{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T00:25:42Z","timestamp":1760228742060,"version":"build-2065373602"},"reference-count":35,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,5,19]],"date-time":"2022-05-19T00:00:00Z","timestamp":1652918400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Initiative for Global Research Network on Infectious Diseases","doi-asserted-by":"publisher","award":["JP19fm0108008","JP22wm0125008","22fk0108142","17K15367","21H02376","18K07135","1801"],"award-info":[{"award-number":["JP19fm0108008","JP22wm0125008","22fk0108142","17K15367","21H02376","18K07135","1801"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Program for Infectious Diseases Research and Infrastructur","doi-asserted-by":"publisher","award":["JP19fm0108008","JP22wm0125008","22fk0108142","17K15367","21H02376","18K07135","1801"],"award-info":[{"award-number":["JP19fm0108008","JP22wm0125008","22fk0108142","17K15367","21H02376","18K07135","1801"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Research Program on Emerging and Re-emerging Infectious Diseases","doi-asserted-by":"publisher","award":["JP19fm0108008","JP22wm0125008","22fk0108142","17K15367","21H02376","18K07135","1801"],"award-info":[{"award-number":["JP19fm0108008","JP22wm0125008","22fk0108142","17K15367","21H02376","18K07135","1801"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Japan Agency for Medical Research and Development (AMED), the Global Institution for Collaborative Research and Education (GI-CoRE) program of Hokkaido University, the Program for Leading Graduate Schools (F01)","award":["JP19fm0108008","JP22wm0125008","22fk0108142","17K15367","21H02376","18K07135","1801"],"award-info":[{"award-number":["JP19fm0108008","JP22wm0125008","22fk0108142","17K15367","21H02376","18K07135","1801"]}]},{"name":"Japan Society for the Promotion of Science (JSPS), and Doctoral Program for World-leading Innovative &amp;","award":["JP19fm0108008","JP22wm0125008","22fk0108142","17K15367","21H02376","18K07135","1801"],"award-info":[{"award-number":["JP19fm0108008","JP22wm0125008","22fk0108142","17K15367","21H02376","18K07135","1801"]}]},{"name":"Smart Education (WISE) Program (1801) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT)","award":["JP19fm0108008","JP22wm0125008","22fk0108142","17K15367","21H02376","18K07135","1801"],"award-info":[{"award-number":["JP19fm0108008","JP22wm0125008","22fk0108142","17K15367","21H02376","18K07135","1801"]}]},{"DOI":"10.13039\/501100001691","name":"M. Ohno","doi-asserted-by":"publisher","award":["JP19fm0108008","JP22wm0125008","22fk0108142","17K15367","21H02376","18K07135","1801"],"award-info":[{"award-number":["JP19fm0108008","JP22wm0125008","22fk0108142","17K15367","21H02376","18K07135","1801"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"M. Shingai","doi-asserted-by":"publisher","award":["JP19fm0108008","JP22wm0125008","22fk0108142","17K15367","21H02376","18K07135","1801"],"award-info":[{"award-number":["JP19fm0108008","JP22wm0125008","22fk0108142","17K15367","21H02376","18K07135","1801"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001700","name":"WISE Program","doi-asserted-by":"publisher","award":["JP19fm0108008","JP22wm0125008","22fk0108142","17K15367","21H02376","18K07135","1801"],"award-info":[{"award-number":["JP19fm0108008","JP22wm0125008","22fk0108142","17K15367","21H02376","18K07135","1801"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Despite the use of vaccines, seasonal influenza remains a risk to public health. We previously proposed the inactivated whole virus particle vaccine (WPV) as an alternative to the widely used split vaccine (SV) for the control of seasonal and pandemic influenza based on the superior priming potency of WPV to that of SV. In this study, we further examined and compared the immunological potency of monovalent WPV and SV of A\/California\/7\/2009 (X-179A) (H1N1) pdm09 (CA\/09) to generate immune responses against heterologous viruses, A\/Singapore\/GP1908\/2015 (IVR-180) (H1N1) pdm09 (SG\/15), and A\/duck\/Hokkaido\/Vac-3\/2007 (H5N1) (DH\/07) in mice. Following challenge with a lethal dose of heterologous SG\/15, lower virus titer in the lungs and milder weight loss were observed in WPV-vaccinated mice than in SV-vaccinated ones. To investigate the factors responsible for the differences in the protective effect against SG\/15, the sera of vaccinated mice were analyzed by hemagglutination-inhibition (HI) and neuraminidase-inhibition (NI) assays to evaluate the antibodies induced against viral hemagglutinin (HA) and neuraminidase (NA), respectively. While the two vaccines induced similar levels of HI antibodies against SG\/15 after the second vaccination, only WPV-vaccinated mice induced significantly higher titers of NI antibodies against the strain. Furthermore, given the significant elevation of NI antibody titers against DH\/07, an H5N1 avian influenza virus, WPV was also demonstrated to induce NA-inhibiting antibodies that recognize NA of divergent strains. This could be explained by the higher conservation of epitopes of NA among strains than for HA. Taking these findings together, NA-specific antibodies induced by WPV may have contributed to better protection from infection with heterologous influenza virus SG\/15, compared with SV. The present results indicate that WPV is an effective vaccine for inducing antibodies against both HA and NA of heterologous viruses and may be a useful vaccine to conquer vaccine strain mismatch.<\/jats:p>","DOI":"10.3390\/vaccines10050804","type":"journal-article","created":{"date-parts":[[2022,5,20]],"date-time":"2022-05-20T00:18:11Z","timestamp":1653005891000},"page":"804","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Inactivated Whole Virus Particle Influenza Vaccine Induces Anti-Neuraminidase Antibodies That May Contribute to Cross-Protection against Heterologous Virus Infection"],"prefix":"10.3390","volume":"10","author":[{"given":"Chimuka","family":"Handabile","sequence":"first","affiliation":[{"name":"International Institute for Zoonosis Control, Hokkaido University, Kita-20 Nishi-10, Kita-ku, Sapporo 001-0020, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshiki","family":"Sekiya","sequence":"additional","affiliation":[{"name":"International Institute for Zoonosis Control, Hokkaido University, Kita-20 Nishi-10, Kita-ku, Sapporo 001-0020, Japan"},{"name":"Global Station for Zoonosis Control, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Sapporo 001-0020, Japan"},{"name":"Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC 3000, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naoki","family":"Nomura","sequence":"additional","affiliation":[{"name":"International Institute for Zoonosis Control, Hokkaido University, Kita-20 Nishi-10, Kita-ku, Sapporo 001-0020, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1086-8244","authenticated-orcid":false,"given":"Marumi","family":"Ohno","sequence":"additional","affiliation":[{"name":"International Institute for Zoonosis Control, Hokkaido University, Kita-20 Nishi-10, Kita-ku, Sapporo 001-0020, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3723-0013","authenticated-orcid":false,"given":"Tomomi","family":"Kawakita","sequence":"additional","affiliation":[{"name":"International Institute for Zoonosis Control, Hokkaido University, Kita-20 Nishi-10, Kita-ku, Sapporo 001-0020, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3214-4626","authenticated-orcid":false,"given":"Masashi","family":"Shingai","sequence":"additional","affiliation":[{"name":"International Institute for Zoonosis Control, Hokkaido University, Kita-20 Nishi-10, Kita-ku, Sapporo 001-0020, Japan"},{"name":"Global Station for Zoonosis Control, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Sapporo 001-0020, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroshi","family":"Kida","sequence":"additional","affiliation":[{"name":"International Institute for Zoonosis Control, Hokkaido University, Kita-20 Nishi-10, Kita-ku, Sapporo 001-0020, Japan"},{"name":"Global Station for Zoonosis Control, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Sapporo 001-0020, Japan"},{"name":"Collaborating Research Center for the Control of Infectious Diseases, Nagasaki University, Nagasaki 852-8523, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/S1473-3099(02)00366-3","article-title":"Influenza\u2013WHO cares","volume":"2","year":"2002","journal-title":"Lancet Infect. Dis."},{"unstructured":"(2011). Manual for the Laboratory Diagnosis and Virological Surveillance of Influenza, World Health Organization.","key":"ref_2"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1093\/jac\/44.suppl_2.3","article-title":"Epidemiology and pathogenesis of influenza","volume":"44","author":"Zambon","year":"1999","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1038\/nrmicro.2017.118","article-title":"The evolution of seasonal influenza viruses","volume":"16","author":"Petrova","year":"2018","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.15585\/mmwr.rr6908a1","article-title":"Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices\u2014United States, 2020\u20132021 Influenza Season","volume":"69","author":"Grohskopf","year":"2020","journal-title":"MMWR Recomm. Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1016\/j.cell.2009.01.029","article-title":"The Influenza Virus Enigma","volume":"136","author":"Salomon","year":"2009","journal-title":"Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/S0264-410X(02)00509-1","article-title":"Selection of influenza vaccine strains and developing pandemic vaccines","volume":"20","author":"Wood","year":"2002","journal-title":"Vaccine"},{"doi-asserted-by":"crossref","unstructured":"Coudeville, L., Bailleux, F., Riche, B., Megas, F., Andre, P., and Ecochard, R. (2010). Relationship between haemagglutination-inhibiting antibody titres and clinical protection against influenza: Development and application of a bayesian random-effects model. BMC Med. Res. Methodol., 10.","key":"ref_8","DOI":"10.1186\/1471-2288-10-18"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1016\/S1473-3099(16)00129-8","article-title":"Variable influenza vaccine effectiveness by subtype: A systematic review and meta-analysis of test-negative design studies","volume":"16","author":"Belongia","year":"2016","journal-title":"Lancet Infect. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e4244","DOI":"10.1093\/cid\/ciaa1884","article-title":"Effect of Antigenic Drift on Influenza Vaccine Effectiveness in the United States\u20142019\u20132020","volume":"73","author":"Tenforde","year":"2021","journal-title":"Clin. Infect. Dis."},{"doi-asserted-by":"crossref","unstructured":"Sekiya, T., Ohno, M., Nomura, N., Handabile, C., Shingai, M., Jackson, D.C., Brown, L.E., and Kida, H. (2021). Selecting and Using the Appropriate Influenza Vaccine for Each Individual. Viruses, 13.","key":"ref_11","DOI":"10.3390\/v13060971"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2158","DOI":"10.1016\/j.vaccine.2019.02.057","article-title":"Inactivated whole virus particle vaccine with potent immunogenicity and limited IL-6 induction is ideal for influenza","volume":"37","author":"Sekiya","year":"2019","journal-title":"Vaccine"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3940","DOI":"10.1016\/j.vaccine.2021.05.065","article-title":"Potent priming by inactivated whole influenza virus particle vaccines is linked to viral RNA uptake into antigen presenting cells","volume":"39","author":"Shingai","year":"2021","journal-title":"Vaccine"},{"key":"ref_14","first-page":"767","article-title":"The role of serum haemagglutination-inhibiting antibody in protection against challenge infection with influenza A2 and B viruses","volume":"70","author":"Hobson","year":"1972","journal-title":"J. Hyg."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1879","DOI":"10.1093\/infdis\/jir661","article-title":"Influenza hemagglutination-inhibition antibody titer as a correlate of vaccine-induced protection","volume":"204","author":"Ohmit","year":"2011","journal-title":"J. Infect. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1128\/CVI.00604-15","article-title":"Correlates of Protection against Influenza in the Elderly: Results from an Influenza Vaccine Efficacy Trial","volume":"23","author":"Dunning","year":"2016","journal-title":"Clin. Vaccine Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1097\/EDE.0000000000000402","article-title":"Quantifying Protection Against Influenza Virus Infection Measured by Hemagglutination-inhibition Assays in Vaccine Trials","volume":"27","author":"Zhao","year":"2016","journal-title":"Epidemiology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1861","DOI":"10.1098\/rstb.2001.0999","article-title":"The evolution of human influenza viruses","volume":"356","author":"Hay","year":"2001","journal-title":"Philos. Trans. R. Soc. B Biol. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1016\/j.vaccine.2007.11.031","article-title":"A vaccine prepared from a non-pathogenic H5N1 avian influenza virus strain confers protective immunity against highly pathogenic avian influenza virus infection in cynomolgus macaques","volume":"26","author":"Itoh","year":"2008","journal-title":"Vaccine"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3212","DOI":"10.1016\/S0264-410X(03)00234-2","article-title":"Intranasal immunization with formalin-inactivated virus vaccine induces a broad spectrum of heterosubtypic immunity against influenza A virus infection in mice","volume":"21","author":"Takada","year":"2003","journal-title":"Vaccine"},{"key":"ref_21","first-page":"199","article-title":"Influenza virus neuraminidase and neuraminidase inhibition test procedures","volume":"48","author":"Coleman","year":"1973","journal-title":"Bull. World Health Organ."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.cell.2018.03.030","article-title":"Influenza Infection in Humans Induces Broadly Cross-Reactive and Protective Neuraminidase-Reactive Antibodies","volume":"173","author":"Chen","year":"2018","journal-title":"Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1038\/s41591-019-0463-x","article-title":"Novel correlates of protection against pandemic H1N1 influenza A virus infection","volume":"25","author":"Ng","year":"2019","journal-title":"Nat. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.virol.2019.07.008","article-title":"Neuraminidase expressing virus-like particle vaccine provides effective cross-protection against influenza virus","volume":"535","author":"Kim","year":"2019","journal-title":"Virology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e02556","DOI":"10.1128\/mBio.02556-14","article-title":"Vaccination with adjuvanted recombinant neuraminidase induces broad heterologous, but not heterosubtypic, cross-protection against influenza virus infection in mice","volume":"6","author":"Wohlbold","year":"2015","journal-title":"MBio"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3053","DOI":"10.1128\/JVI.02434-12","article-title":"Neuraminidase-Inhibiting Antibody Is a Correlate of Cross-Protection against Lethal H5N1 Influenza Virus in Ferrets Immunized with Seasonal Influenza Vaccine","volume":"87","author":"Rockman","year":"2013","journal-title":"J. Virol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1016\/j.chom.2019.10.003","article-title":"Influenza H7N9 Virus Neuraminidase-Specific Human Monoclonal Antibodies Inhibit Viral Egress and Protect from Lethal Influenza Infection in Mice","volume":"26","author":"Gilchuk","year":"2019","journal-title":"Cell Host Microbe"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"0265","DOI":"10.1371\/journal.pmed.0040059","article-title":"Cross-reactive neuraminidase antibodies afford partial protection against H5N1 in mice and are present in unexposed humans","volume":"4","author":"Sandbulte","year":"2007","journal-title":"PLoS Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.virol.2012.06.003","article-title":"Protection against a lethal H5N1 influenza challenge by intranasal immunization with virus-like particles containing 2009 pandemic H1N1 neuraminidase in mice","volume":"432","author":"Easterbrook","year":"2012","journal-title":"Virology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1128\/jvi.2.8.778-786.1968","article-title":"Protective Effects of Specific Immunity to Viral Neuraminidase on Influenza Virus Infection of Mice","volume":"2","author":"Schulman","year":"1968","journal-title":"J. Virol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1093\/oxfordjournals.aje.a112273","article-title":"Comparative Trial of Influenza Vaccines","volume":"104","author":"Barry","year":"1976","journal-title":"Am. J. Epidemiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1128\/iai.10.6.1329-1336.1974","article-title":"Inactivated influenza vaccine efficacy: Diminished antigenicity of split product vaccines in mice","volume":"10","author":"Barry","year":"1974","journal-title":"Infect. Immun."},{"doi-asserted-by":"crossref","unstructured":"Marcelin, G., DuBois, R., Rubrum, A., Russell, C.J., McElhaney, J.E., and Webby, R.J. (2011). A contributing role for anti-neuraminidase antibodies on immunity to pandemic H1N1 2009 influenza a virus. PLoS ONE, 6.","key":"ref_33","DOI":"10.1371\/journal.pone.0026335"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1016\/S0140-6736(73)92196-X","article-title":"Effect of Neuraminidase Antibody on Hong Kong Influenza","volume":"301","author":"Monto","year":"1973","journal-title":"Lancet"},{"key":"ref_35","first-page":"647","article-title":"The role of antineuraminidase antibody in immunity to influenza virus infection","volume":"41","author":"Schulman","year":"1969","journal-title":"Bull. World Health Organ."}],"container-title":["Vaccines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-393X\/10\/5\/804\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:14:55Z","timestamp":1760138095000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-393X\/10\/5\/804"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,19]]},"references-count":35,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["vaccines10050804"],"URL":"https:\/\/doi.org\/10.3390\/vaccines10050804","relation":{},"ISSN":["2076-393X"],"issn-type":[{"type":"electronic","value":"2076-393X"}],"subject":[],"published":{"date-parts":[[2022,5,19]]}}}