title: New vaccine design based on defective genomes that combines features of attenuated and inactivated vaccines.
abstract: BACKGROUND
  New vaccine designs are needed to control diseases associated with antigenically variable RNA viruses. Foot-and-mouth disease (FMD) is a highly contagious disease of livestock that inflicts severe economic losses. Although the current whole-virus chemically inactivated vaccine has proven effective, it has led to new outbreaks of FMD because of incomplete inactivation of the virus or the escape of infectious virus from vaccine production premises. We have previously shown that serial passages of FMD virus (FMDV) C-S8c1 at high multiplicity of infection in cell culture resulted in virus populations consisting of defective genomes that are infectious by complementation (termed C-S8p260).
  
  
  RESULTS
  Here we evaluate the immunogenicity of C-S8p260, first in a mouse model system to establish a proof of principle, and second, in swine, the natural host of FMDV C-S8c1. Mice were completely protected against a lethal challenge with FMDV C-S8c1, after vaccination with a single dose of C-S8p260. Pigs immunized with different C-S8p260 doses and challenged with FMDV C-S8c1 either did not develop any clinical signs or showed delayed and mild disease symptoms. C-S8p260 induced high titers of both FMDV-specific, neutralizing antibodies and activated FMDV-specific T cells in swine, that correlated with solid protection against FMDV.
  
  
  CONCLUSIONS
  The defective virus-based vaccine did not produce detectable levels of transmissible FMDV. Therefore, a segmented, replication-competent form of a virus, such as FMDV C-S8p260, can provide the basis of a new generation of attenuated antiviral vaccines with two safety barriers. The design can be extended to any viral pathogen that encodes trans-acting gene products, allowing complementation between replication-competent, defective forms.
authors.affiliation: Centro de Investigación en Sanidad Animal, Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria, Madrid, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Rodríguez-Calvo
authors.forename: Samuel
authors.initials: S
authors.lastname: Ojosnegros
authors.forename: Marta
authors.initials: M
authors.lastname: Sanz-Ramos
authors.forename: Juan
authors.initials: J
authors.lastname: García-Arriaza
authors.forename: Cristina
authors.initials: C
authors.lastname: Escarmís
authors.forename: Esteban
authors.initials: E
authors.lastname: Domingo
authors.forename: Noemí
authors.initials: N
authors.lastname: Sevilla
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing; D005536:Foot-and-Mouth Disease / Q000628:therapy*; D029544:Foot-and-Mouth Disease Virus; D016679:Genome, Viral; D051379:Mice; D012692:Serial Passage; D013552:Swine; D013601:T-Lymphocytes / Q000276:immunology; D016896:Treatment Outcome; D014613:Vaccines, Attenuated; D015164:Vaccines, Inactivated; D014765:Viral Vaccines
chemical_list: D057134:Antibodies, Neutralizing; D014613:Vaccines, Attenuated; D015164:Vaccines, Inactivated; D014765:Viral Vaccines
references.citation: J Virol. 1997 Apr;71(4):2606-14
references.pmid: 9060612
references.citation: Vaccine. 1998 Oct;16(16):1516-22
references.pmid: 9711798
references.citation: J Virol. 2003 Jan;77(2):1621-5
references.pmid: 12502879
references.citation: J Virol. 2004 Apr;78(7):3319-24
references.pmid: 15016853
references.citation: J Virol. 2005 Oct;79(20):12623-34
references.pmid: 16188964
references.citation: Vaccine. 2007 Jan 22;25(6):1043-54
references.pmid: 17157418
references.citation: Virology. 1983 Jul 30;128(2):310-8
references.pmid: 6310859
references.citation: J Virol. 1993 Dec;67(12):6917-21
references.pmid: 8230412
references.citation: Virus Res. 2003 Jan;91(1):47-63
references.pmid: 12527437
references.citation: Vaccine. 1990 Aug;8(4):299-303
references.pmid: 2204242
references.citation: Am J Vet Res. 1968 Mar;29(3):693-701
references.pmid: 4295430
references.citation: Arch Virol. 1975;47(1):47-56
references.pmid: 167679
references.citation: J Virol. 2000 Sep;74(18):8316-23
references.pmid: 10954530
references.citation: J Virol. 2004 Nov;78(21):11678-85
references.pmid: 15479809
references.citation: J Gen Virol. 2000 Jul;81(Pt 7):1699-702
references.pmid: 10859374
references.citation: Virology. 2005 May 10;335(2):155-64
references.pmid: 15840515
references.citation: Vaccine. 1991 May;9(5):319-25
references.pmid: 1872015
references.citation: Virology. 1988 Nov;167(1):113-24
references.pmid: 2460992
references.citation: Virus Res. 2003 Jan;91(1):81-99
references.pmid: 12527439
references.citation: Nature. 1981 Feb 12;289(5798):555-9
references.pmid: 6258084
references.citation: Curr Top Microbiol Immunol. 2009;329:129-62
references.pmid: 19198565
references.citation: Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3473-8
references.pmid: 19208813
references.citation: Proc Natl Acad Sci U S A. 1989 Aug;86(15):5883-7
references.pmid: 2474821
references.citation: Dev Biol (Basel). 2004;119:449-55
references.pmid: 15742659
references.citation: J Virol. 1987 May;61(5):1621-9
references.pmid: 3033288
references.citation: J Virol. 2007 Oct;81(19):10597-605
references.pmid: 17634218
references.citation: Rev Sci Tech. 2002 Dec;21(3):675-87
references.pmid: 12523706
references.citation: Virus Res. 1990 Dec;18(1):3-7
references.pmid: 1964520
references.citation: Rev Sci Tech. 2002 Dec;21(3):711-21
references.pmid: 12523709
references.citation: Virology. 1997 Jan 6;227(1):96-102
references.pmid: 9007062
references.citation: J Immunol. 1991 Jan 15;146(2):749-55
references.pmid: 1702816
references.citation: Adv Virus Res. 1999;53:111-26
references.pmid: 10582097
references.citation: Vet J. 2005 Mar;169(2):197-209
references.pmid: 15727911
references.citation: Virus Res. 1987 Sep;8(3):261-74
references.pmid: 2446442
references.citation: J Virol. 2003 Jan;77(2):1219-26
references.pmid: 12502839
references.citation: J Virol. 2008 Nov;82(21):10465-76
references.pmid: 18715925
references.citation: J Virol. 1992 Apr;66(4):1835-40
references.pmid: 1312607
references.citation: Br Vet J. 1993 May-Jun;149(3):207-23
references.pmid: 8392891
references.citation: Nature. 1985 Apr 11-17;314(6011):548-50
references.pmid: 2986004
references.citation: Virus Res. 2003 Jan;91(1):9-32
references.pmid: 12527435
references.citation: Virology. 2005 Feb 5;332(1):384-96
references.pmid: 15661169
references.citation: Nat Rev Microbiol. 2004 Jun;2(6):473-82
references.pmid: 15152203
references.citation: Science. 1981 Dec 4;214(4525):1125-9
references.pmid: 6272395
references.citation: Curr Top Microbiol Immunol. 2006;299:51-82
references.pmid: 16568896
references.citation: J Mol Biol. 2006 Jul 14;360(3):558-72
references.pmid: 16797586
references.citation: J Hyg (Lond). 1983 Oct;91(2):329-34
references.pmid: 6315814
references.citation: Epidemiol Infect. 1996 Oct;117(2):349-60
references.pmid: 8870633
references.citation: Vaccine. 2007 Apr 20;25(16):2974-83
references.pmid: 17303293
references.citation: Vaccine. 2003 Dec 12;22(2):268-79
references.pmid: 14615155
references.citation: Virus Res. 1998 Aug;56(2):125-33
references.pmid: 9783461
references.citation: Annu Rev Microbiol. 1997;51:151-78
references.pmid: 9343347
references.citation: Vaccine. 2009 May 26;27(25-26):3299-305
references.pmid: 19200842