title: Development of a candidate influenza vaccine based on virus-like particles displaying influenza M2e peptide into the immunodominant region of hepatitis B core antigen: Broad protective efficacy of particles carrying four copies of M2e.
abstract: A long-term objective when designing influenza vaccines is to create one with broad cross-reactivity that will provide effective control over influenza, no matter which strain has caused the disease. Here we summarize the results from an investigation into the immunogenic and protective capacities inherent in variations of a recombinant protein, HBc/4M2e. This protein contains four copies of the ectodomain from the influenza virus protein M2 (M2e) fused within the immunodominant loop of the hepatitis B virus core antigen (HBc). Variations of this basic design include preparations containing M2e from the consensus human influenza virus; the M2e from the highly pathogenic avian A/H5N1 virus and a combination of two copies from human and two copies from avian influenza viruses. Intramuscular delivery in mice with preparations containing four identical copies of M2e induced high IgG titers in blood sera and bronchoalveolar lavages. It also provoked the formation of memory T-cells and antibodies were retained in the blood sera for a significant period of time post immunization. Furthermore, these preparations prevented the death of 75-100% of animals, which were challenged with lethal doses of virus. This resulted in a 1.2-3.5 log10 decrease in viral replication within the lungs. Moreover, HBc particles carrying only "human" or "avian" M2e displayed cross-reactivity in relation to human (A/H1N1, A/H2N2 and A/H3N2) or A/H5N1 and A(H1N1)pdm09 viruses, respectively; however, with the particles carrying both "human" and "avian" M2e this effect was much weaker, especially in relation to influenza virus A/H5N1. It is apparent from this work that to quickly produce vaccine for a pandemic it would be necessary to have several variations of a recombinant protein, containing four copies of M2e (each one against a group of likely influenza virus strains) with these relevant constructs housed within a comprehensive collection Escherichia coli-producers and maintained ready for use.
authors.affiliation: Research Institute of Influenza, Russian Federation Ministry of Health, St. Petersburg, Russia. Electronic address: sovet@influenza.spb.ru.
authors.forename: Liudmila M
authors.initials: LM
authors.lastname: Tsybalova
authors.affiliation: Research Institute of Influenza, Russian Federation Ministry of Health, St. Petersburg, Russia.
authors.forename: Liudmila A
authors.initials: LA
authors.lastname: Stepanova
authors.affiliation: Centre "Bioengineering", Russian Academy of Science, Moscow, Russia.
authors.forename: Victor V
authors.initials: VV
authors.lastname: Kuprianov
authors.affiliation: Centre "Bioengineering", Russian Academy of Science, Moscow, Russia.
authors.forename: Elena A
authors.initials: EA
authors.lastname: Blokhina
authors.affiliation: Research Institute of Influenza, Russian Federation Ministry of Health, St. Petersburg, Russia.
authors.forename: Marina V
authors.initials: MV
authors.lastname: Potapchuk
authors.affiliation: Research Institute of Influenza, Russian Federation Ministry of Health, St. Petersburg, Russia.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Korotkov
authors.affiliation: Research Institute of Influenza, Russian Federation Ministry of Health, St. Petersburg, Russia.
authors.forename: Andrey N
authors.initials: AN
authors.lastname: Gorshkov
authors.affiliation: Research Institute of Influenza, Russian Federation Ministry of Health, St. Petersburg, Russia.
authors.forename: Marina A
authors.initials: MA
authors.lastname: Kasyanenko
authors.affiliation: Centre "Bioengineering", Russian Academy of Science, Moscow, Russia.
authors.forename: Nikolai V
authors.initials: NV
authors.lastname: Ravin
authors.affiliation: Research Institute of Influenza, Russian Federation Ministry of Health, St. Petersburg, Russia.
authors.forename: Oleg I
authors.initials: OI
authors.lastname: Kiselev
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000032:analysis / Q000097:blood; D001769:Blood / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D056738:Cross Protection; D003429:Cross Reactions; D004195:Disease Models, Animal; D000939:Epitopes / Q000235:genetics / Q000276:immunology*; D004926:Escherichia coli / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006512:Hepatitis B Core Antigens / Q000235:genetics; D007074:Immunoglobulin G / Q000032:analysis / Q000097:blood; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D008168:Lung / Q000821:virology; D008807:Mice, Inbred BALB C; D016254:Mutagenesis, Insertional; D009976:Orthomyxoviridae Infections / Q000517:prevention & control; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D058425:Vaccines, Virus-Like Particle / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D019562:Viral Load; D014763:Viral Matrix Proteins / Q000235:genetics / Q000276:immunology*; D000086082:Viroporin Proteins
chemical_list: D000914:Antibodies, Viral; D000939:Epitopes; D006512:Hepatitis B Core Antigens; D007074:Immunoglobulin G; D007252:Influenza Vaccines; D011993:Recombinant Fusion Proteins; D014614:Vaccines, Synthetic; D058425:Vaccines, Virus-Like Particle; D014763:Viral Matrix Proteins; C488937:M2 protein, Influenza A virus; D000086082:Viroporin Proteins; C509609:M2e-HBc influenza vaccine
keywords: HBc/M2e recombinant vaccine; Immunogenicity; Influenza A; Protective properties