Pre-pandemic vaccines against highly pathogenic avian influenza viruses for pandemic preparedness.

摘要

Reports of human infection with both low and highly pathogenic avian influenza A viruses of H5, H7, and H9 subtypes with varying case fatalities highlight the public health threat posed by these viruses. Although human-to-human transmission has been limited and infrequent, it is widely believed that these avian influenza viruses could acquire pandemic potential either by genetic reassortment with a human influenza virus or by mutations in the genome. Vaccines currently stockpiled for pandemic preparedness against H5N1 viruses are strain-specific and, hence, would offer little or no protection against novel viruses emerging from avian influenza virus reservoirs. Newer vaccine approaches with the potential to induce both humoral and cellular immune responses and to confer protection against a broad range of influenza viruses emerging from animal reservoirs are needed. We evaluated the feasibility of an adenovirus based multivalent vaccine approach for pandemic preparedness against H5, H7 and H9 avian influenza viruses in a mouse model. Replication-incompetent adenovirus (AdV) vectors expressing hemagglutinin (HA) from different subtypes induced high levels of humoral and cellular immune responses and conferred protection against virus replication following challenge with heterologous viruses from H5, H7 and H9 avian influenza virus subtypes. Inclusion of NP in the multivalent HA vaccine formulation broadened the spectrum of cross-protection against heterosubtypic virus challenge. Our findings demonstrated the feasibility of a multivalent vaccine approach for pandemic preparedness against multiple avian influenza virus subtypes. Such a multicomponent vaccine could be stockpiled to provide a first line of defense following the emergence of a pandemic threat before a strain-matched vaccine is available. In a pandemic scenario, vaccines conferring early protection are needed to contain a rapidly spreading influenza virus. Although currently licensed H5N1 influenza vaccines have been shown to be effective in inducing protection in animal models when co-administered with suitable adjuvants, the time necessary to induce protective immunity may be a big limitation especially in a pandemic scenario. Murine ss-defensin 2 (Mbd2) has been shown to function as a molecular adjuvant by recruiting and activating immature dendritic cells to the site of the immunization. We evaluated the potential of Mbd2 to enhance the levels of vaccine-induced immune responses and to confer rapid protection against H5N1 virus challenge in a mouse model. A single administrion of mice with both HAd-HA-NP (AdV vector expressing HA and NP of a H5N1 influenza virus) and HAd-Mbd2 (AdV expressing Mbd2) resulted in significantly higher levels of both humoral and cell-mediated immune responses compared to the groups vaccinated only with HAd-HA-NP. These responses were evident even at Day 7 post-immunization. Furthermore, the HAd-HA-NP+HAd-Mbd2-immunized group receiving the lowest vector dose (2 x 107 + 1 x 107) was completely protected against an rgH5N1 virus challenge on Day 7 post-vaccination. Overall, our results highlight the potential utility of Mbd2 as a molecular adjuvant in inducing rapid and robust immune responses to a HAd-based vaccine.