V-4212. Genotypic and Phenotypic Analysis of Respiratory Syncytial Virus Isolated from Immunoprophylaxis Failure Subjects
Session: Slide Session: Respiratory Viruses and Hepatitis
Tuesday, October 28, 2008: 12:00 AM
Room: Room 145A
Background: Motavizumab (MZ) is an affinity-optimized anti-respiratory syncytial virus (RSV) monoclonal antibody (mAb) derived from palivizumab (Synagis®) (PZ). In vitro selection of mAb resistant mutants (MARMs) to PZ and MZ demonstrated amino acid (A.A.) changes at position 272 in the antigenic A site of RSV F protein where both MZ and PZ bind. PZ MARMs (K272M/Q/T/N) were only resistant to PZ, while the MZ MARM (K272E) was resistant to both antibodies. This study investigates whether these mutations appeared in 158 RSV-positive patients in a phase 3, randomized, double-blind, PZ-controlled study of MZ (MI-CP110). Methods: Genotypic analysis was carried out by sequencing the RSV F gene amplified directly from nasal specimen of RSV-positive subjects. The phenotype of the mutants was examined by performing microneutralization assays using recombinant RSV containing the identified mutations. Results: 5 RSV isolates contained an A.A. change at position 275 (S275L or S275F) and 3 isolates at position 272 (K272E or K272Q). The mutation K272Q was only identified in RSV from a PZ recipient, while the other three mutations were found in both treatment groups. The calculated A site mutation frequencies for RSV-positive MZ (4.7%) and PZ recipients (5.2%) were approximately equal. Phenotypic analysis indicated that S275L, S275F and K272Q mutations were associated with resistance to PZ but not to MZ, whereas the K272E mutation resulted in resistance to both mAbs. Conclusions: There were a small number of RSV-positive patients from the MZ (80 out of 3270) and PZ (100 out of 3246) treatment groups in MI-CP110. Among these RSV positive patients there was a low and comparable frequency of A site mutations (~5%) in F protein recovered from each treatment group. The clinical characteristics of the RSV events were consistent with the clinical presentation and time course expected for RSV.
B Liang1, C Yang1, G Losonsky1, J Suzich1, J McAuliffe1, N Patel, BS2, P.A. Kiener1, Qing Zhu3 and  Q. Zhu, None., (1)MedImmune inc., (2)Albany College of Pharmacy, Albany, NY, (3)MedImmune inc., Gaithersburg, MD

Dr. Thomas Lodise is an assistant professor at Albany College of Pharmacy, Albany, New York. Dr. Lodise, a 1999 Summa Cum Laude Doctor of Pharmacy graduate of Temple University School of Pharmacy, joined the faculty at Albany College of Pharmacy in August 2002. Prior to Albany College of Pharmacy, he completed the APhA-ASHP accredited Pharmacy Practice Residency at Thomas Jefferson University Hospital, Philadelphia, Pennsylvania in 2000 and the Infectious Diseases Pharmacotherapy and Outcomes Fellowship at Wayne State University, Detroit, Michigan in 2002.
Through advanced coursework and practical experiences, his post-doctoral training has provided extensive training in infectious diseases epidemiologic and outcomes research. His current research endeavors focus on the epidemiology of bacterial infections and the relationship between antimicrobial exposure and patient outcomes. Specifically, he is interested in identifying addressable process of care variables that are associated with improved patient outcomes and in optimizing outcomes of infections by the use of pharmacokinetic (PK) and pharmacodynamic (PD) principles. Dr. Lodise is implementing epidemiologic and outcomes research proposals at both the Albany Medical Center and Stratton VA Medical Center. He has received funding from both pharmaceutical industry and competitive grant sources for several of his proposals. The results have been presented at major national and international conferences and have been published in several peer-reviewed journals. His clinical practice site is the Stratton VA Medical Center, where he coordinates the antibiotic monitoring service. He is also enrolled in the Ph.D. program in Epidemiology at the State University of New York School of Public Health, Albany, New York.
On a national level, Dr. Lodise is a member of the Society of Infectious Diseases Pharmacists (SIDP), the American Association of Colleges of Pharmacy (AACP) and American College of Clinical Pharmacist (ACCP). On the state level, he actively participates in the New York ACCP chapter and is the chair of the program committee for the Northeastern Chapter of the New York State Council of Health-Systems Pharmacists (NYSCHP). He also serves as a reviewer for Pharmacotherapy.