Development of influenza H7N9 virus like particle (VLP) vaccine: homologous A/Anhui/1/2013 (H7N9) protection and heterologous A/chicken/Jalisco/CPA1/2012 (H7N3) cross-protection in vaccinated mice challenged with H7N9 virus

Abstract

The recent emergence of severe human illness caused by avian-origin influenza A(H7N9) viruses in China has precipitated a global effort to rapidly develop and test vaccine candidates. To date, non-A(H7N9) H7 subtype influenza vaccine candidates have been poorly immunogenic and difficulties in production of A(H7N9) virus seed strains have been encountered. A candidate recombinant A(H7N9) vaccine consisting of full length, unmodified hemagglutinin (HA) and neuraminidase (NA) from the A/Anhui/1/2013 and the matrix 1 (M1) protein from the A/Indonesia/05/2005 (H5N1) were cloned into a baculovirus vector. Baculovirus infected Spodoptera frugiperda (Sf9) insect cells secreted virus like particles (VLP) composed of HA, NA, and M1 that resemble mature influenza virions. Genetic construction of vaccine from acquisition of an H7N9 genomic sequence to production of A(H7N9) VLP occurred in 26 days. The immunogenicity and efficacy of A/Anhui/1/2013 (H7N9) VLP vaccine administered on days 0 and 14 were evaluated in a lethal wild-type challenge Balb/c mouse model. Control groups included a non-homologous H7 vaccine (A/chicken/Jalisco/CPA1/2012 (H7N3)-VLP), and A/Indonesia/05/2005 (H5N1)-VLP, or placebo. All vaccines were administered with or without ISCOMATRIX. A(H7N9) VLP elicited hemagglutination-inhibition (HAI) antibody titers of ≥ 1:64 against the homologous virus, cross-reactive HAI against the heterologous A(H7N3), and 3- to 4-fold higher HAI responses in corresponding ISCOMATRIX subgroups. Similarly, all doses of H7N9 VLP elicited anti-neuraminidase (NA) antibody, with 3- to 4-fold higher responses measured in the corresponding ISCOMATRIX subgroups. The non-homologous H7 vaccine induced both H7N3 and H7N9 HAI but no N9 anti-NA antibodies. A lethal murine wild-type A/Anhui/1/2013 (H7N9) challenge demonstrated 100% survival of all animals receiving A(H7N9) and A(H7N3) vaccine, versus 0% survival in A(H5N1) vaccine and placebo groups. Together, the data demonstrate that recombinant H7N9 vaccine can be rapidly developed that was immunogenic and efficacious supporting testing in man as a pandemic influenza H7N9 vaccine candidate.

Keywords: H7N9; Hemagglutinin; Influenza; Pandemic; Vaccine; Virus like particle.