infection were equally effective for H7N9 infection in ferrets while the combination yielded similar protection when treatment was delayed. MEDI8852 was able to protect nave ferrets from airborne transmission of H1N1pdm09.
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