Evaluation of the efficacy of a pre-pandemic H5N1 vaccine (MG1109) in mouse and ferret models

Abstract

The threat of a highly pathogenic avian influenza (HPAI) H5N1 virus causing the next pandemic remains a major concern. In this study, we evaluated the immunogenicity and efficacy of an inactivated whole-virus H5N1 pre-pandemic vaccine (MG1109) formulated by Green Cross Co., Ltd containing the hemagglutinin (HA) and neuraminidase (NA) genes of the clade 1 A/Vietnam/1194/04 virus in the backbone of A/Puerto Rico/8/34 (RgVietNam/04xPR8/34). Administration of the MG1109 vaccine (2-doses) in mice and ferrets elicited high HI and SN titers in a dose-dependent manner against the homologous (RgVietNam/04xPR8/34) and various heterologous H5N1 strains, (RgKor/W149/06xPR8/34, RgCambodia/04xPR8/34, RgGuangxi/05xPR8/34), including a heterosubtypic H5N2 (A/Aquatic bird/orea/W81/05) virus. However, efficient cross-reactivity was not observed against heterosubtypic H9N2 (A/Ck/Korea/H0802/08) and H1N1 (PR/8/34) viruses. Mice immunized with 1.9 μg HA/dose of MG1109 were completely protected from lethal challenge with heterologous wild-type HPAI H5N1 A/EM/Korea/W149/06 (clade 2.2) and mouse-adapted H5N2 viruses. Furthermore, ferrets administered at least 3.8 μg HA/dose efficiently suppressed virus growth in the upper respiratory tract and lungs. Vaccinated mice and ferrets also demonstrated attenuation of clinical disease signs and limited virus spread to other organs. Thus, this vaccine provided immunogenic responses in mouse and ferret models even against challenge with heterologous HPAI H5N1 and H5N2 viruses. Since the specific strain of HPAI H5N1 virus that would potentially cause the next outbreak is unknown, pre-pandemic vaccine preparation that could provide cross-protection against various H5 strains could be a useful approach in the selection of promising candidate vaccines in the future.

Extrapolating theoretical efficacy of inactivated influenza A/H5N1 virus vaccine from human immunogenicity studies

“…Dose-sparing strategies have been previously studied for seasonal influenza [31–33] and, more recently, for pandemic scenarios [11,12, 35–45]. Previous work suggests that, in a pandemic, an antigen-sparing strategy, where only a single dose of vaccine is given instead of two, is optimal to minimize illness attack rates for primary response levels in the vicinity of 0.50 [13].…”

“…However, the efficacy of H5N1 vaccines in humans remains unproven [9]. Animal challenge studies suggest these vaccines are protective [10–12], but extrapolating these results to efficacy in humans remains poorly understood. Generally two doses of vaccine are recommended to achieve full efficacy for an individual.…”

The significance of avian influenza virus mouse-adaptation and its application in characterizing the efficacy of new vaccines and therapeutic agents

“…Thus, universal vaccines designed to be more broadly reactive to various influenza strains and vaccines immunogenic to the specific emerging viruses are being developed [ 101 ]. Although the major purpose of mouse-adaptation studies with avian influenza were to investigate the molecular determinants altering virulence of avian virus in mammalian hosts, abundant studies have demonstrated the protective efficacy of various intervention approaches using the lethal mouse-adapted avian influenza viruses in mouse model [ 102 103 104 105 106 107 ]. Since a mouse-adapted H5N2 virus was originated from LPAI H5N2 [ 28 ] and exhibited high lethality in mice, it can therefore be used in BL-2 facility which makes it accessible and usable by more researchers interested in evaluating the efficacy of newly developing vaccines.…”

Post-exposure treatment with whole inactivated H5N1 avian influenza virus protects against lethal homologous virus infection in mice

“…Studies have shown that inactivated whole H5N1 virus given as a pre-exposure vaccine can protect mice from homologous and heterologous challenge with HPAI H5N1 viruses 10 11 12 , and can protect against challenge in other animal models including ferrets 13 14 15 and non-human primates 16 . In contrast, post-exposure vaccines against HPAI H5 viruses have not been investigated, even though post-exposure vaccines against other viruses such as rabies, hepatitis B, and smallpox have worked successfully 17 18 19 .…”