{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T04:07:17Z","timestamp":1791518837803,"version":"4.3.4"},"reference-count":59,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T00:00:00Z","timestamp":1762387200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T00:00:00Z","timestamp":1762387200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000060","name":"U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["U01AI148081"],"award-info":[{"award-number":["U01AI148081"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI148369"],"award-info":[{"award-number":["R01AI148369"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["K08A170950"],"award-info":[{"award-number":["K08A170950"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012399","name":"U.S. Department of Health & Human Services | Biomedical Advanced Research and Development Authority","doi-asserted-by":"publisher","award":["HHSO100200600021C"],"award-info":[{"award-number":["HHSO100200600021C"]}],"id":[{"id":"10.13039\/100012399","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Mucosal IgG and IgA, and B-cell immune responses were performed under a contract between BlueWillow Biologics, Inc and the University of Maryland, Baltimore"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Mucosal influenza vaccines may provide improved protection against infection and transmission, but their development is hindered by absence of immune correlates of protection. Here, we report a randomized, controlled phase I trial of a recombinant influenza A\/H5 (A\/Indonesia\/05\/2005, clade 2.1) hemagglutinin vaccine formulated with a nanoemulsion adjuvant (W\n                    <jats:sub>80<\/jats:sub>\n                    5EC). The vaccine is administered intranasally in two doses 28 days apart at three antigen levels. Controls receive unadjuvanted H5 or placebo. Six months later, participants receive an intramuscular boost with unadjuvanted inactivated A\/H5N1 (A\/Vietnam\/1203\/2004, clade 1) vaccine. Primary outcomes are solicited and unsolicited adverse events (AEs), laboratory safety abnormalities, medically-attended AEs, potential immune-mediated conditions, new-onset chronic conditions, and serious AEs. All vaccines are well tolerated. After the intranasal series, hemagglutination inhibition and microneutralization responses are minimal. However, adjuvanted H5 recipients show significant increases in mucosal and serum IgG\/IgA, surface plasmon resonance antibody binding, memory B and CD4 T cell activity, and antibody-dependent cell-mediated cytotoxicity. Following H5N1 boost, participants mount robust responses across measurements and have microneutralization responses against diverse H5N1 clades (including circulating clade 2.3.4.4b). Findings demonstrate successful mucosal priming and broad cross-clade responses. This intranasal vaccine supports further exploration of mucosal immune biomarkers and may accelerate development of intranasal influenza vaccines.\n                    <jats:bold>ClinicalTrials.gov registration:<\/jats:bold>\n                    NCT05397119\n                  <\/jats:p>","DOI":"10.1038\/s41467-025-64686-3","type":"journal-article","created":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T10:14:51Z","timestamp":1762424091000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["An intranasal adjuvanted, recombinant influenza A\/H5 vaccine primes against diverse H5N1 clades: a phase I trial"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2574-0542","authenticated-orcid":false,"given":"Meagan E.","family":"Deming","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9439-0828","authenticated-orcid":false,"given":"Franklin R.","family":"Toapanta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcela","family":"Pasetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hana","family":"Golding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0593-7965","authenticated-orcid":false,"given":"Surender","family":"Khurana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tarek","family":"Hamouda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Fattom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon M.","family":"Tennant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan F.","family":"McGilvray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2421-302X","authenticated-orcid":false,"given":"Paula J.","family":"Bernal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6919-6780","authenticated-orcid":false,"given":"Jennifer J.","family":"Oshinsky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shrimati","family":"Datta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasnehta Permala","family":"Booth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9880-6560","authenticated-orcid":false,"given":"Lynda","family":"Coughlan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen M.","family":"Neuzil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chad D.","family":"Costley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1808-6431","authenticated-orcid":false,"given":"Karen L.","family":"Kotloff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcelo B.","family":"Sztein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3138-5965","authenticated-orcid":false,"given":"Justin R.","family":"Ortiz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"On behalf of the rH5 Writing Group","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hugo","family":"Acosta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vaidehi","family":"Agrawal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James D.","family":"Campbell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingping","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ifayet P. L.","family":"Johnson-Mayo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Insung","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa R.","family":"King","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jody","family":"Manischewitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashish K.","family":"Mishra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph N.","family":"Nkeze","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia","family":"Posadas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rekha R.","family":"Rapaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cosette G.","family":"Schneider","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas M.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,6]]},"reference":[{"key":"64686_CR1","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.02542-24","volume":"15","author":"A Mostafa","year":"2024","unstructured":"Mostafa, A. et al. Avian influenza A (H5N1) virus in dairy cattle: origin, evolution, and cross-species transmission. mBio 15, e0254224 (2024).","journal-title":"mBio"},{"key":"64686_CR2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciae491","author":"EB White","year":"2024","unstructured":"White, E. B. et al. Influenza vaccine effectiveness against illness and asymptomatic infection in 2022-2023: a prospective cohort study. Clin. Infect. Dis.https:\/\/doi.org\/10.1093\/cid\/ciae491 (2024).","journal-title":"Clin. Infect. Dis."},{"key":"64686_CR3","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1016\/j.immuni.2017.09.007","volume":"47","author":"CI Paules","year":"2017","unstructured":"Paules, C. I., Marston, H. D., Eisinger, R. W., Baltimore, D. & Fauci, A. S. The pathway to a universal influenza vaccine. Immunity 47, 599\u2013603 (2017).","journal-title":"Immunity"},{"key":"64686_CR4","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiy103","author":"EJ Erbelding","year":"2018","unstructured":"Erbelding, E. J. et al. A universal influenza vaccine: the strategic plan for the National Institute of Allergy and Infectious Diseases. J. Infect. Dis.https:\/\/doi.org\/10.1093\/infdis\/jiy103 (2018).","journal-title":"J. Infect. Dis."},{"key":"64686_CR5","doi-asserted-by":"publisher","first-page":"5734","DOI":"10.1016\/j.vaccine.2017.08.088","volume":"35","author":"KM Neuzil","year":"2017","unstructured":"Neuzil, K. M. et al. Data and product needs for influenza immunization programs in low- and middle-income countries: rationale and main conclusions of the WHO preferred product characteristics for next-generation influenza vaccines. Vaccine 35, 5734\u20135737 (2017).","journal-title":"Vaccine"},{"key":"64686_CR6","doi-asserted-by":"publisher","first-page":"1055","DOI":"10.1128\/CVI.00131-10","volume":"17","author":"SA Plotkin","year":"2010","unstructured":"Plotkin, S. A. Correlates of protection induced by vaccination. Clin. Vaccin. Immunol. 17, 1055\u20131065 (2010).","journal-title":"Clin. Vaccin. Immunol."},{"key":"64686_CR7","doi-asserted-by":"crossref","unstructured":"Plotkin, S. A. Recent updates on correlates of vaccine-induced protection. Front. Immunol. 13, 1081107 (2022).","DOI":"10.3389\/fimmu.2022.1081107"},{"key":"64686_CR8","unstructured":"U.S. Food and Drug Administration. Clinical Data Needed to Support the Licensure of Seasonal Inactivated Influenza Vaccines, https:\/\/www.fda.gov\/media\/73706\/download (2007)."},{"key":"64686_CR9","doi-asserted-by":"publisher","first-page":"e25","DOI":"10.1016\/S1473-3099(17)30360-2","volume":"18","author":"A Singanayagam","year":"2018","unstructured":"Singanayagam, A., Zambon, M., Lalvani, A. & Barclay, W. Urgent challenges in implementing live attenuated influenza vaccine. Lancet Infect. Dis. 18, e25\u2013e32 (2018).","journal-title":"Lancet Infect. Dis."},{"key":"64686_CR10","doi-asserted-by":"publisher","first-page":"1","DOI":"10.15585\/mmwr.rr7305a1","volume":"73","author":"LA Grohskopf","year":"2024","unstructured":"Grohskopf, L. A., Ferdinands, J. M., Blanton, L. H., Broder, K. R. & Loehr, J. Prevention and control of seasonal influenza with vaccines: recommendations of the advisory committee on immunization practices - United States, 2024-25 influenza season. MMWR Recomm. Rep. 73, 1\u201325 (2024).","journal-title":"MMWR Recomm. Rep."},{"key":"64686_CR11","doi-asserted-by":"publisher","unstructured":"Subbarao, K. Live attenuated cold-adapted influenza vaccines. Cold Spring Harb. Perspect. Med. 11, https:\/\/doi.org\/10.1101\/cshperspect.a038653 (2021).","DOI":"10.1101\/cshperspect.a038653"},{"key":"64686_CR12","doi-asserted-by":"publisher","first-page":"4953","DOI":"10.1016\/j.vaccine.2009.05.099","volume":"27","author":"RA Karron","year":"2009","unstructured":"Karron, R. A. et al. Evaluation of two live attenuated cold-adapted H5N1 influenza virus vaccines in healthy adults. Vaccine 27, 4953\u20134960 (2009).","journal-title":"Vaccine"},{"key":"64686_CR13","doi-asserted-by":"publisher","first-page":"1860","DOI":"10.1093\/infdis\/jiu123","volume":"209","author":"KR Talaat","year":"2014","unstructured":"Talaat, K. R. et al. A live attenuated influenza A(H5N1) vaccine induces long-term immunity in the absence of a primary antibody response. J. Infect. Dis. 209, 1860\u20131869 (2014).","journal-title":"J. Infect. Dis."},{"key":"64686_CR14","doi-asserted-by":"publisher","first-page":"2839","DOI":"10.1080\/21645515.2015.1069931","volume":"11","author":"L Rudenko","year":"2015","unstructured":"Rudenko, L. et al. Assessment of immune responses to H5N1 inactivated influenza vaccine among individuals previously primed with H5N2 live attenuated influenza vaccine. Hum. Vaccin. Immunother. 11, 2839\u20132848 (2015).","journal-title":"Hum. Vaccin. Immunother."},{"key":"64686_CR15","first-page":"181","volume":"386","author":"H Jin","year":"2015","unstructured":"Jin, H. & Subbarao, K. Live attenuated influenza vaccine. Curr. Top. Microbiol. Immunol. 386, 181\u2013204 (2015).","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"64686_CR16","doi-asserted-by":"publisher","first-page":"S15","DOI":"10.1093\/jpids\/piz073","volume":"9","author":"K Subbarao","year":"2020","unstructured":"Subbarao, K. Live attenuated influenza vaccines for pandemic preparedness. J. Pediatr. Infect. Dis. Soc. 9, S15\u2013S18 (2020).","journal-title":"J. Pediatr. Infect. Dis. Soc."},{"key":"64686_CR17","doi-asserted-by":"publisher","first-page":"3227","DOI":"10.3390\/v4113227","volume":"4","author":"JA Chichester","year":"2012","unstructured":"Chichester, J. A. et al. Safety and immunogenicity of a plant-produced recombinant hemagglutinin-based influenza vaccine (HAI-05) derived from A\/Indonesia\/05\/2005 (H5N1) influenza virus: a phase 1 randomized, double-blind, placebo-controlled, dose-escalation study in healthy adults. Viruses 4, 3227\u20133244 (2012).","journal-title":"Viruses"},{"key":"64686_CR18","doi-asserted-by":"publisher","first-page":"6162","DOI":"10.1016\/j.vaccine.2019.08.071","volume":"37","author":"D Smith","year":"2019","unstructured":"Smith, D., Streatfield, S. J., Acosta, H., Ganesan, S. & Fattom, A. A nanoemulsion-adjuvanted intranasal H5N1 influenza vaccine protects ferrets against homologous and heterologous H5N1 lethal challenge. Vaccine 37, 6162\u20136170 (2019).","journal-title":"Vaccine"},{"key":"64686_CR19","doi-asserted-by":"publisher","first-page":"1591","DOI":"10.1016\/j.vaccine.2019.02.002","volume":"37","author":"SH Wang","year":"2019","unstructured":"Wang, S. H. et al. Recombinant H5 hemagglutinin adjuvanted with nanoemulsion protects ferrets against pathogenic avian influenza virus challenge. Vaccine 37, 1591\u20131600 (2019).","journal-title":"Vaccine"},{"key":"64686_CR20","doi-asserted-by":"publisher","first-page":"2771","DOI":"10.1038\/s41591-024-03189-y","volume":"30","author":"S Khurana","year":"2024","unstructured":"Khurana, S. et al. Licensed H5N1 vaccines generate cross-neutralizing antibodies against highly pathogenic H5N1 clade 2.3.4.4b influenza virus. Nat. Med. 30, 2771\u20132776 (2024).","journal-title":"Nat. Med."},{"key":"64686_CR21","doi-asserted-by":"publisher","first-page":"922","DOI":"10.1093\/infdis\/jiv526","volume":"213","author":"M Sobhanie","year":"2016","unstructured":"Sobhanie, M. et al. Evaluation of the safety and immunogenicity of a candidate pandemic live attenuated influenza vaccine (pLAIV) against influenza A(H7N9). J. Infect. Dis. 213, 922\u2013929 (2016).","journal-title":"J. Infect. Dis."},{"key":"64686_CR22","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2018.11.069","author":"CM Oshansky","year":"2018","unstructured":"Oshansky, C. M. et al. Safety and immunogenicity of influenza A(H5N1) vaccine stored up to twelve years in the national pre-pandemic influenza vaccine stockpile (NPIVS). Vaccinehttps:\/\/doi.org\/10.1016\/j.vaccine.2018.11.069 (2018).","journal-title":"Vaccine"},{"key":"64686_CR23","doi-asserted-by":"publisher","first-page":"3953","DOI":"10.1016\/j.vaccine.2015.06.047","volume":"33","author":"KY Chung","year":"2015","unstructured":"Chung, K. Y. et al. ISCOMATRIX adjuvant promotes epitope spreading and antibody affinity maturation of influenza A H7N9 virus like particle vaccine that correlate with virus neutralization in humans. Vaccine 33, 3953\u20133962 (2015).","journal-title":"Vaccine"},{"key":"64686_CR24","doi-asserted-by":"publisher","first-page":"1409","DOI":"10.1001\/jama.2014.12854","volume":"312","author":"MJ Mulligan","year":"2014","unstructured":"Mulligan, M. J. et al. Serological responses to an avian influenza A\/H7N9 vaccine mixed at the point-of-use with MF59 adjuvant: a randomized clinical trial. JAMA. 312, 1409\u20131419 (2014).","journal-title":"JAMA"},{"key":"64686_CR25","doi-asserted-by":"publisher","first-page":"5514","DOI":"10.4049\/jimmunol.1002932","volume":"186","author":"FE Lee","year":"2011","unstructured":"Lee, F. E. et al. Circulating human antibody-secreting cells during vaccinations and respiratory viral infections are characterized by high specificity and lack of bystander effect. J. Immunol. 186, 5514\u20135521 (2011).","journal-title":"J. Immunol."},{"key":"64686_CR26","doi-asserted-by":"publisher","first-page":"1136","DOI":"10.1016\/j.immuni.2020.11.006","volume":"53","author":"RA Elsner","year":"2020","unstructured":"Elsner, R. A. & Shlomchik, M. J. Germinal center and extrafollicular B cell responses in vaccination, immunity, and autoimmunity. Immunity 53, 1136\u20131150 (2020).","journal-title":"Immunity"},{"key":"64686_CR27","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1038\/s41385-021-00471-x","volume":"15","author":"BR Traxinger","year":"2022","unstructured":"Traxinger, B. R., Richert-Spuhler, L. E. & Lund, J. M. Mucosal tissue regulatory T cells are integral in balancing immunity and tolerance at portals of antigen entry. Mucosal Immunol. 15, 398\u2013407 (2022).","journal-title":"Mucosal Immunol."},{"key":"64686_CR28","doi-asserted-by":"publisher","first-page":"896","DOI":"10.1056\/NEJMoa030595","volume":"350","author":"M Mutsch","year":"2004","unstructured":"Mutsch, M. et al. Use of the inactivated intranasal influenza vaccine and the risk of Bell\u2019s palsy in Switzerland. N. Engl. J. Med. 350, 896\u2013903 (2004).","journal-title":"N. Engl. J. Med."},{"key":"64686_CR29","doi-asserted-by":"publisher","first-page":"e6999","DOI":"10.1371\/journal.pone.0006999","volume":"4","author":"DJ Lewis","year":"2009","unstructured":"Lewis, D. J. et al. Transient facial nerve paralysis (Bell\u2019s palsy) following intranasal delivery of a genetically detoxified mutant of Escherichia coli heat labile toxin. PLoS ONE 4, e6999 (2009).","journal-title":"PLoS ONE"},{"key":"64686_CR30","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1038\/s41591-020-1118-7","volume":"27","author":"R Nachbagauer","year":"2021","unstructured":"Nachbagauer, R. et al. A chimeric hemagglutinin-based universal influenza virus vaccine approach induces broad and long-lasting immunity in a randomized, placebo-controlled phase I trial. Nat. Med. 27, 106\u2013114 (2021).","journal-title":"Nat. Med."},{"key":"64686_CR31","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1130725","volume":"14","author":"RD de Vries","year":"2023","unstructured":"de Vries, R. D., Hoschler, K. & Rimmelzwaan, G. F. ADCC: an underappreciated correlate of cross-protection against influenza?. Front. Immunol. 14, 1130725 (2023).","journal-title":"Front. Immunol."},{"key":"64686_CR32","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1016\/j.vaccine.2011.10.094","volume":"30","author":"LR Stanberry","year":"2012","unstructured":"Stanberry, L. R. et al. Safety and immunogenicity of a novel nanoemulsion mucosal adjuvant W805EC combined with approved seasonal influenza antigens. Vaccine 30, 307\u2013316 (2012).","journal-title":"Vaccine"},{"key":"64686_CR33","doi-asserted-by":"crossref","unstructured":"Luke, C. J. & Subbarao, K. Improving pandemic H5N1 influenza vaccines by combining different vaccine platforms. Expert Rev. Vaccines. 13, 873\u2013883 (2014).","DOI":"10.1586\/14760584.2014.922416"},{"key":"64686_CR34","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-38415-7","volume":"14","author":"A Kandeil","year":"2023","unstructured":"Kandeil, A. et al. Rapid evolution of A(H5N1) influenza viruses after intercontinental spread to North America. Nat. Commun. 14, 3082 (2023).","journal-title":"Nat. Commun."},{"key":"64686_CR35","unstructured":"Centers for Disease Control and Prevention. H5 Bird Flu: Current Situation. https:\/\/www.cdc.gov\/bird-flu\/situation-summary\/index.html (2024)."},{"key":"64686_CR36","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1016\/j.vaccine.2020.11.041","volume":"39","author":"A Haveri","year":"2021","unstructured":"Haveri, A., Ikonen, N., Savolainen-Kopra, C. & Julkunen, I. Long-lasting heterologous antibody responses after sequential vaccination with A\/Indonesia\/5\/2005 and A\/Vietnam\/1203\/2004 pre-pandemic influenza A(H5N1) virus vaccines. Vaccine 39, 402\u2013411 (2021).","journal-title":"Vaccine"},{"key":"64686_CR37","doi-asserted-by":"publisher","DOI":"10.1038\/s41541-019-0114-8","volume":"4","author":"MZ Levine","year":"2019","unstructured":"Levine, M. Z. et al. Heterologous prime-boost with A(H5N1) pandemic influenza vaccines induces broader cross-clade antibody responses than homologous prime-boost. NPJ Vaccines 4, 22 (2019).","journal-title":"NPJ Vaccines"},{"key":"64686_CR38","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00449-21","volume":"12","author":"J Wang","year":"2021","unstructured":"Wang, J. et al. Broadly reactive IgG responses to heterologous H5 prime-boost influenza vaccination are shaped by antigenic relatedness to priming strains. mBio. 12, e0044921 (2021).","journal-title":"mBio"},{"key":"64686_CR39","doi-asserted-by":"publisher","first-page":"1408","DOI":"10.1093\/infdis\/jiu616","volume":"211","author":"JL Nayak","year":"2015","unstructured":"Nayak, J. L., Richards, K. A., Yang, H., Treanor, J. J. & Sant, A. J. Effect of influenza A(H5N1) vaccine prepandemic priming on CD4+ T-cell responses. J. Infect. Dis. 211, 1408\u20131417 (2015).","journal-title":"J. Infect. Dis."},{"key":"64686_CR40","doi-asserted-by":"publisher","first-page":"e95496","DOI":"10.1371\/journal.pone.0095496","volume":"9","author":"S Khurana","year":"2014","unstructured":"Khurana, S. et al. Heterologous prime-boost vaccination with MF59-adjuvanted H5 vaccines promotes antibody affinity maturation towards the hemagglutinin HA1 domain and broad H5N1 cross-clade neutralization. PLoS ONE 9, e95496 (2014).","journal-title":"PLoS ONE"},{"key":"64686_CR41","doi-asserted-by":"publisher","first-page":"1087","DOI":"10.1016\/j.vaccine.2008.11.108","volume":"27","author":"Y Shoji","year":"2009","unstructured":"Shoji, Y. et al. Plant-derived hemagglutinin protects ferrets against challenge infection with the A\/Indonesia\/05\/05 strain of avian influenza. Vaccine 27, 1087\u20131092 (2009).","journal-title":"Vaccine"},{"key":"64686_CR42","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbi.2019.103208","volume":"95","author":"PA Harris","year":"2019","unstructured":"Harris, P. A. et al. The REDCap consortium: building an international community of software platform partners. J. Biomed. Inf. 95, 103208 (2019).","journal-title":"J. Biomed. Inf."},{"key":"64686_CR43","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1016\/j.jbi.2008.08.010","volume":"42","author":"PA Harris","year":"2009","unstructured":"Harris, P. A. et al. Research electronic data capture (REDCap)-a metadata-driven methodology and workflow process for providing translational research informatics support. J. Biomed. Inf. 42, 377\u2013381 (2009).","journal-title":"J. Biomed. Inf."},{"key":"64686_CR44","doi-asserted-by":"publisher","first-page":"815","DOI":"10.1016\/j.vaccine.2019.10.093","volume":"38","author":"MK Smatti","year":"2020","unstructured":"Smatti, M. K., Nasrallah, G. K., Al Thani, A. A. & Yassine, H. M. Measuring influenza hemagglutinin (HA) stem-specific antibody-dependent cellular cytotoxicity (ADCC) in human sera using novel stabilized stem nanoparticle probes. Vaccine 38, 815\u2013821 (2020).","journal-title":"Vaccine"},{"key":"64686_CR45","doi-asserted-by":"publisher","DOI":"10.3791\/55833","author":"L Kaufmann","year":"2017","unstructured":"Kaufmann, L. et al. An optimized hemagglutination inhibition (HI) assay to quantify influenza-specific antibody titers. J. Vis. Exp.https:\/\/doi.org\/10.3791\/55833 (2017).","journal-title":"J. Vis. Exp."},{"key":"64686_CR46","doi-asserted-by":"publisher","first-page":"e0179939","DOI":"10.1371\/journal.pone.0179939","volume":"12","author":"G Wilson","year":"2017","unstructured":"Wilson, G. et al. Automated interpretation of influenza hemagglutination inhibition (HAI) assays: Is plate tilting necessary?. PLoS ONE 12, e0179939 (2017).","journal-title":"PLoS ONE"},{"key":"64686_CR47","doi-asserted-by":"publisher","first-page":"15ra15","DOI":"10.1126\/scitranslmed.3000624","volume":"2","author":"S Khurana","year":"2010","unstructured":"Khurana, S. et al. Vaccines with MF59 adjuvant expand the antibody repertoire to target protective sites of pandemic avian H5N1 influenza virus. Sci. Transl. Med. 2, 15ra15 (2010).","journal-title":"Sci. Transl. Med."},{"key":"64686_CR48","doi-asserted-by":"publisher","first-page":"85ra48","DOI":"10.1126\/scitranslmed.3002336","volume":"3","author":"S Khurana","year":"2011","unstructured":"Khurana, S. et al. MF59 adjuvant enhances diversity and affinity of antibody-mediated immune response to pandemic influenza vaccines. Sci. Transl. Med. 3, 85ra48 (2011).","journal-title":"Sci. Transl. Med."},{"key":"64686_CR49","doi-asserted-by":"publisher","first-page":"128","DOI":"10.3389\/fcimb.2012.00128","volume":"2","author":"FR Toapanta","year":"2012","unstructured":"Toapanta, F. R., Bernal, P. J. & Sztein, M. B. Diverse phosphorylation patterns of B cell receptor-associated signaling in naive and memory human B cells revealed by phosphoflow, a powerful technique to study signaling at the single cell level. Front. Cell Infect. Microbiol. 2, 128 (2012).","journal-title":"Front. Cell Infect. Microbiol."},{"key":"64686_CR50","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1291664","volume":"14","author":"FR Toapanta","year":"2023","unstructured":"Toapanta, F. R. et al. Further characterization of Shigella-specific (memory) B cells induced in healthy volunteer recipients of SF2a-TT15, a Shigella flexneri 2a synthetic glycan-based vaccine candidate. Front. Immunol. 14, 1291664 (2023).","journal-title":"Front. Immunol."},{"key":"64686_CR51","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1016\/j.clim.2011.02.003","volume":"139","author":"JK Simon","year":"2011","unstructured":"Simon, J. K. et al. Antigen-specific IgA B memory cell responses to Shigella antigens elicited in volunteers immunized with live attenuated Shigella flexneri 2a oral vaccine candidates. Clin. Immunol. 139, 185\u2013192 (2011).","journal-title":"Clin. Immunol."},{"key":"64686_CR52","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1016\/j.vaccine.2008.10.081","volume":"27","author":"JK Simon","year":"2009","unstructured":"Simon, J. K. et al. Antigen-specific B memory cell responses to lipopolysaccharide (LPS) and invasion plasmid antigen (Ipa) B elicited in volunteers vaccinated with live-attenuated Shigella flexneri 2a vaccine candidates. Vaccine 27, 565\u2013572 (2009).","journal-title":"Vaccine"},{"key":"64686_CR53","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/j.clim.2013.03.009","volume":"148","author":"R Wahid","year":"2013","unstructured":"Wahid, R. et al. Shigella antigen-specific B memory cells are associated with decreased disease severity in subjects challenged with wild-type Shigella flexneri 2a. Clin. Immunol. 148, 35\u201343 (2013).","journal-title":"Clin. Immunol."},{"key":"64686_CR54","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1016\/j.jim.2003.12.015","volume":"286","author":"S Crotty","year":"2004","unstructured":"Crotty, S., Aubert, R. D., Glidewell, J. & Ahmed, R. Tracking human antigen-specific memory B cells: a sensitive and generalized ELISPOT system. J. Immunol. Methods 286, 111\u2013122 (2004).","journal-title":"J. Immunol. Methods"},{"key":"64686_CR55","doi-asserted-by":"publisher","first-page":"294","DOI":"10.3389\/fimmu.2014.00294","volume":"5","author":"JS Booth","year":"2014","unstructured":"Booth, J. S. et al. Characterization and functional properties of gastric tissue-resident memory T cells from children, adults, and the elderly. Front. Immunol. 5, 294 (2014).","journal-title":"Front. Immunol."},{"key":"64686_CR56","doi-asserted-by":"publisher","first-page":"e0003837","DOI":"10.1371\/journal.pntd.0003837","volume":"9","author":"FR Toapanta","year":"2015","unstructured":"Toapanta, F. R. et al. Oral wild-type Salmonella typhi challenge induces activation of circulating monocytes and dendritic cells in individuals who develop typhoid disease. PLoS Negl. Trop. Dis. 9, e0003837 (2015).","journal-title":"PLoS Negl. Trop. Dis."},{"key":"64686_CR57","doi-asserted-by":"publisher","first-page":"e0004766","DOI":"10.1371\/journal.pntd.0004766","volume":"10","author":"FR Toapanta","year":"2016","unstructured":"Toapanta, F. R. et al. Oral challenge with wild-type Salmonella typhi induces distinct changes in B cell subsets in individuals who develop typhoid disease. PLoS Negl. Trop. Dis. 10, e0004766 (2016).","journal-title":"PLoS Negl. Trop. Dis."},{"key":"64686_CR58","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-018-1439-1","volume":"16","author":"FR Toapanta","year":"2018","unstructured":"Toapanta, F. R., Bernal, P. J., Kotloff, K. L., Levine, M. M. & Sztein, M. B. T cell mediated immunity induced by the live-attenuated Shigella flexneri 2a vaccine candidate CVD 1208S in humans. J. Transl. Med. 16, 61 (2018).","journal-title":"J. Transl. Med."},{"key":"64686_CR59","unstructured":"Food and Drug Administration. Good Review Practice: Clinical Review of Investigational New Drug Applications, https:\/\/www.fda.gov\/downloads\/Drugs\/GuidanceComplianceRegulatoryInformation\/UCM377108.pdf (2013)."}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41467-025-64686-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-025-64686-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-025-64686-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T10:15:09Z","timestamp":1762424109000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41467-025-64686-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,6]]},"references-count":59,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["64686"],"URL":"https:\/\/doi.org\/10.1038\/s41467-025-64686-3","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-6059149\/v1","asserted-by":"object"}]},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,6]]},"assertion":[{"value":"11 June 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 September 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 November 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A.F.: Employee of BlueWillow Biologics, Inc. at time of study design. C.G.S.: Institution has received research funds from BlueWillow Biologics, Inc. to support assays performed for this study. C.C.: Employee of BlueWillow Biologics, Inc. D.M.S.: Employee of BlueWillow Biologics, Inc. at time of study design. HA: Employee of BlueWillow Biologics, Inc. I.K.: Institution has received research funds from BlueWillow Biologics, Inc. to support assays performed for this study. I.P.L.J.M.: Institution has received research funds from BlueWillow Biologics, Inc. to support assays performed for this study. J.D.C.: Institution has received research funds from BlueWillow Biologics, Inc. to support assays performed for this study. J.H.: Institution has received research funds from BlueWillow Biologics, Inc. to support assays performed for this study. J.J.O.: Institution has received research funds from BlueWillow Biologics, Inc. to support assays performed for this study. J.N.N.: Institution has received research funds from BlueWillow Biologics, Inc. to support assays performed for this study. J.P.B.: Institution has received research funds from BlueWillow Biologics, Inc. to support assays performed for this study. J.R.O.: Personal: Advisory boards for GSK (RSV Cost Effectiveness Advisory Board, Vaccine Virtual Days 2023), Pfizer (Advisory Committee of Influenza Experts [ACTIvE]), and Moderna (New Vaccines Advisory Board). Consultant for ENA Respiratory. Institution has received research funds from BlueWillow Biologics, Inc. to support assays performed for this study. K.M.N.: Institution has received research funds from BlueWillow Biologics, Inc. to support assays performed for this study. K.L.K.: Institution has received research funds from BlueWillow Biologics, Inc. to support assays performed for this study. M.B.S.: Institution has received research funds from BlueWillow Biologics, Inc. to support assays performed for this study. M.E.D.: Institution has received research funds from BlueWillow Biologics, Inc. to support assays performed for this study. M.F.M.: Institution has received research funds from BlueWillow Biologics, Inc. to support assays performed for this study. M.P.: Institution has received research funds from BlueWillow Biologics, Inc. to support assays performed for this study. R.R.R.: Presently employed at Moderna Therapeutics and may own shares as a condition of employment. Completed involvement in this work prior to this employment. While at University of Maryland, her institution received research funds from BlueWillow Biologics, Inc. to support assays performed for this study. S.D.: Institution has received research funds from BlueWillow Biologics, Inc. to support assays performed for this study. S.M.T.: Institution has received research funds from BlueWillow Biologics, Inc. to support assays. performed for this study. T.H.: Employee of BlueWillow Biologics, Inc. at time of study design. V.A.: Institution has received research funds from BlueWillow Biologics, Inc. to support assays performed for this study. Y.L.: Institution has received research funds from BlueWillow Biologics, Inc. to support assays performed for this study. No other authors have competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"9321"}}