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We previously developed live-intranasal HRSV vaccine candidates attenuated by genetically stabilized temperature sensitivity\/attenuating (\n                      <jats:italic toggle=\"yes\">ts\/att<\/jats:italic>\n                      ) mutations in the HRSV polymerase (L) ORF, including sites \u201c\n                      <jats:italic toggle=\"yes\">1030s<\/jats:italic>\n                      \u201d (L codon changes S1313\n                      <jats:sub>(AGC-to-TCA)<\/jats:sub>\n                      \/Y1321K\n                      <jats:sub>(AAA)<\/jats:sub>\n                      , named after clone number 1030), and \u201c\u03941313\/I1314L,\u201d comprising a genetically stabilized deletion of L codon 1313. In pediatric vaccine studies, HRSV candidates with \u201c\n                      <jats:italic toggle=\"yes\">1030s<\/jats:italic>\n                      \u201d or \u03941313\/I1314L were attenuated, immunogenic, and genetically stable. Given the similarities between HRSV and HMPV, we introduced corresponding modifications into the HMPV L ORF, resulting in HMPV with deletion of codon 1238 (\u03941238), corresponding to HRSV \u03941313\/I1314L, and HMPV with C1238S\n                      <jats:sub>(TCA)<\/jats:sub>\n                      \/Y1246K\n                      <jats:sub>(AAA)<\/jats:sub>\n                      substitutions together (C1238S\/Y1246K, corresponding to HRSV \u201c\n                      <jats:italic toggle=\"yes\">1030s<\/jats:italic>\n                      \u201d), or individually (C1238S, Y1246K), serving as experimental controls. All versions replicated well in Vero cells at 32\u00b0C. At 37\u00b0C, replication of \u03941238, C1238S\/Y1246K, and Y1246K was delayed, and peak titers were ~80-fold, 200-fold, and 25-fold lower than wild-type HMPV. As predicted, the C1238S control was not temperature-sensitive (shutoff temperature [\n                      <jats:italic toggle=\"yes\">T<\/jats:italic>\n                      <jats:sub>SH<\/jats:sub>\n                      ] &gt; 40\u00b0C, similar to wild-type HMPV), while Y1246K and \u03941238 (\n                      <jats:italic toggle=\"yes\">T<\/jats:italic>\n                      <jats:sub>SH<\/jats:sub>\n                      = 39\u00b0C) and C1238S\/Y1246K (\n                      <jats:italic toggle=\"yes\">T<\/jats:italic>\n                      <jats:sub>SH<\/jats:sub>\n                      = 38\u00b0C) had a\n                      <jats:italic toggle=\"yes\">ts<\/jats:italic>\n                      phenotype. Thus, the addition of the C1238S\n                      <jats:sub>(TCA)<\/jats:sub>\n                      substitution increased the temperature sensitivity of Y1246K. The HMPV\n                      <jats:italic toggle=\"yes\">ts\/att<\/jats:italic>\n                      sites were genetically stable under temperature stress. In hamsters inoculated intranasally, C1238S\/Y1246K and \u03941238 were restricted in replication, yet immunogenic and protective against HMPV challenge. Thus, inclusion in the HMPV L ORF of C1238S\/Y1246K and \u03941238 mutations, corresponding to HRSV\n                      <jats:italic toggle=\"yes\">ts\/att<\/jats:italic>\n                      sites, provided genetically stable live-attenuated HMPV, suitable for clinical development.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>Human metapneumovirus (HMPV) is a leading cause of lower respiratory illness in young children, and there are no licensed vaccines. Similarly to immunization strategies against the related human respiratory syncytial virus (HRSV), live-attenuated HMPV vaccines for intranasal immunization would be most suitable for young children. Live-intranasal vaccines infect and induce immunity in the presence of residual maternal antibodies without priming for enhanced respiratory disease. Genetic stability of attenuating mutations represents a challenge in vaccine design. We generated live-attenuated HMPV vaccine candidates by introducing into corresponding sites of the HMPV polymerase gene temperature-sensitivity-inducing attenuating mutations that had been originally developed for HRSV, genetically stabilized, and proven to be free of reversions in HRSV vaccine studies. The resulting HMPV vaccine candidates are temperature-sensitive, attenuated, and genetically stable under temperature stress. In the hamster model, the new HMPV candidates were immunogenic and protective. These live-attenuated HMPV candidates will be advanced to pediatric vaccine studies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.00692-26","type":"journal-article","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T13:22:28Z","timestamp":1783344148000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["Live human metapneumovirus vaccine candidates attenuated by temperature sensitivity mutations from human respiratory syncytial virus"],"prefix":"10.1128","volume":"100","author":[{"given":"Pramila","family":"Lamichhane","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/043z4tv69","id-type":"ROR","asserted-by":"publisher"}],"name":"RNA Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health","place":["Bethesda, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijuan","family":"Yang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/043z4tv69","id-type":"ROR","asserted-by":"publisher"}],"name":"RNA Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health","place":["Bethesda, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celia","family":"Santos","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/043z4tv69","id-type":"ROR","asserted-by":"publisher"}],"name":"RNA Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health","place":["Bethesda, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong-Su","family":"Park","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/043z4tv69","id-type":"ROR","asserted-by":"publisher"}],"name":"RNA Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health","place":["Bethesda, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Ou","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/045p44t13","id-type":"ROR","asserted-by":"publisher"}],"name":"Vaccine Research Center, National Institutes of Health","place":["Bethesda, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3935-4637","authenticated-orcid":true,"given":"Tongqing","family":"Zhou","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/045p44t13","id-type":"ROR","asserted-by":"publisher"}],"name":"Vaccine Research Center, National Institutes of Health","place":["Bethesda, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5719-4112","authenticated-orcid":true,"given":"Cyril","family":"Le Nou\u00ebn","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/043z4tv69","id-type":"ROR","asserted-by":"publisher"}],"name":"RNA Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health","place":["Bethesda, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2329-3198","authenticated-orcid":true,"given":"Ursula J.","family":"Buchholz","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/043z4tv69","id-type":"ROR","asserted-by":"publisher"}],"name":"RNA Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health","place":["Bethesda, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/89098"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa025472"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S2214-109X(20)30393-4"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1405870"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.43.3.1213-1219.2005"},{"key":"e_1_3_5_7_2","volume-title":"Respiratory syncytial virus and metapneumovirus, fields virology: RNA viruses","author":"Buchholz UJ","year":"2023","unstructured":"Buchholz UJ, Anderson LJ, Collins PL, Mejias A. 2023. 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