Abstract
The development of universal influenza vaccines has been a priority for more than 20 years. We conducted a preclinical study in ferrets of two sets of live attenuated influenza vaccines (LAIVs) expressing chimeric hemagglutinin (cHA). These vaccines contained the HA stalk domain from H1N1pdm09 virus but had antigenically unrelated globular head domains from avian influenza viruses H5N1, H8N4 and H9N2. The viral nucleoproteins (NPs) in the two sets of universal LAIV candidates were from different sources: one LAIV set contained NP from A/Leningrad/17 master donor virus (MDV), while in the other set this gene was from wild-type (WT) H1N1pdm09 virus, in order to better match the CD8 T-cell epitopes of currently circulating influenza A viruses. To avoid any difference in protective effect of the various anti-neuraminidase (NA) antibodies, all LAIVs were engineered to contain the NA gene of Len/17 MDV. Naïve ferrets were sequentially immunized with three doses of (i) classical LAIVs containing non-chimeric HA and NP from MDV (LAIVs (NP-MDV)); (ii) cHA-based LAIVs containing NP from MDV (cHA LAIVs (NP-MDV)); and (iii) cHA-based LAIVs containing NP from H1N1pdm09 virus (cHA LAIVs (NP-WT)). All vaccination regimens were safe, producing no significant increase in body temperature or weight loss, in comparison with the placebo group. The two groups of cHA-based vaccines induced a broadly reactive HA stalk-directed antibody, while classical LAIVs did not. A high-dose challenge with H1N1pdm09 virus induced significant pathology in the control, non-immunized ferrets, including high virus titers in respiratory tissues, clinical signs of disease and histopathological changes in nasal turbinates and lung tissues. All three vaccination regimens protected animals from clinical manifestations of disease: immunized ferrets did not lose weight or show clinical symptoms, and their fever was significantly lower than in the control group. Further analysis of virological and pathological data revealed the following hierarchy in the cross-protective efficacy of the vaccines: cHA LAIVs (NP-WT) > cHA LAIVs (NP-MDV) > LAIVs (NP-MDV). This ferret study showed that prototype universal cHA-based LAIVs are highly promising candidates for further clinical development.
Highlights
Influenza viruses are highly contagious respiratory pathogens that pose a constant threat throughout the world
The phenotypic properties of the recombinant live attenuated influenza vaccines (LAIVs) viruses containing chimeric hemagglutinin (cHA) and/or wild-type nucleoprotein generated for this study were compared with those of the analogous LAIVs containing classical full-length HA
Five of six cHA LAIVs preserved the ca phenotype; the cH5 NP/WT candidate that contained both chimeric HA and wild-type NP replicated poorly at 26 ◦ C; the difference in titer compared with growth at 33 ◦ C was 4.5 log10 EID50
Summary
Influenza viruses are highly contagious respiratory pathogens that pose a constant threat throughout the world. In addition to annual epidemics, influenza A viruses can potentially cause pandemics when the new virus differs antigenically from previously circulating variants, meaning the human population is immunologically naïve. A viruses in birds provides the preconditions for interspecies transmission: the past two decades have seen an increase in the number of cases of human infection with avian influenza viruses H5, H7 and H9 [1,2,3]. One of the most important initiatives to prepare for an influenza pandemic is focused on developing and evaluating appropriate vaccines. Different approaches and platforms have been used to develop vaccines against potentially pandemic influenza viruses and, over the past few years, a large body of data has been accumulated on the safety and immunogenicity of these vaccines.
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