1923. Development of a Live Attenuated Vaccine for Respiratory Syncytial Virus Using Codon Deoptimization of Virulence Genes and a Subgroup B Fusion Protein
Session: Poster Abstract Session: Vaccines: RSV
Saturday, October 10, 2015
Room: Poster Hall
  • 09_25_15 IDSA_Rostad_final.pdf (937.8 kB)
  • Background: RSV is the leading cause of lower respiratory tract infection in infants.  Therapeutic options for RSV are lacking, and a safe, effective vaccine is needed.  Codon deoptimization of RSV virulence genes is a strategy to attenuate a live attenuated vaccine (LAV) in a genetically stable way while maintaining immunogenicity and efficacy.  The objectives of this project were to design and rescue an appropriately attenuated, immunogenic RSV LAV and to perform preclinical evaluation in vitro and in vivo in BALB/c mice and cotton rats.

    Methods: The LAV “DB1” was generated from recombinant A2 strain RSV by deleting the small hydrophobic (SH) protein gene; recoding the genes for non-structural proteins NS1 and NS2 with the least used codons by humans; and replacing the A2 fusion (F) gene with an RSV subgroup B F gene consensus sequence of the Buenos Aires clade.  Viral growth kinetics were measured in Vero cells, BEAS-2B cells, and in BALB/c mice.  Immunogenicity was determined by measuring serum neutralizing antibody titers in BALB/c mice and cotton rats.  Efficacy was determined by lung viral loads in mice and cotton rats on day 4 post-RSV challenge.

    Results: DB1 was attenuated in BEAS-2B cells and BALB/c mice compared to A2-line19F. In Vero cells, a cell line approved for vaccine production, DB1 growth was equivalent to A2-line19F.  In BALB/c mice, DB1 generated broad neutralizing antibody responses against a panel of RSV A and B viruses and completely protected against RSV challenge.  In cotton rats, DB1 generated similar neutralizing antibody responses to RSV/A/Tracy and RSV/B/18537 that were sustained at 6 weeks post-vaccination.  When vaccinated cotton rats were challenged with RSV, DB1 reduced lung and nasal wash titers by 2.68 log10 PFU/g tissue and 3.76 log10 total PFU respectively compared to untreated controls (P<0.00001; Student’s t-test, two-tailed).   

    Conclusion: DB1 is a highly attenuated RSV LAV candidate which generates broad neutralizing antibody responses against RSV A and B and protects against RSV challenge in mice and cotton rats.

    Christina Rostad, MD1,2, Christopher Stobart, PhD1,2, Anne Hotard, PhD1,2, Jia Meng, PhD1,2, Brian Gilbert, PhD3, Pedro Piedra, MD, FIDSA3 and Martin Moore, PhD1, (1)Pediatrics, Emory University School of Medicine, Atlanta, GA, (2)Children's Healthcare of Atlanta, Atlanta, GA, (3)Baylor College of Medicine, Houston, TX


    C. Rostad, None

    C. Stobart, None

    A. Hotard, None

    J. Meng, None

    B. Gilbert, None

    P. Piedra, None

    M. Moore, Meissa Vaccines, Inc.: Board Member , Employee , Scientific Advisor and Shareholder , stock

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