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

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.

Investigation of the biological indicator for vaccine efficacy against highly pathogenic avian influenza (HPAI) H5N1 virus challenge in mice and ferrets.

To investigate the biological indicator for vaccine efficacy against HPAI H5N1 virus challenge of varying clades, two inactivated whole-virus H5N1 vaccines containing the hemagglutinin (HA) and neuraminidase (NA) genes of either clade 2.2 A/EM/Korea/W149/06 (RgKoreaW149/06 x PR8) or clade 2.5 A/Ck/Korea/ES/03 (RgKoreaES223N/03XPR8) virus in the background of A/PR/8/34 (H1N1) were generated by reverse genetics. Administration of the vaccines (2-dose 1.77, 3.5, 7.5 or 15microg of HA) elicited high HI titers in a dose-dependent manner. Mice immunized with RgKoreaW149/06 x PR8 were completely protected from challenge against wild-type A/EM/Korea/W149/06 without clinical signs of infection. RgKoreaES223N/03XPR8 could not protect mice at 1.77microg while all immunized ferrets were completely protected. Two-dose (7.5microg) vaccinated mice (HI titer > or =320) and triple dose (7.5 microg) vaccinated ferrets with RgKoreaES223N/03xPR8 (HI titer > or =640) protected vaccine recipients from mortality, inhibited nasal virus shedding and limited influenza virus tropism. Thus, these vaccines provided cross-protectivity in both models. More importantly, these results collectively suggested a positive correlation between vaccine-induced HI titers and inhibition of virus shedding including block of viral proliferation in major organs against a heterologous HPAI H5N1 virus. Although developing technologies or methods that will enable the reduction of administration dose/frequency remains to be resolved, our study demonstrated a considerable biological marker (> or =640 HI titer) for full protection of the vaccinated hosts that could provide a preliminary basis for the assessment of complete immunization.