Development of adenovirus vector based H5N1 influenza vaccine

Neetu Singh, Purdue University


The emergence of a highly pathogenic influenza A strain H5N1 in the past several years, beginning in Southeast Asia and then spreading into Africa, the Middle East, and Europe has evoked the fear of a global influenza pandemic. Outbreaks have been reported in humans, poultry and migratory birds in several Asian, European and African countries. Vaccination remains an important intervention strategy to combat the threat of a H5N1 influenza pandemic. With the anticipation that egg-dependent influenza vaccine manufacturing strategies alone may not fulfill the huge global demand for a pandemic vaccine, a host of egg-independent vaccine strategies are being explored for pandemic influenza vaccines including our strategy of adenoviral vectored influenza vaccine. Our findings demonstrated that the breadth of the immune response and protective efficacy of a human adenovirus (Ad)- vector- based H5N1 influenza vaccine can be enhanced by inclusion of hemagglutinin (HA) antigen from antigenically distinct clades of H5N1 influenza viruses. In addition we also demonstrated that the inclusion of nucleoprotein (NP) antigen along with the HA in the Ad vectored vaccine further enhanced the vaccine's immunogenicity and protective efficacy. Due to the high prevalence of adenovirus infections in humans, it is believed that the preexisting adenoviral neutralizing antibodies and/or cytotoxic CD8 T cells may reduce the antigen expression by human adenoviral vectors and thereby negatively impact the resultant immune response. In order to evaluate whether bovine Ad subtype 3 (BAd3) can effectively elude high levels of pre-existing vector immunity, naïve and HAd serotype 5 (HAd)-primed mice were immunized with BAd-H5HA [BAd3 vector expressing the hemagglutinin (HA) gene from H5N1 influenza virus] and the immunogenicity and protective efficacy of the vaccine in the presence and absence of vector immunity were evaluated. Our findings demonstrated that bovine Ad-vector expressing the HA antigen from a H5N1 influenza virus (BAd-H5HA) was immunogenic and protective and also effectively circumvented exceptionally high levels of vector immunity. In addition, we demonstrated that the use of HAd and BAd vectored H5N1 vaccines in a heterologous prime-boost regimen resulted in enhanced humoral and similar cell mediated immune responses compared to the responses obtained with either vectored vaccine alone. In conclusion, the present research work demonstrated the ability of human Ad vectored H5N1 influenza vaccine formulations to provide protection across antigenically distinct clades of H5N1 viruses and that bovine Ad vectored vaccine can serve as an alternate or supplement to HAd vectored vaccines.




Mittal, Purdue University.

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