Jennifer E Schuster1, Reagan G Cox2, Andrew K Hastings2, Kelli L Boyd2, Jay Wadia3, Zhifeng Chen4, Dennis R Burton4, R Anthony Williamson5, John V Williams6. 1. Department of Pediatrics. 2. Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee. 3. Crucell Vaccine Institute, San Diego. 4. Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California. 5. Crucell Vaccine Institute, London, United Kingdom. 6. Department of Pediatrics Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee.
Abstract
BACKGROUND: Human metapneumovirus (HMPV) is a leading cause of acute respiratory tract infection, with significant morbidity and mortality. No licensed vaccines or therapeutic agents exist. Monoclonal antibodies (mAbs) are effective at preventing other infectious diseases and could be used against HMPV in high-risk hosts. METHODS: In vitro assays were performed to assess the neutralizing activity and affinity kinetics of human mAb 54G10. A new mouse model was developed to assess prophylactic and therapeutic efficacy in vivo. The epitope of 54G10 was identified by generating mAb-resistant mutants (MARMs). RESULTS: At low concentrations, 54G10 neutralized all 4 subgroups of HMPV in vitro and had subnanomolar affinity for the fusion protein. DBA/2 mice were permissive for all 4 HMPV subgroups, and 54G10 was effective both prophylactically and therapeutically against HMPV in vivo. Sequencing of HMPV MARMs identified the 54G10 epitope, which was similar to an antigenic site on respiratory syncytial virus (RSV). 54G10 also exhibited in vitro neutralizing activity and in vivo protective and therapeutic efficacy against RSV. CONCLUSIONS: Human mAb 54G10 has broad neutralizing activity against HMPV and could have prophylactic and therapeutic utility clinically. The conserved epitope could represent a structural vaccine target for HMPV and RSV.
BACKGROUND:Human metapneumovirus (HMPV) is a leading cause of acute respiratory tract infection, with significant morbidity and mortality. No licensed vaccines or therapeutic agents exist. Monoclonal antibodies (mAbs) are effective at preventing other infectious diseases and could be used against HMPV in high-risk hosts. METHODS: In vitro assays were performed to assess the neutralizing activity and affinity kinetics of human mAb 54G10. A new mouse model was developed to assess prophylactic and therapeutic efficacy in vivo. The epitope of 54G10 was identified by generating mAb-resistant mutants (MARMs). RESULTS: At low concentrations, 54G10 neutralized all 4 subgroups of HMPV in vitro and had subnanomolar affinity for the fusion protein. DBA/2 mice were permissive for all 4 HMPV subgroups, and 54G10 was effective both prophylactically and therapeutically against HMPV in vivo. Sequencing of HMPV MARMs identified the 54G10 epitope, which was similar to an antigenic site on respiratory syncytial virus (RSV). 54G10 also exhibited in vitro neutralizing activity and in vivo protective and therapeutic efficacy against RSV. CONCLUSIONS:Human mAb 54G10 has broad neutralizing activity against HMPV and could have prophylactic and therapeutic utility clinically. The conserved epitope could represent a structural vaccine target for HMPV and RSV.
Authors: Nancy D Ulbrandt; Hong Ji; Nita K Patel; Jeffrey M Riggs; Yambasu A Brewah; Shannon Ready; Nanci E Donacki; Karyn Folliot; Arnita S Barnes; Kannaki Senthil; Susan Wilson; Mingzhong Chen; Lori Clarke; Mia MacPhail; Jia Li; Robert M Woods; Kathy Coelingh; Jennifer L Reed; Michael P McCarthy; David S Pfarr; Albert D M E Osterhaus; Ron A M Fouchier; Peter A Kiener; JoAnn A Suzich Journal: J Virol Date: 2006-08 Impact factor: 5.103
Authors: R Maini; E W St Clair; F Breedveld; D Furst; J Kalden; M Weisman; J Smolen; P Emery; G Harriman; M Feldmann; P Lipsky Journal: Lancet Date: 1999-12-04 Impact factor: 79.321
Authors: John V Williams; Chiaoyin K Wang; Chin-Fen Yang; Sharon J Tollefson; Frances S House; Josh M Heck; Marla Chu; Jennifer B Brown; Linda D Lintao; Joe D Quinto; David Chu; Richard R Spaete; Kathryn M Edwards; Peter F Wright; James E Crowe Journal: J Infect Dis Date: 2005-12-30 Impact factor: 5.226
Authors: Kathryn M Edwards; Yuwei Zhu; Marie R Griffin; Geoffrey A Weinberg; Caroline B Hall; Peter G Szilagyi; Mary A Staat; Marika Iwane; Mila M Prill; John V Williams Journal: N Engl J Med Date: 2013-02-14 Impact factor: 91.245
Authors: Teresa C T Peret; Guy Boivin; Yan Li; Michel Couillard; Charles Humphrey; Albert D M E Osterhaus; Dean D Erdman; Larry J Anderson Journal: J Infect Dis Date: 2002-05-03 Impact factor: 5.226
Authors: B G van den Hoogen; J C de Jong; J Groen; T Kuiken; R de Groot; R A Fouchier; A D Osterhaus Journal: Nat Med Date: 2001-06 Impact factor: 53.440
Authors: Yange Zhang; Senthilkumar K Sakthivel; Anna Bramley; Seema Jain; Amber Haynes; James D Chappell; Weston Hymas; Noel Lenny; Anami Patel; Chao Qi; Krow Ampofo; Sandra R Arnold; Wesley H Self; Derek J Williams; David Hillyard; Evan J Anderson; Carlos G Grijalva; Yuwei Zhu; Richard G Wunderink; Kathryn M Edwards; Andrew T Pavia; Jonathan A McCullers; Dean D Erdman Journal: J Clin Microbiol Date: 2016-12-28 Impact factor: 5.948
Authors: John T Bates; Jennifer A Pickens; Jennifer E Schuster; Monika Johnson; Sharon J Tollefson; John V Williams; Nancy L Davis; Robert E Johnston; Nancy Schultz-Darken; James C Slaughter; Frances Smith-House; James E Crowe Journal: Vaccine Date: 2016-01-07 Impact factor: 3.641