1252. Human Monoclonal Antibody 54G10 is Highly Effective against Human Metapneumovirus in Vivo in a New Mouse Model
Session: Oral Abstract Session: Laboratory and Clinical Virology
Saturday, October 5, 2013: 11:00 AM
Room: The Moscone Center: 300
Background: Human metapneumovirus (HMPV) is a recently discovered paramyxovirus. It is a leading cause of respiratory tract infection in children. Morbidity and mortality are highest in premature infants, the elderly, and immunocompromised patients. No antiviral therapy or vaccine exists for HMPV. We sought to evaluate the in vitro and in vivo efficacy of a human monoclonal antibody (mAb), 54G10, against HMPV. Human mAb 54G10 was generated from a human immunoglobulin B cell screened against the fusion (F) protein of HMPV. To assess in vivo efficacy of HMPV, we describe a new animal model, the DBA/2 mouse, which is permissive for all 4 subgroups of HMPV. 

Methods: We determined the in vitro neutralization activity of 54G10 against all subgroups of HMPV. To establish a permissive animal model, we ascertained the replication kinetics of HMPV and virus titer of the 4 subgroups in the DBA/2 mouse. Then, we infected six-week-old female DBA/2 mice intranasally with 10plaque-forming units (pfu) of HMPV strain TN/94-49 (A2 subgroup). Mice were intranasally inoculated with 54G10 at various concentrations. Mice were euthanized at the time of peak viral replication, and virus titer was determined from lung and nasal turbinates. To determine prophylactic efficacy, we intraperitoneally inoculated mice with 54G10, and 24 hours later, we intranasally challenged the mice with HMPV. Virus titer was determined as described.

Results: DBA/2 mice are permissive for all four subgroups of HMPV. Human mAb 54G10 neutralized all subgroups of HMPV in vitro at micromolar concentrations. In vivo, 54G10 reduced virus in the lungs of infected animals to undetectable levels in a dose-dependent manner. In the prophylactic model, mice treated with 54G10 had undetectable lung virus titer on the day of expected peak replication. 

Conclusion: The DBA/2 mouse is a permissive animal model for all four subgroups of HMPV. The human mAb 54G10 is effective against HMPV in a mouse model of acute lower respiratory disease when given therapeutically and prophylactically. Further investigation is warranted to identify the epitope of 54G10, which may identify potential vaccine targets for human metapneumovirus.

Jennifer Schuster, MD, Pediatric Infectious Diseases, Vanderbilt University Medical Center, Nashville, TN, Sharon Tollefson, BA, Vanderbilt University Medical Center, Nashville, TN, Kelli Boyd, DVM, PhD, Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, Dennis R. Burton, PhD, Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, R. Anthony Williamson, PhD, Crucell Vaccine Institute, London, United Kingdom and John Williams, MD, Pediatric Infectious Diseases, Vanderbilt University School of Medicine, Nashville, TN

Disclosures:

J. Schuster, None

S. Tollefson, None

K. Boyd, None

D. R. Burton, None

R. A. Williamson, None

J. Williams, Quidel: Scientific Advisor, Consulting fee

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