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Sci Rep. 2016 Mar 7;6:22666. doi: 10.1038/srep22666.

Stalking influenza by vaccination with pre-fusion headless HA mini-stem.

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HKU-Pasteur Research Pole, School of Public Health, HKU Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
Center of Influenza Research and School of Public Health, The University of Hong Kong, Hong Kong.
Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India.
Viral Pseudotype Unit, School of Pharmacy, University of Kent, Kent, United Kingdom.


Inaccuracies in prediction of circulating viral strain genotypes and the possibility of novel reassortants causing a pandemic outbreak necessitate the development of an anti-influenza vaccine with increased breadth of protection and potential for rapid production and deployment. The hemagglutinin (HA) stem is a promising target for universal influenza vaccine as stem-specific antibodies have the potential to be broadly cross-reactive towards different HA subtypes. Here, we report the design of a bacterially expressed polypeptide that mimics a H5 HA stem by protein minimization to focus the antibody response towards the HA stem. The HA mini-stem folds as a trimer mimicking the HA prefusion conformation. It is resistant to thermal/chemical stress, and it binds to conformation-specific, HA stem-directed broadly neutralizing antibodies with high affinity. Mice vaccinated with the group 1 HA mini-stems are protected from morbidity and mortality against lethal challenge by both group 1 (H5 and H1) and group 2 (H3) influenza viruses, the first report of cross-group protection. Passive transfer of immune serum demonstrates the protection is mediated by stem-specific antibodies. Furthermore, antibodies induced by these HA stems have broad HA reactivity, yet they do not have antibody-dependent enhancement activity.

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