• VTH 201
    UniFluVec
  • Background

    The development of influenza vaccines has a long tradition. Currently available  vaccines are either killed or life virus vaccines, which contain the predicted antigens of the emerging viruses. Accuracy of prediction rates are  between 50 and 90%.  Life virus vaccines have the advantage of a better stimulation of the cellular (T-cell) response, resulting in a more broad stimulation of the immune system.  Using the technology of virus engineering the founders of Vacthera previously developed a novel type of influenza vaccine which was based on the finding that influenza viruses express the immune-suppressive NS1 protein. The deletion of this immunosuppressive protein led to attenuated viruses which are high immunogenic.

    Moreover those NS1 deletion vaccine prototypes were shown to be safe in humans.

    However the  production of those prototypes in Vero cells remained a problem as the purification substantially diminished the viral titers. Vacthera has solved this problem by developing a new viral vector that is highly immunogenic but can also be produced at high titers.

    Publications by the founders supporting the use of  influenza A viruses  containing NS1 deletions as vaccine vectors

     Washington Poster 2016 03 24

    List of Publication for UniFluVec

    Tabynov K, Sansyzbay A, Kydyrbayev Z, Yespembetov B, Ryskeldinova S, Zinina N,Assanzhanova N, Sultankulova K, Sandybayev N, Khairullin B, Kuznetsova I, Ferko B, Egorov A. Influenza viral vectors expressing the Brucella OMP16 or L7/L12 proteins as vaccines against B. abortus infection. Virol J. 2014 Apr 10;11:69. doi: 10.1186/1743-422X-11-69. PubMed PMID: 24716528; PubMed Central PMCID:PMC3997475.

    Kuznetsova I, Shurygina AP, Wolf B, Wolschek M, Enzmann F, Sansyzbay A, Khairullin B, Sandybayev N, Stukova M, Kiselev O, Egorov A, Bergmann M. Adaptive mutation in nuclear export protein allows stable transgene expression in a chimaeric influenza A virus vector. J Gen Virol. 2014 Feb;95(Pt 2):337-49. doi: 10.1099/vir.0.056036-0. Epub 2013 Nov 12. PubMed PMID: 24222196.

    Park HJ, Ferko B, Byun YH, Song JH, Han GY, Roethl E, Egorov A, Muster T, Seong B, Kweon MN, Song M, Czerkinsky C, Nguyen HH. Sublingual immunization with a live attenuated influenza a virus lacking the nonstructural protein 1 induces broad protective immunity in mice. PLoS One. 2012;7(6):e39921. doi: 10.1371/journal.pone.0039921. Epub 2012 Jun 27. PubMed PMID: 22761928; PubMed Central PMCID: PMC3384633.

    Krenn BM, Egorov A, Romanovskaya-Romanko E, Wolschek M, Nakowitsch S, Ruthsatz T, Kiefmann B, Morokutti A, Humer J, Geiler J, Cinatl J, Michaelis M, Wressnigg N, Sturlan S, Ferko B, Batishchev OV, Indenbom AV, Zhu R, Kastner M, Hinterdorfer P, Kiselev O, Muster T, Romanova J. Single HA2 mutation increases the infectivity and immunogenicity of a live attenuated H5N1 intranasal influenza vaccine candidate lacking NS1. PLoS One. 2011 Apr 7;6(4):e18577. PubMed PMID: 21490925; PubMed Central PMCID: PMC3072404.

    Nakowitsch S, Wolschek M, Morokutti A, Ruthsatz T, Krenn BM, Ferko B, Ferstl N, Triendl A, Muster T, Egorov A, Romanova J. Mutations affecting the stability of the haemagglutinin molecule impair the immunogenicity of live attenuated H3N2 intranasal influenza vaccine candidates lacking NS1. Vaccine. 2011 Apr 27;29(19):3517-24. Epub 2011 Mar 12. PubMed PMID: 21406268.

    Wolschek M, Samm E, Seper H, Sturlan S, Kuznetsova I, Schwager C, Khassidov A, Kittel C, Muster T, Egorov A, Bergmann M. Establishment of a chimeric, replication-deficient influenza A virus vector by modulation of splicing efficiency. J Virol. 2011 Mar;85(5):2469-73. Epub 2010 Dec 22. PubMed PMID: 21177819; PubMed Central PMCID: PMC3067781.

    Wacheck V*, Egorov A*, Groiss F, Pfeiffer A, Fuereder T, Hoeflmayer D, Kundi M,Popow-Kraupp T, Redlberger-Fritz M, Mueller CA, Cinatl J, Michaelis M, Geiler J, Bergmann M, Romanova J, Roethl E, Morokutti A, Wolschek M, Ferko B, Seipelt J, Dick-Gudenus R, Muster T. A novel type of influenza vaccine: safety and immunogenicity of replication-deficient influenza virus created by deletion of the interferon antagonist NS1. J Infect Dis. 2010 Feb 1;201(3):354-62. *) equal contribution

    Ogbomo H, Michaelis M, Geiler J, van Rikxoort M, Muster T, Egorov A, Doerr HW, Cinatl J Jr. Tumor cells infected with oncolytic influenza A virus prime natural killer cells for lysis of resistant tumor cells. Med Microbiol Immunol. 2009 Dec 15. PubMed PMID: 20012989.

    Romanova J, Krenn BM, Wolschek M, Ferko B, Romanovskaja-Romanko E, MorokuttiA, Shurygina AP, Nakowitsch S, Ruthsatz T, Kiefmann B, König U, Bergmann M, Sachet M, Balasingam S, Mann A, Oxford J, Slais M, Kiselev O, Muster T, Egorov A. Preclinical evaluation of a replication-deficient intranasal DeltaNS1 H5N1 influenza vaccine. PLoS One. 2009 Jun 19;4(6):e5984.

    Wressnigg N, Shurygina AP, Wolff T, Redlburger-Frity M, Popow-Kraup T, Muster T, Egorov A, Kittel C. Influenza B mutant viruses with truncated NS1 proteins grow efficiently in Vero cells and are immunogenic in mice. J Gen Virol. 2009 Feb;90(Pt 2):366-74.

    Sereinig S, Stukova M, Zabolotnyh N, Ferko B, Kittel C, Romanova J, Vinogradova T, Katinger H, Kiselev O, Egorov A. Influenza virus NS vectors expressing the mycobacterium tuberculosis ESAT-6 protein induce CD4+ Th1 immune response and protect animals against tuberculosis challenge. Clin Vaccine Immunol. 2006 Aug;13(8):898-904.

    Stukova MA, Sereinig S, Zabolotnyh NV, Ferko B, Kittel C, Romanova J,Vinogradova TI, Katinger H, Kiselev OI, Egorov A. Vaccine potential of influenza vectors expressing Mycobacterium tuberculosis ESAT-6 protein. Tuberculosis (Edinb). 2006 May-Jul;86(3-4):236-46.

    Kittel C, Ferko B, Kurz M, Voglauer R, Sereinig S, Romanova J, Stiegler G,Katinger H, Egorov A. Generation of an influenza A virus vector expressing biologically active human interleukin-2 from the NS gene segment. J Virol. 2005 Aug;79(16):10672-7.

    Stasakova J, Ferko B, Kittel C, Sereinig S, Romanova J, Katinger H, Egorov A. Influenza A mutant viruses with altered NS1 protein function provoke caspase-1 activation in primary human macrophages, resulting in fast apoptosis and release of high levels of interleukins 1beta and 18.

    J Gen Virol. 2005 Jan;86(Pt 1):185-95.

    Ferko B, Stasakova J, Romanova J, Kittel C, Sereinig S, Katinger H, Egorov A. Immunogenicity and protection efficacy of replication-deficient influenza A viruses with altered NS1 genes. J Virol. 2004 Dec;78(23):13037-45.

    Kittel C, Sereinig S, Ferko B, Stasakova J, Romanova J, Wolkerstorfer A, Katinger H, Egorov A. Rescue of influenza virus expressing GFP from the NS1 reading frame. Virology. 2004 Jun 20;324(1):67-73.

    Romanova J, Katinger D, Ferko B, Vcelar B, Sereinig S, Kuznetsov O, Stukova M, Erofeeva M, Kiselev O, Katinger H, Egorov A. Live cold-adapted influenza A vaccine produced in Vero cell line. Virus Res. 2004 Jul;103(1-2):187-93.

    Romanova J, Katinger D, Ferko B, Voglauer R, Mochalova L, Bovin N, Lim W, Katinger H, Egorov A. Distinct host range of influenza H3N2 virus isolates in Vero and MDCK cells is determined by cell specific glycosylation pattern.Virology. 2003 Mar 1;307(1):90-7.

    Ferko B, Stasakova J, Sereinig S, Romanova J, Katinger D, Niebler B,Katinger H, Egorov A. Hyperattenuated recombinant influenza A virus nonstructural-protein-encoding vectors induce human immunodeficiency virus type 1 Nef-specific systemic and mucosal immune responses in mice.

    J Virol. 2001 Oct;75(19):8899-908.

    Shaw MW, Kiseleva IV, Egorov AY, Hemphill ML, Xu X. Generation of influenza transfectants using purified recombinant nucleocapsid protein. J Virol Methods. 1998 Dec;76(1-2):149-51.

    Garcia-Sastre A, Egorov A, Matassov D, Brandt S, Levy DE, Durbin JE, Palese P, Muster T. Influenza A virus lacking the NS1 gene replicates in interferon-deficient systems. Virology. 1998 Dec 20;252(2):324-30.

    Ferko B, Katinger D, Grassauer A, Egorov A, Romanova J, Niebler B, Katinger H, Muster T. Chimeric influenza virus replicating predominantly in the murine upper respiratory tract induces local immune responses against human immunodeficiency virus type 1 in the genital tract. J Infect Dis. 1998 Nov;178(5):1359-68.

    Egorov A, Brandt S, Sereinig S, Romanova J, Ferko B, Katinger D, Grassauer A, Alexandrova G, Katinger H, Muster T. Transfectant influenza A viruses with long deletions in the NS1 protein grow efficiently in Vero cells. J Virol. 1998 Aug;72(8):6437-41.

    Grassauer A, Egorov AY, Ferko B, Romanova I, Katinger H, Muster T.  A host restriction-based selection system for influenza haemagglutinin transfectant viruses. J Gen Virol. 1998 Jun;79 ( Pt 6):1405-9.

    Klimov AI, Egorov AY, Gushchina MI, Medvedeva TE, Gamble WC, Rudenko LG, Alexandrova GI, Cox NJ. Genetic stability of cold-adapted A/Leningrad/134/47/57 (H2N2) influenza virus:sequence analysis of live cold-adapted reassortant vaccine strains before and after replication in children. J Gen Virol. 1995 Jun;76 ( Pt 6):1521-5.

     

     

Background

The development of influenza vaccines has a long tradition. Currently available  vaccines are either killed or life virus vaccines, which contain the predicted antigens of the emerging viruses. Accuracy of prediction rates are  between 50 and 90%.  Life virus vaccines have the advantage of a better stimulation of the cellular (T-cell) response, resulting in a more broad stimulation of the immune system.  Using the technology of virus engineering the founders of Vacthera previously developed a novel type of influenza vaccine which was based on the finding that influenza viruses express the immune-suppressive NS1 protein. The deletion of this immunosuppressive protein led to attenuated viruses which are high immunogenic.

Moreover those NS1 deletion vaccine prototypes were shown to be safe in humans.

However the  production of those prototypes in Vero cells remained a problem as the purification substantially diminished the viral titers. Vacthera has solved this problem by developing a new viral vector that is highly immunogenic but can also be produced at high titers.

Publications by the founders supporting the use of  influenza A viruses  containing NS1 deletions as vaccine vectors

 Washington Poster 2016 03 24

List of Publication for UniFluVec

Tabynov K, Sansyzbay A, Kydyrbayev Z, Yespembetov B, Ryskeldinova S, Zinina N,Assanzhanova N, Sultankulova K, Sandybayev N, Khairullin B, Kuznetsova I, Ferko B, Egorov A. Influenza viral vectors expressing the Brucella OMP16 or L7/L12 proteins as vaccines against B. abortus infection. Virol J. 2014 Apr 10;11:69. doi: 10.1186/1743-422X-11-69. PubMed PMID: 24716528; PubMed Central PMCID:PMC3997475.

Kuznetsova I, Shurygina AP, Wolf B, Wolschek M, Enzmann F, Sansyzbay A, Khairullin B, Sandybayev N, Stukova M, Kiselev O, Egorov A, Bergmann M. Adaptive mutation in nuclear export protein allows stable transgene expression in a chimaeric influenza A virus vector. J Gen Virol. 2014 Feb;95(Pt 2):337-49. doi: 10.1099/vir.0.056036-0. Epub 2013 Nov 12. PubMed PMID: 24222196.

Park HJ, Ferko B, Byun YH, Song JH, Han GY, Roethl E, Egorov A, Muster T, Seong B, Kweon MN, Song M, Czerkinsky C, Nguyen HH. Sublingual immunization with a live attenuated influenza a virus lacking the nonstructural protein 1 induces broad protective immunity in mice. PLoS One. 2012;7(6):e39921. doi: 10.1371/journal.pone.0039921. Epub 2012 Jun 27. PubMed PMID: 22761928; PubMed Central PMCID: PMC3384633.

Krenn BM, Egorov A, Romanovskaya-Romanko E, Wolschek M, Nakowitsch S, Ruthsatz T, Kiefmann B, Morokutti A, Humer J, Geiler J, Cinatl J, Michaelis M, Wressnigg N, Sturlan S, Ferko B, Batishchev OV, Indenbom AV, Zhu R, Kastner M, Hinterdorfer P, Kiselev O, Muster T, Romanova J. Single HA2 mutation increases the infectivity and immunogenicity of a live attenuated H5N1 intranasal influenza vaccine candidate lacking NS1. PLoS One. 2011 Apr 7;6(4):e18577. PubMed PMID: 21490925; PubMed Central PMCID: PMC3072404.

Nakowitsch S, Wolschek M, Morokutti A, Ruthsatz T, Krenn BM, Ferko B, Ferstl N, Triendl A, Muster T, Egorov A, Romanova J. Mutations affecting the stability of the haemagglutinin molecule impair the immunogenicity of live attenuated H3N2 intranasal influenza vaccine candidates lacking NS1. Vaccine. 2011 Apr 27;29(19):3517-24. Epub 2011 Mar 12. PubMed PMID: 21406268.

Wolschek M, Samm E, Seper H, Sturlan S, Kuznetsova I, Schwager C, Khassidov A, Kittel C, Muster T, Egorov A, Bergmann M. Establishment of a chimeric, replication-deficient influenza A virus vector by modulation of splicing efficiency. J Virol. 2011 Mar;85(5):2469-73. Epub 2010 Dec 22. PubMed PMID: 21177819; PubMed Central PMCID: PMC3067781.

Wacheck V*, Egorov A*, Groiss F, Pfeiffer A, Fuereder T, Hoeflmayer D, Kundi M,Popow-Kraupp T, Redlberger-Fritz M, Mueller CA, Cinatl J, Michaelis M, Geiler J, Bergmann M, Romanova J, Roethl E, Morokutti A, Wolschek M, Ferko B, Seipelt J, Dick-Gudenus R, Muster T. A novel type of influenza vaccine: safety and immunogenicity of replication-deficient influenza virus created by deletion of the interferon antagonist NS1. J Infect Dis. 2010 Feb 1;201(3):354-62. *) equal contribution

Ogbomo H, Michaelis M, Geiler J, van Rikxoort M, Muster T, Egorov A, Doerr HW, Cinatl J Jr. Tumor cells infected with oncolytic influenza A virus prime natural killer cells for lysis of resistant tumor cells. Med Microbiol Immunol. 2009 Dec 15. PubMed PMID: 20012989.

Romanova J, Krenn BM, Wolschek M, Ferko B, Romanovskaja-Romanko E, MorokuttiA, Shurygina AP, Nakowitsch S, Ruthsatz T, Kiefmann B, König U, Bergmann M, Sachet M, Balasingam S, Mann A, Oxford J, Slais M, Kiselev O, Muster T, Egorov A. Preclinical evaluation of a replication-deficient intranasal DeltaNS1 H5N1 influenza vaccine. PLoS One. 2009 Jun 19;4(6):e5984.

Wressnigg N, Shurygina AP, Wolff T, Redlburger-Frity M, Popow-Kraup T, Muster T, Egorov A, Kittel C. Influenza B mutant viruses with truncated NS1 proteins grow efficiently in Vero cells and are immunogenic in mice. J Gen Virol. 2009 Feb;90(Pt 2):366-74.

Sereinig S, Stukova M, Zabolotnyh N, Ferko B, Kittel C, Romanova J, Vinogradova T, Katinger H, Kiselev O, Egorov A. Influenza virus NS vectors expressing the mycobacterium tuberculosis ESAT-6 protein induce CD4+ Th1 immune response and protect animals against tuberculosis challenge. Clin Vaccine Immunol. 2006 Aug;13(8):898-904.

Stukova MA, Sereinig S, Zabolotnyh NV, Ferko B, Kittel C, Romanova J,Vinogradova TI, Katinger H, Kiselev OI, Egorov A. Vaccine potential of influenza vectors expressing Mycobacterium tuberculosis ESAT-6 protein. Tuberculosis (Edinb). 2006 May-Jul;86(3-4):236-46.

Kittel C, Ferko B, Kurz M, Voglauer R, Sereinig S, Romanova J, Stiegler G,Katinger H, Egorov A. Generation of an influenza A virus vector expressing biologically active human interleukin-2 from the NS gene segment. J Virol. 2005 Aug;79(16):10672-7.

Stasakova J, Ferko B, Kittel C, Sereinig S, Romanova J, Katinger H, Egorov A. Influenza A mutant viruses with altered NS1 protein function provoke caspase-1 activation in primary human macrophages, resulting in fast apoptosis and release of high levels of interleukins 1beta and 18.

J Gen Virol. 2005 Jan;86(Pt 1):185-95.

Ferko B, Stasakova J, Romanova J, Kittel C, Sereinig S, Katinger H, Egorov A. Immunogenicity and protection efficacy of replication-deficient influenza A viruses with altered NS1 genes. J Virol. 2004 Dec;78(23):13037-45.

Kittel C, Sereinig S, Ferko B, Stasakova J, Romanova J, Wolkerstorfer A, Katinger H, Egorov A. Rescue of influenza virus expressing GFP from the NS1 reading frame. Virology. 2004 Jun 20;324(1):67-73.

Romanova J, Katinger D, Ferko B, Vcelar B, Sereinig S, Kuznetsov O, Stukova M, Erofeeva M, Kiselev O, Katinger H, Egorov A. Live cold-adapted influenza A vaccine produced in Vero cell line. Virus Res. 2004 Jul;103(1-2):187-93.

Romanova J, Katinger D, Ferko B, Voglauer R, Mochalova L, Bovin N, Lim W, Katinger H, Egorov A. Distinct host range of influenza H3N2 virus isolates in Vero and MDCK cells is determined by cell specific glycosylation pattern.Virology. 2003 Mar 1;307(1):90-7.

Ferko B, Stasakova J, Sereinig S, Romanova J, Katinger D, Niebler B,Katinger H, Egorov A. Hyperattenuated recombinant influenza A virus nonstructural-protein-encoding vectors induce human immunodeficiency virus type 1 Nef-specific systemic and mucosal immune responses in mice.

J Virol. 2001 Oct;75(19):8899-908.

Shaw MW, Kiseleva IV, Egorov AY, Hemphill ML, Xu X. Generation of influenza transfectants using purified recombinant nucleocapsid protein. J Virol Methods. 1998 Dec;76(1-2):149-51.

Garcia-Sastre A, Egorov A, Matassov D, Brandt S, Levy DE, Durbin JE, Palese P, Muster T. Influenza A virus lacking the NS1 gene replicates in interferon-deficient systems. Virology. 1998 Dec 20;252(2):324-30.

Ferko B, Katinger D, Grassauer A, Egorov A, Romanova J, Niebler B, Katinger H, Muster T. Chimeric influenza virus replicating predominantly in the murine upper respiratory tract induces local immune responses against human immunodeficiency virus type 1 in the genital tract. J Infect Dis. 1998 Nov;178(5):1359-68.

Egorov A, Brandt S, Sereinig S, Romanova J, Ferko B, Katinger D, Grassauer A, Alexandrova G, Katinger H, Muster T. Transfectant influenza A viruses with long deletions in the NS1 protein grow efficiently in Vero cells. J Virol. 1998 Aug;72(8):6437-41.

Grassauer A, Egorov AY, Ferko B, Romanova I, Katinger H, Muster T.  A host restriction-based selection system for influenza haemagglutinin transfectant viruses. J Gen Virol. 1998 Jun;79 ( Pt 6):1405-9.

Klimov AI, Egorov AY, Gushchina MI, Medvedeva TE, Gamble WC, Rudenko LG, Alexandrova GI, Cox NJ. Genetic stability of cold-adapted A/Leningrad/134/47/57 (H2N2) influenza virus:sequence analysis of live cold-adapted reassortant vaccine strains before and after replication in children. J Gen Virol. 1995 Jun;76 ( Pt 6):1521-5.