Intradermal Immunization of Soluble Influenza HA Derived from a Lethal Virus Induces High Magnitude and Breadth of Antibody Responses and Provides Complete Protection In Vivo

Immunogens mimicking the native-like structure of surface-exposed viral antigens are considered promising vaccine candidates. Influenza viruses are important zoonotic respiratory viruses with high pandemic potential. Recombinant soluble hemagglutinin (HA) glycoprotein-based protein subunit vaccines against Influenza have been shown to induce protective efficacy when administered intramuscularly. Here, we have expressed a recombinant soluble trimeric HA protein in Expi 293F cells and purified the protein derived from the Inf A/Guangdong-Maonan/ SWL1536/2019 virus which was found to be highly virulent in the mouse. The trimeric HA protein was found to be in the oligomeric state, highly stable, and the efficacy study in the BALB/c mouse challenge model through intradermal immunization with the prime-boost regimen conferred complete protection against a high lethal dose of homologous and mouse-adapted InfA/PR8 virus challenge. Furthermore, the immunogen induced high hemagglutinin inhibition (HI) titers and showed cross-protection against other Inf A and Inf B subtypes. The results are promising and warrant trimeric HA as a suitable vaccine candidate.

[1]  N. Brown,et al.  Reversible structural changes in the influenza hemagglutinin precursor at membrane fusion pH , 2022, Proceedings of the National Academy of Sciences of the United States of America.

[2]  L. Rudenko,et al.  Understanding the Variability of Certain Biological Properties of H1N1pdm09 Influenza Viruses , 2022, Vaccines.

[3]  D. Rudin,et al.  Unique features of a recombinant haemagglutinin influenza vaccine that influence vaccine performance , 2021, NPJ vaccines.

[4]  A. Awasthi,et al.  Crystallographic landscape provides molecular insights into the modes of action of diverse ROR-γt modulators. , 2021, Drug discovery today.

[5]  A. Awasthi,et al.  Targeting cryptic-orthosteric site of PD-L1 for inhibitor identification using structure-guided approach. , 2021, Archives of biochemistry and biophysics.

[6]  Veysel Kayser,et al.  An Overview of Influenza Viruses and Vaccines , 2021, Vaccines.

[7]  K. To,et al.  Intradermal vaccination of live attenuated influenza vaccine protects mice against homologous and heterologous influenza challenges , 2021, NPJ vaccines.

[8]  R. Sanders,et al.  Influenza A Virus Hemagglutinin Trimer, Head and Stem Proteins Identify and Quantify Different Hemagglutinin-Specific B Cell Subsets in Humans , 2021, Vaccines.

[9]  K. Nagashima,et al.  Next-Generation Influenza HA Immunogens and Adjuvants in Pursuit of a Broadly Protective Vaccine , 2021, Viruses.

[10]  E. Weaver,et al.  Strategies Targeting Hemagglutinin as a Universal Influenza Vaccine , 2021, Vaccines.

[11]  A. Pollard,et al.  A guide to vaccinology: from basic principles to new developments , 2020, Nature reviews. Immunology.

[12]  Hongmei Yang,et al.  Recombinant HA-based vaccine outperforms split and subunit vaccines in elicitation of influenza-specific CD4 T cells and CD4 T cell-dependent antibody responses in humans , 2020, npj Vaccines.

[13]  T. Kurosaki,et al.  Influenza vaccination strategies targeting the hemagglutinin stem region , 2020, Immunological reviews.

[14]  J. Yewdell,et al.  Hemagglutinin head-specific responses dominate over stem-specific responses following prime boost with mismatched vaccines. , 2019, JCI insight.

[15]  Y. Kawaoka,et al.  Soluble Recombinant Hemagglutinin Protein of H1N1pdm09 Influenza Virus Elicits Cross-Protection Against a Lethal H5N1 Challenge in Mice , 2019, Front. Microbiol..

[16]  P. Thomas,et al.  Influenza virus-related critical illness: pathophysiology and epidemiology , 2019, Critical Care.

[17]  Anthony S Fauci,et al.  Influenza Vaccines: Good, but We Can Do Better. , 2019, The Journal of infectious diseases.

[18]  P. Palese,et al.  Universal Influenza Virus Vaccines That Target the Conserved Hemagglutinin Stalk and Conserved Sites in the Head Domain. , 2019, The Journal of infectious diseases.

[19]  J. Yewdell,et al.  Influenza Hemagglutinin and Neuraminidase: Yin–Yang Proteins Coevolving to Thwart Immunity , 2019, Viruses.

[20]  Beom Jeung Hwang,et al.  Universal monoclonal antibody-based influenza hemagglutinin quantitative enzyme-linked immunosorbent assay. , 2019, Vaccine.

[21]  D. Dou,et al.  Influenza A Virus Cell Entry, Replication, Virion Assembly and Movement , 2018, Front. Immunol..

[22]  Gavin J. D. Smith,et al.  Influenza , 2018, Nature Reviews Disease Primers.

[23]  Javier G. Magadán,et al.  Influenza A virus hemagglutinin glycosylation compensates for antibody escape fitness costs , 2018, PLoS pathogens.

[24]  Javier G. Magadán,et al.  Influenza A virus hemagglutinin glycosylation compensates for antibody escape fitness costs , 2018, PLoS pathogens.

[25]  C. Russell,et al.  The evolution of seasonal influenza viruses , 2017, Nature Reviews Microbiology.

[26]  A. Egli,et al.  An Optimized Hemagglutination Inhibition (HI) Assay to Quantify Influenza-specific Antibody Titers. , 2017, Journal of visualized experiments : JoVE.

[27]  S. Sambhara,et al.  Vaccine approaches conferring cross-protection against influenza viruses , 2017, Expert review of vaccines.

[28]  Erica D. Dawson,et al.  Automated interpretation of influenza hemagglutination inhibition (HAI) assays: Is plate tilting necessary? , 2017, PloS one.

[29]  F. Krammer.  Novel universal influenza virus vaccine approaches. , 2016, Current opinion in virology.

[30]  Mark Jit,et al.  A systematic review of the social and economic burden of influenza in low- and middle-income countries. , 2015, Vaccine.

[31]  Nancy R. Zhang,et al.  Emergence of Hemagglutinin Mutations During the Course of Influenza Infection , 2015, Scientific Reports.

[32]  S. Harrison,et al.  Viral membrane fusion. , 2015, Virology.

[33]  K. Subbarao,et al.  Influenza vaccines: challenges and solutions. , 2015, Cell host & microbe.

[34]  E. Holmes,et al.  Influenza Virus Reservoirs and Intermediate Hosts: Dogs, Horses, and New Possibilities for Influenza Virus Exposure of Humans , 2014, Journal of Virology.

[35]  Vidya Subramanian,et al.  Broadly neutralizing influenza hemagglutinin stem-specific antibody CR8020 targets residues that are prone to escape due to host selection pressure. , 2014, Cell host & microbe.

[36]  R. Webby,et al.  Single-dose monomeric HA subunit vaccine generates full protection from influenza challenge , 2014, Human vaccines & immunotherapeutics.

[37]  S. Maurer-Stroh,et al.  Playing Hide and Seek: How Glycosylation of the Influenza Virus Hemagglutinin Can Modulate the Immune Response to Infection , 2014, Viruses.

[38]  Yeu‐Chun Kim,et al.  Microneedle patches for vaccine delivery , 2013, Clinical and experimental vaccine research.

[39]  James R. Swartz,et al.  Production and stabilization of the trimeric influenza hemagglutinin stem domain for potentially broadly protective influenza vaccines , 2013, Proceedings of the National Academy of Sciences.

[40]  R. Webby,et al.  Traditional and New Influenza Vaccines , 2013, Clinical Microbiology Reviews.

[41]  Ryan McBride,et al.  Hemagglutinin homologue from H17N10 bat influenza virus exhibits divergent receptor-binding and pH-dependent fusion activities , 2013, Proceedings of the National Academy of Sciences.

[42]  N. Sriwilaijaroen,et al.  Molecular basis of the structure and function of H1 hemagglutinin of influenza virus , 2012, Proceedings of the Japan Academy. Series B, Physical and biological sciences.

[43]  K. Lindblade,et al.  A distinct lineage of influenza A virus from bats , 2012, Proceedings of the National Academy of Sciences.

[44]  Martin H. Koldijk,et al.  A Highly Conserved Neutralizing Epitope on Group 2 Influenza A Viruses , 2011, Science.

[45]  Yvonne Perrie,et al.  Administration routes affect the quality of immune responses: A cross-sectional evaluation of particulate antigen-delivery systems. , 2010, Journal of controlled release : official journal of the Controlled Release Society.

[46]  Steven J. Gamblin,et al.  Influenza Hemagglutinin and Neuraminidase Membrane Glycoproteins , 2010, The Journal of Biological Chemistry.

[47]  James M Aramini,et al.  Structures of influenza A proteins and insights into antiviral drug targets , 2010, Nature Structural &Molecular Biology.

[48]  Manon M J Cox,et al.  FluBlok, a next generation influenza vaccine manufactured in insect cells. , 2009, Biologicals : journal of the International Association of Biological Standardization.

[49]  Gira Bhabha,et al.  Antibody Recognition of a Highly Conserved Influenza Virus Epitope , 2009, Science.

[50]  Nicole M. Bouvier,et al.  The biology of influenza viruses. , 2008, Vaccine.

[51]  P. Laurent,et al.  Evaluation of the clinical performance of a new intradermal vaccine administration technique and associated delivery system. , 2007, Vaccine.

[52]  N. Harvey,et al.  Preclinical Evaluation of Microneedle Technology for Intradermal Delivery of Influenza Vaccines , 2007, Clinical and Vaccine Immunology.

[53]  Ian A. Wilson,et al.  Structure of the Uncleaved Human H1 Hemagglutinin from the Extinct 1918 Influenza Virus , 2004, Science.

[54]  W. Blackwelder,et al.  Safety and immunogenicity of a recombinant hemagglutinin vaccine for H5 influenza in humans. , 2001, Vaccine.

[55]  R. Krug,et al.  The Influenza Viruses , 2011, The Viruses.

[56]  S. Cusack,et al.  Structure of the influenza virus haemagglutinin complexed with its receptor, sialic acid , 1988, Nature.

[57]  A. Hernández Lezana,et al.  [Transcatheter embolization of bronchial arteries in the treatment of massive hemoptysis]. , 1988, Revista clinica espanola.