Profiling of hMPV F-specific antibodies isolated from human memory B cells
Xiao Xiao1,2,3, Arthur Fridman4, Lu Zhang5
1Infectious Diseases and Vaccines Discovery, Merck & Co., Inc., West Point, PA, USA.
Abstract:
Human metapneumovirus (hMPV) belongs to the Pneumoviridae family and is closely related to respiratory syncytial virus (RSV). The surface fusion (F) glycoprotein mediates viral fusion and is the primary target of neutralizing antibodies against hMPV. Here we report 113 hMPV-F specific monoclonal antibodies (mAbs) isolated from memory B cells of human donors. We characterize the antibodies' germline usage, epitopes, neutralization potencies, and binding specificities. We find that unlike RSV-F specific mAbs, antibody responses to hMPV F are less dominant against the apex of the antigen, and the majority of the potent neutralizing mAbs recognize epitopes on the side of hMPV F. Furthermore, neutralizing epitopes that differ from previously defined antigenic sites on RSV F are identified, and multiple binding modes of site V and II mAbs are discovered. Interestingly, mAbs that bind preferentially to the unprocessed prefusion F show poor neutralization potency. These results elucidate the immune recognition of hMPV infection and provide novel insights for future hMPV antibody and vaccine development.
Insights
Researchers identified 113 human metapneumovirus (hMPV) fusion (F) glycoprotein specific monoclonal antibodies (mAbs). Most potent neutralizing antibodies target the side, not the apex, of hMPV F, offering new insights for hMPV therapies.
Area of Science:
- Virology
- Immunology
- Structural Biology
Background:
- Human metapneumovirus (hMPV) is a significant respiratory pathogen, closely related to respiratory syncytial virus (RSV).
- The hMPV fusion (F) glycoprotein is a key target for neutralizing antibodies due to its role in viral entry.
- Understanding antibody recognition of hMPV F is crucial for developing effective vaccines and therapeutics.
Purpose of the Study:
- To isolate and characterize a comprehensive panel of human monoclonal antibodies (mAbs) targeting the hMPV F glycoprotein.
- To delineate the epitopes and binding characteristics of these mAbs.
- To gain insights into the humoral immune response against hMPV for future therapeutic and vaccine strategies.
Main Methods:
- Isolation of 113 hMPV-F specific mAbs from memory B cells of human donors.
- Characterization of mAbs including germline gene usage, epitope mapping, neutralization potency assays, and binding specificity analysis.
- Structural and functional analysis of antibody-antigen interactions.
Main Results:
- The majority of potent neutralizing mAbs recognized epitopes on the lateral surface of the hMPV F glycoprotein, unlike RSV-F specific mAbs which often target the apex.
- Novel neutralizing epitopes distinct from those on RSV F were identified.
- Multiple binding modes for antibodies targeting specific sites (e.g., site V, site II) were observed.
- mAbs binding preferentially to the unprocessed prefusion F form exhibited lower neutralization potency.
Conclusions:
- The immune recognition of hMPV F differs significantly from RSV F, with a greater emphasis on lateral epitopes for potent neutralization.
- These findings provide a detailed map of hMPV antigenic sites and antibody binding modes.
- The study offers critical insights for the rational design of hMPV vaccines and antibody-based therapies.
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