Immunogenicity and protective efficacy of a live attenuated H5N1 vaccine in nonhuman primates

• Published in: PLoS pathogens Vol. 5; no. 5; p. e1000409
• Main Authors: Fan, Shufang, Gao, Yuwei, Shinya, Kyoko, Li, Chris Kafai, Li, Yanbing, Shi, Jianzhong, Jiang, Yongping, Suo, Yongbing, Tong, Tiegang, Zhong, Gongxun, Song, Jiasheng, Zhang, Ying, Tian, Guobin, Guan, Yuntao, Xu, Xiao-Ning, Bu, Zhigao, Kawaoka, Yoshihiro, Chen, Hualan
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.05.2009; Public Library of Science (PLoS)
• Subjects: Administration, Intranasal; Animals; Antibodies, Viral - blood; Avian influenza; Birds; Body Temperature; Causes of; Drug resistance; Fatalities; Female; Immune response; Infections; Influenza A Virus, H5N1 Subtype - immunology; Influenza A Virus, H5N1 Subtype - physiology; Influenza vaccines; Influenza Vaccines - immunology; Influenza virus; Injections, Intravenous; Macaca mulatta; Mice; Mice, Inbred BALB C; Monkeys & apes; Mustela; Orthomyxoviridae Infections - prevention & control; Orthomyxoviridae Infections - virology; Pandemics; Physiological aspects; Prevention; Primates; Production capacity; Properties; Reassortant Viruses - immunology; Respiratory system; Statistical analysis; T-Lymphocytes - immunology; Vaccination; Vaccines; Vaccines, Attenuated - immunology; Viral Load; Virology/Vaccines; Virus Replication; Virus Shedding; Viruses; United States; United Kingdom; Japan
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1000409

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.