Immunogenicity and protective efficacy of a live attenuated H5N1 vaccine in nonhuman primates.
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.
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, PR China.
Shufang
S
Fan
Yuwei
Y
Gao
Kyoko
K
Shinya
Chris Kafai
CK
Li
Yanbing
Y
Li
Jianzhong
J
Shi
Yongping
Y
Jiang
Yongbing
Y
Suo
Tiegang
T
Tong
Gongxun
G
Zhong
Jiasheng
J
Song
Ying
Y
Zhang
Guobin
G
Tian
Yuntao
Y
Guan
Xiao-Ning
XN
Xu
Zhigao
Z
Bu
Yoshihiro
Y
Kawaoka
Hualan
H
Chen
D000281:Administration, Intranasal; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood*; D001831:Body Temperature; D005260:Female; D053124:Influenza A Virus, H5N1 Subtype / Q000276:immunology* / Q000502:physiology; D007252:Influenza Vaccines / Q000276:immunology*; D007275:Injections, Intravenous; D008253:Macaca mulatta; D051379:Mice; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections / Q000517:prevention & control* / Q000821:virology; D016865:Reassortant Viruses / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014611:Vaccination; D014613:Vaccines, Attenuated / Q000276:immunology; D019562:Viral Load; D014779:Virus Replication; D017201:Virus Shedding
D000914:Antibodies, Viral; D007252:Influenza Vaccines; D014613:Vaccines, Attenuated