ArticlePLoS pathogens2023
Structure-based design of a single-chain triple-disulfide-stabilized fusion-glycoprotein trimer that elicits high-titer neutralizing responses against human metapneumovirus.
Article in PLoS pathogens, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 13 citations in OpenAlex.
- Stabilization of prefusion hMPV F improves manufacturability and protective immunity across hMPV lineages.Virologica Sinica · 2026Article
- Advances in Detection Methods for Human Respiratory Syncytial Virus Neutralizing Antibodies.Vaccines · 2026Review
- Mechanistic insights and emerging applications of human metapneumovirus (HMPV) treatment: From molecular design to translational immunity.Folia microbiologica · 2026Review
- A potently neutralizing and protective human antibody targeting antigenic site V on RSV and hMPV fusion glycoprotein.Cell reports. Medicine · 2026Article
- Development of a potent monoclonal antibody for treatment of human metapneumovirus infections.Nature communications · 2026Article
- Human metapneumovirus prevention in children: emerging roles of monoclonal antibodies and vaccines.Frontiers in immunology · 2026Review
- Intranasal bovine/human parainfluenza virus 3 vaccine candidates expressing human metapneumovirus wild-type or pre-fusion F protein elicit protective immunity against human metapneumovirus in hamsters.Journal of virology · 2025Article
- A second-generation molecular clamp stabilised bivalent candidate vaccine for protection against diseases caused by respiratory syncytial virus and human metapneumovirus.PLoS pathogens · 2025Article
- Article
- Rational design of uncleaved prefusion-closed trimer vaccines for human respiratory syncytial virus and metapneumovirus.Nature communications · 2024Article
- Efficacious human metapneumovirus vaccine based on AI-guided engineering of a closed prefusion trimer.Nature communications · 2024Article
- Engineered dityrosine-bonding of the RSV prefusion F protein imparts stability and potency advantages.Nature communications · 2024Article
- A tale of two fusion proteins: understanding the metastability of human respiratory syncytial virus and metapneumovirus and implications for rational design of uncleaved prefusion-closed trimers.bioRxiv : the preprint server for biology · 2024Article
- Structural characterization of M8C10, a neutralizing antibody targeting a highly conserved prefusion-specific epitope on the metapneumovirus fusion trimerization interface.Journal of virology · 2023Article
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Authors and funding
20 authors at 4 institutions in 1 country.
Funding
Abstract
The Pneumoviridae family of viruses includes human metapneumovirus (HMPV) and respiratory syncytial virus (RSV). The closely related Paramyxoviridae family includes parainfluenza viruses (PIVs). These three viral pathogens cause acute respiratory tract infections with substantial disease burden in the young, the elderly, and the immune-compromised. While promising subunit vaccines are being developed with prefusion-stabilized forms of the fusion glycoproteins (Fs) of RSV and PIVs, for which neutralizing titers elicited by the prefusion (pre-F) conformation of F are much higher than for the postfusion (post-F) conformation, with HMPV, pre-F and post-F immunogens described thus far elicit similar neutralizing responses, and it has been unclear which conformation, pre-F or post-F, would be the most effective HMPV F-vaccine immunogen. Here, we investigate the impact of further stabilizing HMPV F in the pre-F state. We replaced the furin-cleavage site with a flexible linker, creating a single chain F that yielded increased amounts of pre-F stabilized trimers, enabling the generation and assessment of F trimers stabilized by multiple disulfide bonds. Introduced prolines could increase both expression yields and antigenic recognition by the pre-F specific antibody, MPE8. The cryo-EM structure of a triple disulfide-stabilized pre-F trimer with the variable region of antibody MPE8 at 3.25-Å resolution confirmed the formation of designed disulfides and provided structural details on the MPE8 interface. Immunogenicity assessments in naïve mice showed the triple disulfide-stabilized pre-F trimer could elicit high titer neutralization, >10-fold higher than elicited by post-F. Immunogenicity assessments in pre-exposed rhesus macaques showed the triple disulfide-stabilized pre-F could recall high neutralizing titers after a single immunization, with little discrimination in the recall response between pre-F and post-F immunogens. However, the triple disulfide-stabilized pre-F adsorbed HMPV-directed responses from commercially available pooled human immunoglobulin more fully than post-F. Collectively, these results suggest single-chain triple disulfide-stabilized pre-F trimers to be promising HMPV-vaccine antigens.
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