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.
Fan
Shufang
S
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.
Gao
Yuwei
Y
Shinya
Kyoko
K
Li
Chris Kafai
CK
Li
Yanbing
Y
Shi
Jianzhong
J
Jiang
Yongping
Y
Suo
Yongbing
Y
Tong
Tiegang
T
Zhong
Gongxun
G
Song
Jiasheng
J
Zhang
Ying
Y
Tian
Guobin
G
Guan
Yuntao
Y
Xu
Xiao-Ning
XN
Bu
Zhigao
Z
Kawaoka
Yoshihiro
Y
Chen
Hualan
H
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