871. Staphylococcus aureus Alpha Toxin Expression is Highly Conserved in MSSA and MRSA Hospital Respiratory Isolates Collected from an International Surveillance Study
Session: Poster Abstract Session: Bacterial Infections: Pathogenesis and Immunity
Friday, October 9, 2015
Room: Poster Hall
Posters
  • TaborDT ASPIRE SA-AT Poster IDWeek2015 TO PRINT.pdf (802.0 kB)
  • Background:

    Staphylococcus aureus is a leading cause of morbidity and mortality worldwide, resulting in a diverse array of infections ranging from mild skin and soft-tissue infections to serious invasive diseases such endocarditis, osteomyelitis, and pneumonia.  Alpha toxin (AT) is a 33 kDa cytolytic, pore-forming toxin encoded by the hla gene that is thought to play a key role in S. aureus pathogenesis. We are currently testing a monoclonal antibody, MEDI4893, against alpha toxin in a phase 2 clinical trial for the prevention of ventilator-associated S. aureuspneumonia. 

    Methods:

    To better understand the prevalence of alpha toxin gene conservation and protein expression in S. aureus clinical respiratory isolates, we characterized the sequence of hla, in vitro AT protein expression levels and susceptibility to MEDI4893 in MSSA and MRSA isolates from diverse patient populations and geographical locations collected from 136 hospitals in 33 countries in 2012/2013 as part of an international surveillance program.  In addition, whole genome sequencing (WGS) was performed on a randomly-selected subset of isolates (96) in order to perform MLST and toxome content analysis.  

    Results:

    Results showed that the hla gene was highly conserved in >99% of the isolates and AT expression in vitro was detected in 82.6% of isolates regardless of geographic region, sample type, age of the subject or hospital locale.  Interestingly, more methicillin sensitive than methicillin resistant isolates expressed AT in vitro (87% vs. 79%, P<0.0001). Mutations in the hla gene revealed over 50 hlagenotypes that were mapped to the heptameric structure of AT in relation to the MEDI4893 epitope.

    Conclusion:

    This study provides compelling data that AT is highly conserved in diverse S. aureus respiratory isolates from around the world and suggests that AT is a good target for prophylactic mAb and vaccine development.

    David E. Tabor, Ph.D.1, Li Yu, Ph.D.2, Hoyin Mok, Ph.D.1, Bret Sellman, Ph.D.2, Christine Tkaczyk, PhD2, Yuling Wu, Ph.D.2, Vaheh Oganesyan, MS2, Hasan Jafri, M.D.2, Michael Mccarthy, M.D.2, Timothy Slidel, Ph.D.3, Patricia Bradford, PhD4 and Mark T. Esser, Ph.D.2, (1)MedImmune LLC, Mountain View, CA, (2)MedImmune LLC, Gaithersburg, MD, (3)MedImmune LLC, Cambridge, United Kingdom, (4)AstraZeneca, Waltham, MA

    Disclosures:

    D. E. Tabor, MedImmune LLC: Employee and Shareholder , Salary

    L. Yu, MedImmune LLC: Employee and Shareholder , Salary

    H. Mok, MedImmune LLC: Employee and Shareholder , Salary

    B. Sellman, MedImmune LLC: Employee and Shareholder , Salary

    C. Tkaczyk, MedImmune LLC: Employee and Shareholder , Salary

    Y. Wu, MedImmune LLC: Employee and Shareholder , Salary

    V. Oganesyan, MedImmune LLC: Employee and Shareholder , Salary

    H. Jafri, MedImmune LLC: Employee and Shareholder , Salary

    M. Mccarthy, MedImmune LLC: Employee and Shareholder , Salary

    T. Slidel, MedImmune LLC: Employee and Shareholder , Salary

    P. Bradford, AstraZeneca: Employee and Shareholder , Salary

    M. T. Esser, MedImmune LLC: Employee and Shareholder , Salary

    Findings in the abstracts are embargoed until 12:01 a.m. PDT, Wednesday Oct. 7th with the exception of research findings presented at the IDWeek press conferences.