A Bivalent Vaccine Based on a PB2-Knockout Influenza Virus Protects Mice From Secondary Pneumococcal Pneumonia.

BACKGROUND Secondary bacterial infections after influenza can be a serious problem, especially in young children and the elderly, yet the efficacy of current vaccines is limited. Earlier work demonstrated that a replication-incompetent PB2-knockout (PB2-KO) influenza virus possessing a foreign gene in the coding region of its PB2 segment can serve as a platform for a bivalent vaccine. METHODS In the current study, we generated the PB2-KO virus expressing pneumococcal surface protein A (PspA), PB2-KO-PspA virus, the replication of which is restricted to PB2-expressing cells. We then examined the protective efficacy of intranasal immunization with this virus as a bivalent vaccine in a mouse model. RESULTS High levels of influenza virus-specific and PspA-specific antibodies were induced in the serum and airways of immunized mice. The intranasally immunized mice were protected from lethal doses of influenza virus or Streptococcus pneumoniae. These mice were also completely protected from secondary pneumococcal pneumonia after influenza virus infection. CONCLUSIONS These findings indicate that our recombinant influenza virus serves as a novel and powerful bivalent vaccine against primary and secondary pneumococcal pneumonia as well as influenza.

[1]  Y. Wiener-Well,et al.  Initial Effects of the National PCV7 Childhood Immunization Program on Adult Invasive Pneumococcal Disease in Israel , 2014, PloS one.

[2]  M. Kiso,et al.  A Novel Bivalent Vaccine Based on a PB2-Knockout Influenza Virus Protects Mice from Pandemic H1N1 and Highly Pathogenic H5N1 Virus Challenges , 2013, Journal of Virology.

[3]  J. Rello,et al.  Impact of the emergence of non-vaccine pneumococcal serotypes on the clinical presentation and outcome of adults with invasive pneumococcal pneumonia. , 2013, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[4]  D. Briles,et al.  PspA Family Distribution, unlike Capsular Serotype, Remains Unaltered following Introduction of the Heptavalent Pneumococcal Conjugate Vaccine , 2012, Clinical and Vaccine Immunology.

[5]  H. Katsura,et al.  A Replication-Incompetent PB2-Knockout Influenza A Virus Vaccine Vector , 2012, Journal of Virology.

[6]  H. Poo,et al.  Association of Glutathione S-transferase genes (GSTM1 and GSTT1) polymorphisms with hypertension in lead-exposed workers , 2012, Molecular & Cellular Toxicology.

[7]  M. Lipsitch,et al.  Serotype replacement in disease after pneumococcal vaccination , 2011, The Lancet.

[8]  G. Neumann,et al.  Replication-incompetent influenza A viruses that stably express a foreign gene. , 2011, The Journal of general virology.

[9]  K. Ishii,et al.  Intranasal vaccination with pneumococcal surface protein A plus poly(I:C) protects against secondary pneumococcal pneumonia in mice. , 2011, Vaccine.

[10]  A. Fauci,et al.  Induction of unnatural immunity: prospects for a broadly protective universal influenza vaccine , 2010, Nature Medicine.

[11]  D. Briles,et al.  Secretory-IgA Antibodies Play an Important Role in the Immunity to Streptococcus pneumoniae , 2010, The Journal of Immunology.

[12]  D. Isaacman,et al.  Burden of invasive pneumococcal disease and serotype distribution among Streptococcus pneumoniae isolates in young children in Europe: impact of the 7-valent pneumococcal conjugate vaccine and considerations for future conjugate vaccines. , 2010, International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases.

[13]  W. Schaffner,et al.  Sustained reductions in invasive pneumococcal disease in the era of conjugate vaccine. , 2010, The Journal of infectious diseases.

[14]  D. Morens,et al.  Bacterial pathogens and death during the 1918 influenza pandemic. , 2009, The New England journal of medicine.

[15]  T. Cherian,et al.  Burden of disease caused by Streptococcus pneumoniae in children younger than 5 years: global estimates , 2009, The Lancet.

[16]  N. Cox,et al.  Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009. , 2009 .

[17]  K. Oishi,et al.  Intranasal immunization with a mixture of PspA and a Toll-like receptor agonist induces specific antibodies and enhances bacterial clearance in the airways of mice. , 2009, Vaccine.

[18]  E. Miyaji,et al.  Characterization of Protective Mucosal and Systemic Immune Responses Elicited by Pneumococcal Surface Protein PspA and PspC Nasal Vaccines against a Respiratory Pneumococcal Challenge in Mice , 2009, Clinical and Vaccine Immunology.

[19]  I. Stephenson,et al.  Influenza vaccines for the future , 2009 .

[20]  D. Rolo,et al.  Epidemiology of invasive pneumococcal disease among adult patients in barcelona before and after pediatric 7-valent pneumococcal conjugate vaccine introduction, 1997-2007. , 2009, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[21]  W. Cao,et al.  Increased sensitivity for detecting avian influenza-specific antibodies by a modified hemagglutination inhibition assay using horse erythrocytes. , 2008, Journal of virological methods.

[22]  Anthony S Fauci,et al.  Predominant role of bacterial pneumonia as a cause of death in pandemic influenza: implications for pandemic influenza preparedness. , 2008, The Journal of infectious diseases.

[23]  G. Kayali,et al.  Testing human sera for antibodies against avian influenza viruses: horse RBC hemagglutination inhibition vs. microneutralization assays. , 2008, Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology.

[24]  D. Briles,et al.  Vaccine-induced human antibodies to PspA augment complement C3 deposition on Streptococcus pneumoniae. , 2008, Microbial pathogenesis.

[25]  A. Osterhaus,et al.  Influenza virus-specific cytotoxic T lymphocytes: a correlate of protection and a basis for vaccine development. , 2007, Current opinion in biotechnology.

[26]  W. Schaffner,et al.  Incidence of pneumococcal disease due to non-pneumococcal conjugate vaccine (PCV7) serotypes in the United States during the era of widespread PCV7 vaccination, 1998-2004. , 2007, The Journal of infectious diseases.

[27]  L. Hammitt,et al.  Invasive pneumococcal disease caused by nonvaccine serotypes among alaska native children with high levels of 7-valent pneumococcal conjugate vaccine coverage. , 2007, JAMA.

[28]  M. J. Jedrzejas.  Unveiling molecular mechanisms of pneumococcal surface protein A interactions with antibodies and lactoferrin. , 2006, Clinica chimica acta; international journal of clinical chemistry.

[29]  D. Briles,et al.  Nasal Colonization with Streptococcus pneumoniae Includes Subpopulations of Surface and Invasive Pneumococci , 2005, Infection and Immunity.

[30]  M. Kiso,et al.  Enhanced Expression of an α2,6-Linked Sialic Acid on MDCK Cells Improves Isolation of Human Influenza Viruses and Evaluation of Their Sensitivity to a Neuraminidase Inhibitor , 2005, Journal of Clinical Microbiology.

[31]  S. Obaro,et al.  Efficacy of nine-valent pneumococcal conjugate vaccine against pneumonia and invasive pneumococcal disease in The Gambia: randomised, double-blind, placebo-controlled trial , 2005, The Lancet.

[32]  R. de Groot,et al.  Streptococcus pneumoniae colonisation: the key to pneumococcal disease. , 2004, The Lancet. Infectious diseases.

[33]  R. Cox,et al.  Influenza Virus: Immunity and Vaccination Strategies. Comparison of the Immune Response to Inactivated and Live, Attenuated Influenza Vaccines , 2004, Scandinavian journal of immunology.

[34]  D. Briles,et al.  Effects of PspA and Antibodies to PspA on Activation and Deposition of Complement on the Pneumococcal Surface , 2004, Infection and Immunity.

[35]  S. Madhi,et al.  A trial of a 9-valent pneumococcal conjugate vaccine in children with and those without HIV infection. , 2003, The New England journal of medicine.

[36]  D. Briles,et al.  Immunizations with pneumococcal surface protein A and pneumolysin are protective against pneumonia in a murine model of pulmonary infection with Streptococcus pneumoniae. , 2003, The Journal of infectious diseases.

[37]  B. Arulanandam,et al.  Intranasal Vaccination with Pneumococcal Surface Protein A and Interleukin-12 Augments Antibody-Mediated Opsonization and Protective Immunity against Streptococcus pneumoniae Infection , 2001, Infection and Immunity.

[38]  E. Lamani,et al.  Characterization of Selected Strains of Pneumococcal Surface Protein A* , 2001, The Journal of Biological Chemistry.

[39]  D. Briles,et al.  Immunization of healthy adults with a single recombinant pneumococcal surface protein A (PspA) variant stimulates broadly cross-reactive antibodies to heterologous PspA molecules. , 2000, Vaccine.

[40]  E. Swiatlo,et al.  Intranasal Immunization of Mice with a Mixture of the Pneumococcal Proteins PsaA and PspA Is Highly Protective against Nasopharyngeal Carriage of Streptococcus pneumoniae , 2000, Infection and Immunity.

[41]  D. Briles,et al.  Pneumococcal Surface Protein A Inhibits Complement Activation by Streptococcus pneumoniae , 1999, Infection and Immunity.

[42]  Tokiko Watanabe,et al.  Generation of influenza A viruses entirely from cloned cDNAs. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[43]  K. Subbarao,et al.  Influenza vaccines: present and future. , 1999, Advances in virus research.

[44]  L. McDaniel,et al.  Comparison of the PspA Sequence from Streptococcus pneumoniae EF5668 to the Previously Identified PspA Sequence from Strain Rx1 and Ability of PspA from EF5668 To Elicit Protection against Pneumococci of Different Capsular Types , 1998, Infection and Immunity.

[45]  E. Swiatlo,et al.  Pneumococcal Diversity: Considerations for New Vaccine Strategies with Emphasis on Pneumococcal Surface Protein A (PspA) , 1998, Clinical Microbiology Reviews.

[46]  L. McDaniel,et al.  Systemic and Mucosal Protective Immunity to Pneumococcal Surface Protein A , 1996, Annals of the New York Academy of Sciences.

[47]  N. Cox,et al.  Comparison of US inactivated split-virus and Russian live attenuated, cold-adapted trivalent influenza vaccines in Russian schoolchildren. , 1996, The Journal of infectious diseases.

[48]  W. Roper,et al.  Prevention and control of influenza: Part I, Vaccines. Recommendations of the Advisory Committee on Immunization Practices (ACIP). , 1994, MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports.

[49]  L. McDaniel,et al.  PspA, a surface protein of Streptococcus pneumoniae, is capable of eliciting protection against pneumococci of more than one capsular type , 1991, Infection and immunity.

[50]  L. McDaniel,et al.  Pneumococcal surface protein A (PspA) is serologically highly variable and is expressed by all clinically important capsular serotypes of Streptococcus pneumoniae , 1990, Infection and immunity.

[51]  R. Webster,et al.  Biological activity of monoclonal antibodies to operationally defined antigenic regions on the hemagglutinin molecule of A/Seal/Massachusetts/1/80 (H7N7) influenza virus. , 1982, Virology.