Immunogenicity and Protective Efficacy of a Live Attenuated H5N1 Vaccine in Nonhuman Primates

PLoS Pathogens

Shufang Fan¹  Yongping Jiang¹  Yuntao Guan¹  Ying Zhang¹  Yongbing Suo¹  Jianzhong Shi¹  Jiasheng Song¹  Gongxun Zhong¹  Yanbing Li¹  Tiegang Tong¹  Guobin Tian¹  Zhigao Bu¹  Yuwei Gao¹  Hualan Chen²  Chris Kafai Li³  Xiao-Ning Xu³  Yoshihiro Kawaoka⁴  Kyoko Shinya⁴ 

[1] Animal Influenza Laboratory of the Ministry of Agriculture and National Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, People's Republic of China;Division of Virology, Department of Microbiology and Immunology, and International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan;MRC Human Immunology Unit, The Weatherall Institute of Molecular Medicine, University of Oxford, United Kingdom;The International Center for Medical Research and Treatment, Kobe University, Kobe, Japan

关键词: H5N1;    Antibodies;    Enzyme-linked immunoassays;    Viral vaccines;    Macaque;    T cells;    Vaccination;    immunization;    Viral replication;   

DOI  :  10.1371/journal.ppat.1000409

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

The continued spread of highly pathogenic H5N1 influenza viruses among poultry and wild birds, together with the emergence of drug-resistant variants and the possibility of human-to-human transmission, has spurred attempts to develop an effective vaccine. Inactivated subvirion or whole-virion H5N1 vaccines have shown promising immunogenicity in clinical trials, but their ability to elicit protective immunity in unprimed human populations remains unknown. A cold-adapted, live attenuated vaccine with the hemagglutinin (HA) and neuraminidase (NA) genes of an H5N1 virus A/VN/1203/2004 (clade 1) was protective against the pulmonary replication of homologous and heterologous wild-type H5N1 viruses in mice and ferrets. In this study, we used reverse genetics to produce a cold-adapted, live attenuated H5N1 vaccine (AH/AAca) that contains HA and NA genes from a recent H5N1 isolate, A/Anhui/2/05 virus (AH/05) (clade 2.3), and the backbone of the cold-adapted influenza H2N2 A/AnnArbor/6/60 virus (AAca). AH/AAca was attenuated in chickens, mice, and monkeys, and it induced robust neutralizing antibody responses as well as HA-specific CD4+ T cell immune responses in rhesus macaques immunized twice intranasally. Importantly, the vaccinated macaques were fully protected from challenge with either the homologous AH/05 virus or a heterologous H5N1 virus, A/bar-headed goose/Qinghai/3/05 (BHG/05; clade 2.2). These results demonstrate for the first time that a cold-adapted H5N1 vaccine can elicit protective immunity against highly pathogenic H5N1 virus infection in a nonhuman primate model and provide a compelling argument for further testing of double immunization with live attenuated H5N1 vaccines in human trials.

【 授权许可】

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