title: A bivalent vaccine based on a replication-incompetent influenza virus protects against Streptococcus pneumoniae and influenza virus infection.
abstract: Streptococcus pneumoniae is a major causative pathogen in community-acquired pneumonia; together with influenza virus, it represents an important public health burden. Although vaccination is the most effective prophylaxis against these infectious agents, no single vaccine simultaneously provides protective immunity against both S. pneumoniae and influenza virus. Previously, we demonstrated that several replication-incompetent influenza viruses efficiently elicit IgG in serum and IgA in the upper and lower respiratory tracts. Here, we generated a replication-incompetent hemagglutinin knockout (HA-KO) influenza virus possessing the sequence for the antigenic region of pneumococcal surface protein A (PspA). Although this virus (HA-KO/PspA virus) could replicate only in an HA-expressing cell line, it infected wild-type cells and expressed both viral proteins and PspA. PspA- and influenza virus-specific antibodies were detected in nasal wash and bronchoalveolar lavage fluids and in sera from mice intranasally inoculated with HA-KO/PspA virus, and mice inoculated with HA-KO/PspA virus were completely protected from lethal challenge with either S. pneumoniae or influenza virus. Further, bacterial colonization of the nasopharynx was prevented in mice immunized with HA-KO/PspA virus. These results indicate that HA-KO/PspA virus is a promising bivalent vaccine candidate that simultaneously confers protective immunity against both S. pneumoniae and influenza virus. We believe that this strategy offers a platform for the development of bivalent vaccines, based on replication-incompetent influenza virus, against pathogens that cause respiratory infectious diseases.
  
  
  OBJECTIVE
  Streptococcus pneumoniae and influenza viruses cause contagious diseases, but no single vaccine can simultaneously provide protective immunity against both pathogens. Here, we used reverse genetics to generate a replication-incompetent influenza virus carrying the sequence for the antigenic region of pneumococcal surface protein A and demonstrated that mice immunized with this virus were completely protected from lethal doses of infection with either influenza virus or Streptococcus pneumoniae. We believe that this strategy, which is based on a replication-incompetent influenza virus possessing the antigenic region of other respiratory pathogens, offers a platform for the development of bivalent vaccines.
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Katsura
authors.affiliation: Laboratory of Clinical Research on Infectious Diseases, International Research Center for Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Piao
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Iwatsuki-Horimoto
authors.affiliation: Laboratory of Clinical Research on Infectious Diseases, International Research Center for Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Akeda
authors.affiliation: ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama, Japan Laboratory of Veterinary Microbiology, Department of Veterinary Sciences, University of Miyazaki, Miyazaki, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: Department of Veterinary Microbiology, Graduate School of Agriculture and Life Science, University of Tokyo, Tokyo, Japan.
authors.forename: Taisuke
authors.initials: T
authors.lastname: Horimoto
authors.affiliation: Laboratory of Clinical Research on Infectious Diseases, International Research Center for Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan Infectious Disease Surveillance Center, National Institute of Infectious Diseases, Tokyo, Japan oishik@nih.go.jp kawaoka@ims.u-tokyo.ac.jp.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Oishi
authors.affiliation: Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan ERATO Infection-Induced Host Responses Project, Japan Science and Technology Agency, Saitama, Japan Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA Department of Special Pathogens, International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan oishik@nih.go.jp kawaoka@ims.u-tokyo.ac.jp.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kawaoka
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology; D002353:Carrier State / Q000517:prevention & control; D004195:Disease Models, Animal; D005260:Female; D055786:Gene Knockout Techniques; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics; D006801:Humans; D009980:Influenza A virus / Q000235:genetics / Q000276:immunology*; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D009305:Nasopharynx / Q000382:microbiology; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000517:prevention & control*; D011008:Pneumococcal Infections / Q000276:immunology / Q000517:prevention & control*; D022541:Streptococcal Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D013296:Streptococcus pneumoniae / Q000235:genetics / Q000276:immunology*; D016019:Survival Analysis; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology
chemical_list: D001426:Bacterial Proteins; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007252:Influenza Vaccines; D022541:Streptococcal Vaccines; D014614:Vaccines, Synthetic; C051592:pneumococcal surface protein A