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

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Abstract
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. H5N1 influenza viruses have caused human infections with more than 60% fatality in 14 countries and may yet be the source of the next pandemic. Therefore, the development of effective vaccines against these viruses is the highest priority for H5N1 pandemic preparedness. A high dosage or adjuvants improve the immunogenicity of H5N1 inactivated vaccines; however, limited production capacity for conventional inactivated influenza virus vaccines could severely hinder the ability to control the spread of H5N1 influenza through vaccination. Here, we generated and tested the efficacy of a cold-adapted, live attenuated H5N1 vaccine in mice and nonhuman primates. We found that the vaccine provided complete protection in these animals against homologous and heterologous H5N1 virus challenge. Since live vaccines require less processing than inactivated vaccines and do not require adjuvants, our study represents a major advance in vaccine development for H5N1 pandemic influenza.