title: A pandemic influenza H1N1 live vaccine based on modified vaccinia Ankara is highly immunogenic and protects mice in active and passive immunizations.
abstract: BACKGROUND
  The development of novel influenza vaccines inducing a broad immune response is an important objective. The aim of this study was to evaluate live vaccines which induce both strong humoral and cell-mediated immune responses against the novel human pandemic H1N1 influenza virus, and to show protection in a lethal animal challenge model.
  
  
  RESULTS
  For this purpose, the hemagglutinin (HA) and neuraminidase (NA) genes of the influenza A/California/07/2009 (H1N1) strain (CA/07) were inserted into the replication-deficient modified vaccinia Ankara (MVA) virus--a safe poxviral live vector--resulting in MVA-H1-Ca and MVA-N1-Ca vectors. These live vaccines, together with an inactivated whole virus vaccine, were assessed in a lung infection model using immune competent Balb/c mice, and in a lethal challenge model using severe combined immunodeficient (SCID) mice after passive serum transfer from immunized mice. Balb/c mice vaccinated with the MVA-H1-Ca virus or the inactivated vaccine were fully protected from lung infection after challenge with the influenza H1N1 wild-type strain, while the neuraminidase virus MVA-N1-Ca induced only partial protection. The live vaccines were already protective after a single dose and induced substantial amounts of neutralizing antibodies and of interferon-gamma-secreting (IFN-gamma) CD4- and CD8 T-cells in lungs and spleens. In the lungs, a rapid increase of HA-specific CD4- and CD8 T cells was observed in vaccinated mice shortly after challenge with influenza swine flu virus, which probably contributes to the strong inhibition of pulmonary viral replication observed. In addition, passive transfer of antisera raised in MVA-H1-Ca vaccinated immune-competent mice protected SCID mice from lethal challenge with the CA/07 wild-type virus.
  
  
  CONCLUSIONS
  The non-replicating MVA-based H1N1 live vaccines induce a broad protective immune response and are promising vaccine candidates for pandemic influenza.
authors.affiliation: R&D Vaccines, Biomedical Research Center, Baxter BioScience, Orth/Donau, Austria.
authors.forename: Annett
authors.initials: A
authors.lastname: Hessel
authors.forename: Michael
authors.initials: M
authors.lastname: Schwendinger
authors.forename: Daniela
authors.initials: D
authors.lastname: Fritz
authors.forename: Sogue
authors.initials: S
authors.lastname: Coulibaly
authors.forename: Georg W
authors.initials: GW
authors.lastname: Holzer
authors.forename: Nicolas
authors.initials: N
authors.lastname: Sabarth
authors.forename: Otfried
authors.initials: O
authors.lastname: Kistner
authors.forename: Walter
authors.initials: W
authors.lastname: Wodal
authors.forename: Astrid
authors.initials: A
authors.lastname: Kerschbaum
authors.forename: Helga
authors.initials: H
authors.lastname: Savidis-Dacho
authors.forename: Brian A
authors.initials: BA
authors.lastname: Crowe
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Kreil
authors.forename: P Noel
authors.initials: PN
authors.lastname: Barrett
authors.forename: Falko G
authors.initials: FG
authors.lastname: Falkner
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D000918:Antibody Specificity / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D003429:Cross Reactions / Q000276:immunology; D004196:Disease Outbreaks; D005260:Female; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000276:immunology; D006801:Humans; D007116:Immunization, Passive / Q000379:methods*; D007121:Immunocompetence / Q000276:immunology; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D007252:Influenza Vaccines / Q000276:immunology*; D007251:Influenza, Human / Q000453:epidemiology* / Q000517:prevention & control*; D008168:Lung / Q000276:immunology; D051379:Mice; D009439:Neuraminidase / Q000276:immunology; D013154:Spleen / Q000276:immunology; D014611:Vaccination / Q000379:methods*; D014613:Vaccines, Attenuated / Q000276:immunology
chemical_list: C543345:H1N1 virus hemagglutinin; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007252:Influenza Vaccines; D014613:Vaccines, Attenuated; D009439:Neuraminidase
references.citation: J Virol. 2009 May;83(10):5192-203
references.pmid: 19279103
references.citation: Virology. 1998 Sep 1;248(2):295-304
references.pmid: 9721238
references.citation: PLoS One. 2009 Nov 12;4(11):e7790
references.pmid: 19915662
references.citation: J Virol. 1968 Apr;2(4):281-8
references.pmid: 4911843
references.citation: Curr Top Microbiol Immunol. 2009;333:3-24
references.pmid: 19768398
references.citation: J Immunol. 2005 May 1;174(9):5332-40
references.pmid: 15843530
references.citation: Virology. 1993 Oct;196(2):660-5
references.pmid: 8372439
references.citation: J Infect Dis. 2009 Feb 1;199(3):405-13
references.pmid: 19061423
references.citation: Arch Virol. 1998;143(3):467-74
references.pmid: 9572548
references.citation: Proc Natl Acad Sci U S A. 2000 Apr 11;97(8):4309-14
references.pmid: 10725408
references.citation: Vaccine. 2009 Oct 23;27(45):6296-9
references.pmid: 19840663
references.citation: J Immunol. 1999 Nov 15;163(10):5535-43
references.pmid: 10553081
references.citation: J Virol. 2000 Aug;74(16):7651-5
references.pmid: 10906221
references.citation: Virology. 1998 Sep 15;249(1):160-6
references.pmid: 9740787
references.citation: Vaccine. 2009 Aug 6;27(36):4953-60
references.pmid: 19540952
references.citation: J Virol. 2002 May;76(10):4886-90
references.pmid: 11967305
references.citation: Scand J Immunol. 1978;8(5):413-20
references.pmid: 82995
references.citation: Virology. 2009 Dec 20;395(2):280-8
references.pmid: 19833372
references.citation: Vaccine. 2007 Aug 10;25(32):6028-36
references.pmid: 17614165
references.citation: Immunol Rev. 2006 Jun;211:8-22
references.pmid: 16824113
references.citation: Proc Natl Acad Sci U S A. 1987 Sep;84(18):6417-21
references.pmid: 3476956
references.citation: J Gen Virol. 1991 May;72 ( Pt 5):1031-8
references.pmid: 2033387
references.citation: J Immunol. 2009 Oct 1;183(7):4177-81
references.pmid: 19767567
references.citation: PLoS One. 2010 Feb 23;5(2):e9349
references.pmid: 20186321
references.citation: Vaccine. 1996 Oct;14(15):1451-8
references.pmid: 8994321
references.citation: Rev Med Virol. 1999 Oct-Dec;9(4):237-44
references.pmid: 10578119
references.citation: Virology. 1998 May 10;244(2):365-96
references.pmid: 9601507
references.citation: J Immunol. 1998 Jan 1;160(1):322-7
references.pmid: 9551987
references.citation: Science. 2009 Jul 24;325(5939):484-7
references.pmid: 19574347
references.citation: Infect Immun. 1984 Jun;44(3):734-9
references.pmid: 6724695
references.citation: J Immunol. 1992 Jan 1;148(1):212-7
references.pmid: 1530795
references.citation: Influenza Other Respir Viruses. 2009 Sep;3(5):233-40
references.pmid: 21462400
references.citation: J Infect Dis. 2007 Jun 1;195(11):1598-606
references.pmid: 17471429
references.citation: Nat Rev Microbiol. 2004 Oct;2(10):842-7
references.pmid: 15378048
references.citation: Arch Virol Suppl. 1999;15:131-8
references.pmid: 10470274
references.citation: Virology. 1994 Feb 15;199(1):89-97
references.pmid: 8116258
references.citation: J Immunol. 2009 Mar 1;182(5):3063-71
references.pmid: 19234203
references.citation: J Virol. 2002 Aug;76(15):7713-23
references.pmid: 12097585