title: Stalking influenza by vaccination with pre-fusion headless HA mini-stem.
abstract: 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.
authors.affiliation: 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.
authors.forename: Sophie A
authors.initials: SA
authors.lastname: Valkenburg
authors.affiliation: Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India.
authors.forename: V Vamsee Aditya
authors.initials: VV
authors.lastname: Mallajosyula
authors.affiliation: Center of Influenza Research and School of Public Health, The University of Hong Kong, Hong Kong.
authors.forename: Olive T W
authors.initials: OT
authors.lastname: Li
authors.affiliation: Center of Influenza Research and School of Public Health, The University of Hong Kong, Hong Kong.
authors.forename: Alex W H
authors.initials: AW
authors.lastname: Chin
authors.affiliation: Viral Pseudotype Unit, School of Pharmacy, University of Kent, Kent, United Kingdom.
authors.forename: George
authors.initials: G
authors.lastname: Carnell
authors.affiliation: Viral Pseudotype Unit, School of Pharmacy, University of Kent, Kent, United Kingdom.
authors.forename: Nigel
authors.initials: N
authors.lastname: Temperton
authors.affiliation: Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India.
authors.forename: Raghavan
authors.initials: R
authors.lastname: Varadarajan
authors.affiliation: Center of Influenza Research and School of Public Health, The University of Hong Kong, Hong Kong.
authors.forename: Leo L M
authors.initials: LL
authors.lastname: Poon
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D000914:Antibodies, Viral / Q000276:immunology; D004195:Disease Models, Animal; D004355:Drug Stability; D005260:Female; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007116:Immunization, Passive; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D007251:Influenza, Human / Q000517:prevention & control*; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections / Q000517:prevention & control; D011485:Protein Binding; D017510:Protein Folding; D055503:Protein Multimerization; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology; D016019:Survival Analysis; D016896:Treatment Outcome; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007252:Influenza Vaccines; D011994:Recombinant Proteins; D014614:Vaccines, Synthetic; C109963:hemagglutinin, avian influenza A virus