Development of a broadly reactive vaccine for highly pathogenic H5N1 influenza

Giles, Brendan M. Development of a broadly reactive vaccine for highly pathogenic H5N1 influenza. Doctoral Dissertation, University of Pittsburgh.

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Abstract

Emerging and re-emerging infectious diseases are increasing throughout the world and highly pathogenic influenza is among those that pose a significant threat to mankind. Pandemic outbreaks of influenza are caused by the emergence of a highly pathogenic and transmissible virus to which the human population is immunologically naïve. Ongoing outbreaks of highly pathogenic avian influenza of the H5N1 subtype are of particular concern because of the high mortality rate (>60%) and novel subtype. Vaccines are considered the most effective way to prevent the morbidity and mortality associated with pandemic influenza and therefore developing an H5N1 vaccine is a public health priority. One of the hurdles facing H5N1 vaccine development is the antigenic diversity of the subtype as evidenced by the identification of ten phylogenetic clades. To overcome the challenge of antigenic diversity, a centralized hemagglutinin was developed and termed computationally optimized broadly reactive antigen (COBRA). The COBRA HA sequence was based upon HA amino acid sequences from clade 2 H5N1 human infections and the expressed protein retained the ability to bind the receptor, as well as mediate particle fusion. COBRA virus-like particle (VLP) vaccines elicited broadly reactive receptor blocking antibodies in multiple animal species: mice, ferrets and non-human primates. The reactivity profile was broader than that elicited by primary isolate-based vaccines given in either monovalent or polyvalent formulations. Although all vaccinated animals were protected from severe disease and death from experimental infection with highly pathogenic H5N1 virus, animals receiving the COBRA vaccine had reduced peak virus replication and cleared the infection more rapidly. COBRA vaccines were shown to be superior to primary isolate-based vaccines with both a broader antibody profile and more efficient protective efficacy. The development of COBRA resulted in a novel antigen generation methodology that is applicable to both pandemic and seasonal influenza.

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