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Here, we report on a key modification that overcomes that obstacle. Thus, we constructed an IgG\u2010Fc vaccine platform for dengue, termed D\u2010PCF, which in addition to a dengue antigen incorporates the cholera toxin non\u2010toxic B subunit (CTB) as a molecular adjuvant, with all three proteins expressed as a single polypeptide. Following expression in <jats:italic>Nicotiana benthamiana<\/jats:italic> plants, the D\u2010PCF assembled as polymeric structures of similar size to human IgM, a process driven by the pentamerization of CTB. A marked improvement of functional properties <jats:italic>in vitro<\/jats:italic> and immunogenicity <jats:italic>in vivo<\/jats:italic> over a previous iteration of the Fc\u2010fusion protein without CTB [1] was demonstrated. These include enhanced antigen presenting cell binding, internalization and activation, complement activation, epithelial cell interactions and ganglioside binding, as well as more efficient polymerization within the expression host. Following immunization of mice with D\u2010PCF by a combination of systemic and mucosal (intranasal) routes, we observed robust systemic and mucosal immune responses, as well as systemic T cell responses, significantly higher than those induced by a related Fc\u2010fusion protein but without CTB. The induced antibodies could bind to the domain III of the dengue virus envelope protein from all four dengue serotypes. Finally, we also demonstrated feasibility of aerosolization of D\u2010PCF as a prerequisite for vaccine delivery by the respiratory route.<\/jats:p>","DOI":"10.1111\/pbi.14275","type":"journal-article","created":{"date-parts":[[2024,1,1]],"date-time":"2024-01-01T14:25:11Z","timestamp":1704119111000},"page":"1402-1416","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Marked enhancement of the immunogenicity of plant\u2010expressed <scp>IgG\u2010Fc<\/scp> fusion proteins by inclusion of cholera toxin non\u2010toxic B subunit within the single polypeptide"],"prefix":"10.1111","volume":"22","author":[{"given":"Mi\u2010Young","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Molecular Biology Jeonbuk National University  Jeonju Republic of Korea"},{"name":"Institute for Infection and Immunity St George's University of London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emil","family":"Vergara","sequence":"additional","affiliation":[{"name":"Institute for Infection and Immunity St George's University of London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andy","family":"Tran","sequence":"additional","affiliation":[{"name":"Institute for Infection and Immunity St George's University of London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew John","family":"Paul","sequence":"additional","affiliation":[{"name":"Institute for Infection and Immunity St George's University of London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tae\u2010Ho","family":"Kwon","sequence":"additional","affiliation":[{"name":"Gencellbiotech Inc.  Wanju Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0767-0042","authenticated-orcid":false,"given":"Julian K.C.","family":"Ma","sequence":"additional","affiliation":[{"name":"Institute for Infection and Immunity St George's University of London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong\u2010Suk","family":"Jang","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology Jeonbuk National University  Jeonju Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4351-8355","authenticated-orcid":false,"given":"Rajko","family":"Reljic","sequence":"additional","affiliation":[{"name":"Institute for Infection and Immunity St George's University of London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,1]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1005315"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.02212"},{"key":"e_1_2_8_4_1","first-page":"259","article-title":"In planta Agrobacterium\u2010mediated transformation of adult Arabidopsis thaliana plants by vacuum infiltration","volume":"82","author":"Bechtold N.","year":"1998","journal-title":"Methods Mol. 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