{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T12:10:08Z","timestamp":1780488608105,"version":"3.54.1"},"reference-count":29,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2022,4,20]],"date-time":"2022-04-20T00:00:00Z","timestamp":1650412800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,4,20]],"date-time":"2022-04-20T00:00:00Z","timestamp":1650412800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100014588","name":"Sanofi Pasteur","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100014588","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Glycoconj J"],"published-print":{"date-parts":[[2022,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Bacterial capsular polysaccharide vaccines are generally poorly immunogenic in infants and older adults. The immunogenicity of capsular polysaccharide vaccines can be improved by conjugating them to immunogenic carrier proteins. One of the most recently licensed conjugate vaccines is the quadrivalent meningococcal vaccine with serogroups A, C, Y, and W conjugated to a tetanus toxoid protein carrier (MenACYW-TT; MenQuadfi, Sanofi Pasteur, Swiftwater, PA, USA). MenACYW-TT was developed to induce optimal immune responses against each of the meningococcal serogroups A, C, W, and Y, and across all age groups, especially infants and older adults (those aged\u2009\u2265\u200950\u00a0years). Here, we detail the early iterative vaccine development approach taken, whereby many different \u2018small-scale\u2019 conjugate vaccine candidates were prepared and examined for immunogenicity in a mouse model to identify the most immunogenic vaccine. Additional insights from phase I clinical studies informed further optimization of the vaccine candidates by tailoring their conjugation parameter attributes for the optimal immune response in humans. The parameters studied included: different carrier proteins [PR]; polysaccharide [PS] sizes; conjugation chemistries [linker vs. no-linker; lattice vs. neoglycoprotein; activation\/derivatization levels]; conjugate size; PS:PR loading ratio; percent free PS; percent free PR; and<jats:italic>O<\/jats:italic>-acetylation content. The lead quadrivalent conjugate vaccine (polysaccharides of\u2009&gt;\u200950\u00a0kDa size conjugated to TT at a high PS:PR ratio via reductive amination for serogroups C, W and Y, and carbonyldiimidazole\/adipic acid dihydrazide linker chemistry for serogroup A) empirically identified from the extensive preclinical studies, was ultimately confirmed by the robust antibody responses observed in all age groups in the various clinical studies, including in the most challenging infant and older adult age groups, and subsequently led to the licensed formulation.<\/jats:p><jats:p><jats:bold>Graphical abstract<\/jats:bold><\/jats:p>","DOI":"10.1007\/s10719-022-10050-2","type":"journal-article","created":{"date-parts":[[2022,4,20]],"date-time":"2022-04-20T09:03:57Z","timestamp":1650445437000},"page":"381-392","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Preclinical development of the quadrivalent meningococcal (ACYW) tetanus toxoid conjugate vaccine, MenQuadfi\u00ae"],"prefix":"10.1007","volume":"39","author":[{"given":"Richard","family":"Kensinger","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arun B.","family":"Arunachalam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,4,20]]},"reference":[{"key":"10050_CR1","unstructured":"McNamara, L.A., Blain, A.: Meningococcal Disease. In: Roush, S.W., Baldy, L.M., Kirkcobbell, M.A. (eds.) Manual for the surveillance of vaccine-preventable diseases. 1\u20139 (2019)"},{"issue":"4","key":"10050_CR2","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1080\/14760584.2017.1258308","volume":"16","author":"R Borrow","year":"2017","unstructured":"Borrow, R., Alarcon, P., Carlos, J., Caugant, D.A., Christensen, H., Debbag, R., De Wals, P., Echaniz-Aviles, G., Findlow, J., Head, C., Holt, D., Kamiya, H., Saha, S.K., Sidorenko, S., Taha, M.K., Trotter, C., Vazquez Moreno, J.A., von Gottberg, A., Safadi, M.A., Global Meningococcal, I.: The Global Meningococcal Initiative: global epidemiology, the impact of vaccines on meningococcal disease and the importance of herd protection. Expert Rev Vaccines 16(4), 313\u2013328 (2017). https:\/\/doi.org\/10.1080\/14760584.2017.1258308","journal-title":"Expert Rev Vaccines"},{"issue":"4","key":"10050_CR3","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1016\/j.jinf.2020.05.079","volume":"81","author":"SR Parikh","year":"2020","unstructured":"Parikh, S.R., Campbell, H., Bettinger, J.A., Harrison, L.H., Marshall, H.S., Martinon-Torres, F., Safadi, M.A., Shao, Z., Zhu, B., von Gottberg, A., Borrow, R., Ramsay, M.E., Ladhani, S.N.: The everchanging epidemiology of meningococcal disease worldwide and the potential for prevention through vaccination. J Infect 81(4), 483\u2013498 (2020). https:\/\/doi.org\/10.1016\/j.jinf.2020.05.079","journal-title":"J Infect"},{"key":"10050_CR4","unstructured":"Centers for Disease Control and Prevention.: Meningococcal disease. In: Hamborsky, J., Kroger, A., Wolfe, C. (eds.) Epidemiology and Prevention of Vaccine-Preventable Diseases, 13th Edition. Washington D.C. Public Health Foundation. https:\/\/www.cdc.gov\/vaccines\/pubs\/pinkbook\/mening.html. (2015). Accessed 25 January 2021"},{"key":"10050_CR5","unstructured":"European Centre for Disease Prevention and Control.: Factsheet about meningococcal disease. https:\/\/www.ecdc.europa.eu\/en\/meningococcal-disease\/factsheet. (2019). Accessed 25 January 2021"},{"key":"10050_CR6","unstructured":"Centers for Disease Control and Prevention.: Meningococcal disease: technical and clinical information. https:\/\/www.cdc.gov\/meningococcal\/clinical-info.html. (2019). Accessed 25 January 2021"},{"issue":"2 Suppl","key":"10050_CR7","doi-asserted-by":"publisher","first-page":"S3","DOI":"10.1016\/j.jadohealth.2016.04.012","volume":"59","author":"SI Pelton","year":"2016","unstructured":"Pelton, S.I.: The Global Evolution of Meningococcal Epidemiology Following the Introduction of Meningococcal Vaccines. J Adolesc Health 59(2 Suppl), S3\u2013S11 (2016). https:\/\/doi.org\/10.1016\/j.jadohealth.2016.04.012","journal-title":"J Adolesc Health"},{"issue":"1","key":"10050_CR8","doi-asserted-by":"publisher","first-page":"e99","DOI":"10.1093\/cid\/ciaa610","volume":"73","author":"M McMillan","year":"2021","unstructured":"McMillan, M., Walters, L., Sullivan, T., Leong, L.E.X., Turra, M., Lawrence, A., Koehler, A.P., Finn, A., Andrews, R.M., Marshall, H.S.: Impact of Meningococcal B (4CMenB) Vaccine on Pharyngeal Neisseria meningitidis Carriage Density and Persistence in Adolescents. Clin Infect Dis 73(1), e99\u2013e106 (2021). https:\/\/doi.org\/10.1093\/cid\/ciaa610","journal-title":"Clin Infect Dis"},{"issue":"6","key":"10050_CR9","doi-asserted-by":"publisher","first-page":"717","DOI":"10.1586\/erv.09.37","volume":"8","author":"SI Pelton","year":"2009","unstructured":"Pelton, S.I., Gilmet, G.P.: Expanding prevention of invasive meningococcal disease. 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Accessed 5 July 2021"},{"issue":"9","key":"10050_CR29","doi-asserted-by":"publisher","first-page":"1123","DOI":"10.1080\/14760584.2021.1964962","volume":"20","author":"F Martinon-Torres","year":"2021","unstructured":"Martinon-Torres, F., Bertrand-Gerentes, I., Oster, P.: A novel vaccine to prevent meningococcal disease beyond the first year of life: an early review of MenACYW-TT. 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RK was an employee of Sanofi Pasteur at the time of the research.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}