{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T13:12:58Z","timestamp":1776258778755,"version":"3.50.1"},"reference-count":27,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2019,9,1]],"date-time":"2019-09-01T00:00:00Z","timestamp":1567296000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,9,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Avian influenza vaccines exhibit poor immunogenicity in humans. We hypothesized that one factor underlying weak B cell responses was sequence divergence between avian and seasonal influenza hemagglutinin proteins, thus limiting the availability of adequate CD4 T cell help. To test this, a novel chimeric hemagglutinin protein (cH7\/3) was derived, comprised of the stem domain from seasonal H3 hemagglutinin and the head domain from avian H7. Immunological memory to seasonal influenza was established in mice, through strategies that included seasonal inactivated vaccines, Flumist, and synthetic peptides derived from the H3 stalk domain. After establishment of memory, mice were vaccinated with H7 or cH7\/3 protein. The cH7\/3 Ag was able to recall H3-specific CD4 T cells, and this potentiated CD4 T cell response was associated with enhanced early germinal center response and rapid elicitation of Abs to H7, including Abs specific for the H7 head domain. These results suggest that in pandemic situations, inclusion of CD4 T cell epitopes from seasonal viruses have the potential to overcome the poor immunogenicity of avian vaccines by helping B cells and conferring greater subtype-specific Ab response to viral HA.<\/jats:p>","DOI":"10.4049\/jimmunol.1900819","type":"journal-article","created":{"date-parts":[[2019,8,9]],"date-time":"2019-08-09T19:55:14Z","timestamp":1565380514000},"page":"1502-1508","source":"Crossref","is-referenced-by-count":19,"title":["A Novel Vaccine Strategy to Overcome Poor Immunogenicity of Avian Influenza Vaccines through Mobilization of Memory CD4 T Cells Established by Seasonal Influenza"],"prefix":"10.1093","volume":"203","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1989-8351","authenticated-orcid":false,"given":"Anthony T","family":"DiPiazza","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, D.H. Smith Center for Vaccine Biology and Immunology, University of Rochester Medical Center , Rochester, NY 14642"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1606-6229","authenticated-orcid":false,"given":"Shufang","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin , Madison, Madison, WI 53706"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ajitanuj","family":"Rattan","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, D.H. Smith Center for Vaccine Biology and Immunology, University of Rochester Medical Center , Rochester, NY 14642"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7888-7372","authenticated-orcid":false,"given":"Marta L","family":"DeDiego","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, D.H. Smith Center for Vaccine Biology and Immunology, University of Rochester Medical Center , Rochester, NY 14642"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2818-2526","authenticated-orcid":false,"given":"Francisco","family":"Chaves","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, D.H. Smith Center for Vaccine Biology and Immunology, University of Rochester Medical Center , Rochester, NY 14642"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriele","family":"Neumann","sequence":"additional","affiliation":[{"name":"Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin , Madison, Madison, WI 53706"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshihiro","family":"Kawaoka","sequence":"additional","affiliation":[{"name":"Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin , Madison, Madison, WI 53706"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea J","family":"Sant","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, D.H. Smith Center for Vaccine Biology and Immunology, University of Rochester Medical Center , Rochester, NY 14642"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2019,9,15]]},"reference":[{"key":"2025030417542184600_r1","doi-asserted-by":"crossref","first-page":"172","DOI":"10.3390\/vaccines3010172","article-title":"Emerging influenza strains in the last two decades: a threat of a new pandemic?","volume":"3","author":"Trombetta","year":"2015","journal-title":"Vaccines (Basel)"},{"key":"2025030417542184600_r2","doi-asserted-by":"crossref","DOI":"10.1128\/mBio.00445-13","article-title":"H7N9 avian influenza A virus and the perpetual challenge of potential human pandemicity","volume":"4","author":"Morens","year":"2013","journal-title":"MBio"},{"key":"2025030417542184600_r3","doi-asserted-by":"crossref","first-page":"S111","DOI":"10.1086\/507544","article-title":"Vaccines for seasonal and pandemic influenza","volume":"194","author":"Nichol","year":"2006","journal-title":"J. Infect. Dis."},{"key":"2025030417542184600_r4","article-title":"Avian influenza a virus pandemic preparedness and vaccine development","volume":"6","author":"de Vries","year":"2018","journal-title":"Vaccines (Basel)"},{"key":"2025030417542184600_r5","doi-asserted-by":"crossref","first-page":"13133","DOI":"10.1073\/pnas.1414070111","article-title":"Induction of broadly cross-reactive antibody responses to the influenza HA stem region following H5N1 vaccination in humans","volume":"111","author":"Ellebedy","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030417542184600_r6","first-page":"3478","article-title":"Memory T cells established by seasonal human influenza A infection cross-react with avian influenza A (H5N1) in healthy individuals. [Published erratum appears in 2012 J. Clin. Invest. 122: 4301.]","volume":"118","author":"Lee","year":"2008","journal-title":"J. Clin. Invest."},{"key":"2025030417542184600_r7","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1093\/infdis\/jiu662","article-title":"Seasonal influenza can poise hosts for CD4 T-cell immunity to H7N9 avian influenza","volume":"212","author":"Richards","year":"2015","journal-title":"J. Infect. Dis."},{"key":"2025030417542184600_r8","doi-asserted-by":"crossref","first-page":"1758","DOI":"10.4049\/jimmunol.180.3.1758","article-title":"Healthy human subjects have CD4+ T cells directed against H5N1 influenza virus","volume":"180","author":"Roti","year":"2008","journal-title":"J. Immunol."},{"key":"2025030417542184600_r9","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1086\/590916","article-title":"Immune responses of healthy subjects to a single dose of intramuscular inactivated influenza A\/Vietnam\/1203\/2004 (H5N1) vaccine after priming with an antigenic variant","volume":"198","author":"Goji","year":"2008","journal-title":"J. Infect. Dis."},{"key":"2025030417542184600_r10","doi-asserted-by":"crossref","first-page":"1408","DOI":"10.1093\/infdis\/jiu616","article-title":"Effect of influenza A(H5N1) vaccine prepandemic priming on CD4+ T-cell responses","volume":"211","author":"Nayak","year":"2015","journal-title":"J. Infect. Dis."},{"key":"2025030417542184600_r11","doi-asserted-by":"crossref","first-page":"5774","DOI":"10.1128\/JVI.00137-12","article-title":"Influenza viruses expressing chimeric hemagglutinins: globular head and stalk domains derived from different subtypes","volume":"86","author":"Hai","year":"2012","journal-title":"J. Virol."},{"key":"2025030417542184600_r12","doi-asserted-by":"crossref","first-page":"4047","DOI":"10.1128\/JVI.03422-13","article-title":"Flow cytometry reveals that H5N1 vaccination elicits cross-reactive stem-directed antibodies from multiple Ig heavy-chain lineages","volume":"88","author":"Whittle","year":"2014","journal-title":"J. Virol."},{"key":"2025030417542184600_r13","doi-asserted-by":"crossref","first-page":"1591","DOI":"10.2165\/11206860-000000000-00000","article-title":"Live attenuated influenza vaccine (FluMist\u00ae; Fluenz\u2122): a review of its use in the prevention of seasonal influenza in children and adults","volume":"71","author":"Carter","year":"2011","journal-title":"Drugs"},{"key":"2025030417542184600_r14","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1111\/j.1750-2659.2008.00054.x","article-title":"A vaccine manufacturer\u2019s approach to address medical needs related to seasonal and pandemic influenza viruses","volume":"2","author":"Baras","year":"2008","journal-title":"Influenza Other Respir. Viruses"},{"key":"2025030417542184600_r15","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1128\/JVI.02077-13","article-title":"CD4 T cell help is limiting and selective during the primary B cell response to influenza virus infection","volume":"88","author":"Alam","year":"2014","journal-title":"J. Virol."},{"key":"2025030417542184600_r16","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1005578","article-title":"Broadly-reactive neutralizing and non-neutralizing antibodies directed against the H7 influenza virus hemagglutinin reveal divergent mechanisms of protection","volume":"12","author":"Tan","year":"2016","journal-title":"PLoS Pathog."},{"key":"2025030417542184600_r17","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1016\/j.vaccine.2016.12.049","article-title":"Nanoparticles decorated with viral antigens are more immunogenic at low surface density","volume":"35","author":"Brewer","year":"2017","journal-title":"Vaccine"},{"key":"2025030417542184600_r18","doi-asserted-by":"crossref","first-page":"2694","DOI":"10.1016\/j.jmb.2017.06.015","article-title":"A perspective on the structural and functional constraints for immune evasion: insights from influenza virus","volume":"429","author":"Wu","year":"2017","journal-title":"J. Mol. Biol."},{"key":"2025030417542184600_r19","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1038\/nm1210-1389","article-title":"Induction of unnatural immunity: prospects for a broadly protective universal influenza vaccine","volume":"16","author":"Nabel","year":"2010","journal-title":"Nat. Med."},{"key":"2025030417542184600_r20","first-page":"1169","article-title":"Overarching immunodominance patterns and substantial diversity in specificity and functionality in the circulating human influenza A and B virus-specific CD4+ T-cell repertoire","volume-title":"J. Infect. Dis.","author":"Richards","year":"2018"},{"key":"2025030417542184600_r21","doi-asserted-by":"crossref","first-page":"4998","DOI":"10.4049\/jimmunol.1001395","article-title":"Cutting edge: CD4 T cells generated from encounter with seasonal influenza viruses and vaccines have broad protein specificity and can directly recognize naturally generated epitopes derived from the live pandemic H1N1 virus","volume":"185","author":"Richards","year":"2010","journal-title":"J. Immunol."},{"key":"2025030417542184600_r22","doi-asserted-by":"crossref","first-page":"6566","DOI":"10.1128\/JVI.00302-09","article-title":"Infection of HLA-DR1 transgenic mice with a human isolate of influenza a virus (H1N1) primes a diverse CD4 T-cell repertoire that includes CD4 T cells with heterosubtypic cross-reactivity to avian (H5N1) influenza virus","volume":"83","author":"Richards","year":"2009","journal-title":"J. Virol."},{"key":"2025030417542184600_r23","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0043603","article-title":"A carboxy-terminal trimerization domain stabilizes conformational epitopes on the stalk domain of soluble recombinant hemagglutinin substrates","volume":"7","author":"Krammer","year":"2012","journal-title":"PLoS One"},{"key":"2025030417542184600_r24","doi-asserted-by":"crossref","DOI":"10.1128\/JVI.01202-17","article-title":"Inactivated H7 influenza virus vaccines protect mice despite inducing only low levels of neutralizing antibodies","volume":"91","author":"Kamal","year":"2017","journal-title":"J. Virol."},{"key":"2025030417542184600_r25","doi-asserted-by":"crossref","first-page":"4975","DOI":"10.1016\/j.vaccine.2015.07.026","article-title":"Recombinant H7 hemagglutinin forms subviral particles that protect mice and ferrets from challenge with H7N9 influenza virus","volume":"33","author":"Pushko","year":"2015","journal-title":"Vaccine"},{"key":"2025030417542184600_r26","article-title":"Broad cross-reactive IgG responses elicited by adjuvanted vaccination with recombinant influenza hemagglutinin (rHA) in ferrets and mice","volume":"13","author":"Wang","year":"2018","journal-title":"PLoS One"},{"key":"2025030417542184600_r27","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1080\/21645515.2015.1012013","article-title":"Cocktail of H5N1 COBRA HA vaccines elicit protective antibodies against H5N1 viruses from multiple clades","volume":"11","author":"Crevar","year":"2015","journal-title":"Hum. Vaccin. Immunother."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/203\/6\/1502\/61420319\/ji1900819.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/203\/6\/1502\/61420319\/ji1900819.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T20:10:30Z","timestamp":1741119030000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/203\/6\/1502\/7952429"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9]]},"references-count":27,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2019,9,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1900819","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2019,9]]},"published":{"date-parts":[[2019,9]]}}}