{"doi":"10.1371/journal.pone.0301773","title":"Mutations in the F protein of the live-attenuated respiratory syncytial virus vaccine candidate ΔNS2/Δ1313/I1314L increase the stability of infectivity and content of prefusion F protein","abstract":"Respiratory syncytial virus (RSV) is the leading viral cause of bronchiolitis and pneumonia in infants and toddlers, but there currently is no licensed pediatric vaccine. A leading vaccine candidate that has been evaluated for intranasal immunization in a recently completed phase 1/2 clinical trial is an attenuated version of RSV strain A2 called RSV/ΔNS2/Δ1313/I1314L (hereafter called ΔNS2). ΔNS2 is attenuated by deletion of the interferon antagonist NS2 gene and introduction into the L polymerase protein gene of a codon deletion (Δ1313) that confers temperature-sensitivity and is stabilized by a missense mutation (I1314L). Previously, introduction of four amino acid changes derived from a second RSV strain \"line 19\" (I79M, K191R, T357K, N371Y) into the F protein of strain A2 increased the stability of infectivity and the proportion of F protein in the highly immunogenic pre-fusion (pre-F) conformation. In the present study, these four \"line 19\" assignments were introduced into the ΔNS2 candidate, creating ΔNS2-L19F-4M. During in vitro growth in Vero cells, ΔNS2-L19F-4M had growth kinetics and peak titer similar to the ΔNS2 parent. ΔNS2-L19F-4M exhibited an enhanced proportion of pre-F protein, with a ratio of pre-F/total F that was 4.5- to 5.0-fold higher than that of the ΔNS2 parent. The stability of infectivity during incubation at 4°C, 25°C, 32°C and 37°C was greater for ΔNS2-L19F-4M; for example, after 28 days at 32°C, its titer was 100-fold greater than ΔNS2. ΔNS2-L19F-4M exhibited similar levels of replication in human airway epithelial (HAE) cells as ΔNS2. The four \"line 19\" F mutations were genetically stable during 10 rounds of serial passage in Vero cells. In African green monkeys, ΔNS2-L19F-4M and ΔNS2 had similar growth kinetics, peak titer, and immunogenicity. These results suggest that ΔNS2-L19F-4M is an improved live attenuated vaccine candidate whose enhanced stability may simplify its manufacture, storage and distribution, which merits further evaluation in a clinical trial in humans.","journal":"PLoS ONE","year":2024,"id":440084,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":9,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9562,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1252113,"name":"Michael Kishko","orcid":null,"position":1,"is_corresponding":false},{"id":266751,"name":"Charles Pin‐Kuang Lai","orcid":"0000-0001-8050-7060","position":2,"is_corresponding":false},{"id":1252114,"name":"Mark Parrington","orcid":null,"position":3,"is_corresponding":false},{"id":744386,"name":"Simon Delagrave","orcid":"0000-0003-0865-2196","position":4,"is_corresponding":false},{"id":438477,"name":"Richard Herbert","orcid":null,"position":5,"is_corresponding":false},{"id":862698,"name":"Ashley Castens","orcid":null,"position":6,"is_corresponding":false},{"id":437336,"name":"Joanna Swerczek","orcid":"0000-0002-0575-0615","position":7,"is_corresponding":false},{"id":346916,"name":"Cindy Luongo","orcid":"0000-0002-3830-3803","position":8,"is_corresponding":false},{"id":346915,"name":"Lijuan Yang","orcid":"0000-0001-6388-6695","position":9,"is_corresponding":false},{"id":80811,"name":"Peter L. Collins","orcid":"0000-0001-7543-7299","position":10,"is_corresponding":false},{"id":235602,"name":"Ursula J. Buchholz","orcid":"0000-0002-2329-3198","position":11,"is_corresponding":false},{"id":1251711,"name":"Linong Zhang","orcid":"0000-0002-8863-8900","position":12,"is_corresponding":false},{"id":1252112,"name":"Judith Alamares-Sapuay","orcid":null,"position":0,"is_corresponding":true}],"reference_count":54,"raw_metadata":null,"created_at":"2026-07-19T02:00:57.233748Z","pmid":"38593167","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}