{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,21]],"date-time":"2026-02-21T01:13:29Z","timestamp":1771636409880,"version":"3.50.1"},"reference-count":59,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2017,9,4]],"date-time":"2017-09-04T00:00:00Z","timestamp":1504483200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100005942","name":"Butantan Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005942","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biotechnology Progress"],"published-print":{"date-parts":[[2017,11]]},"abstract":"<jats:p>\n                    <jats:italic>Haemophilus influenzae<\/jats:italic>\n                    type b (Hib), a Gram\u2010negative capsulated bacterium, is a causative agent of meningitis worldwide. The capsular polysaccharide, a high molecular mass polymer consisting of the repeated units of the polyribosyl\u2010ribitol\u2010phosphate, is considered the main virulence factor and it is used as an antigen to vaccines, conjugated to a carrier protein. The industrial production of the polysaccharide requires the cultivation of Hib in rich medium, which impacts process costs and product recovery. In this study, a central composite rotational experimental design strategy was used to access the influence of key components of culture medium (soy peptone, yeast extract and glucose) on biomass formation and polysaccharide production in shake\u2010flasks. The optimized medium formulation, containing half of the usual yeast extract and soytone concentrations, was further validated in batch bioreactor cultivations. High polysaccharide production (\u223c500 mg\/L) was obtained in a cheaper and more competitive production process for use in Hib vaccine production. In addition, simulations of a metabolic model describing Hib central metabolism were used to assess the role of key amino acids on growth. A chemically defined medium supplemented only with amino acids from \u03b1\u2010ketoglutarate and oxaloacetate families as well as phenylalanine was suggested as a promising alternative for reduced acetate accumulation and enhanced polysaccharide production in Hib cultures. \u00a9 2017 American Institute of Chemical Engineers\n                    <jats:italic>Biotechnol. Prog.<\/jats:italic>\n                    , 33:1508\u20131519, 2017\n                  <\/jats:p>","DOI":"10.1002\/btpr.2546","type":"journal-article","created":{"date-parts":[[2017,8,25]],"date-time":"2017-08-25T04:16:40Z","timestamp":1503634600000},"page":"1508-1519","source":"Crossref","is-referenced-by-count":4,"title":["Experimental design and metabolic flux analysis tools to optimize industrially relevant\n                    <i>Haemophilus influenzae<\/i>\n                    type b growth medium"],"prefix":"10.1002","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8203-6960","authenticated-orcid":false,"given":"Mateus Ribeiro","family":"da Silva","sequence":"first","affiliation":[{"name":"Laboratory of Fermentation Biotechnology Center, Butantan Institute S\u00e3o Paulo 05503\u2010900 Brazil"},{"name":"Brazilian Bioethanol Science and Technology Laboratory, CTBE, Brazilian Center of Research in Energy and Materials, CNPEM S\u00e3o Paulo 13083\u2010100 Brazil"},{"name":"Graduate Program of Biotechnology, Federal University of S\u00e3o Carlos S\u00e3o Paulo 13565\u2010905 Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3921-8798","authenticated-orcid":false,"given":"Carla","family":"Andreia Freixo Portela","sequence":"additional","affiliation":[{"name":"Brazilian Bioethanol Science and Technology Laboratory, CTBE, Brazilian Center of Research in Energy and Materials, CNPEM S\u00e3o Paulo 13083\u2010100 Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6520-6550","authenticated-orcid":false,"given":"Silvia","family":"Maria Ferreira Albani","sequence":"additional","affiliation":[{"name":"Laboratory of Fermentation Biotechnology Center, Butantan Institute S\u00e3o Paulo 05503\u2010900 Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paola","family":"Rizzo de Paiva","sequence":"additional","affiliation":[{"name":"Laboratory of Fermentation Biotechnology Center, Butantan Institute S\u00e3o Paulo 05503\u2010900 Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martha","family":"Massako Tanizaki","sequence":"additional","affiliation":[{"name":"Laboratory of Fermentation Biotechnology Center, Butantan Institute S\u00e3o Paulo 05503\u2010900 Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2882-9588","authenticated-orcid":false,"given":"Teresa Cristina","family":"Zangirolami","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering Federal University of S\u00e3o Carlos S\u00e3o Paulo 13565\u2010905 Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2017,9,4]]},"reference":[{"key":"e_1_2_10_2_1","volume-title":"Pasteurellaceae: Biology, Genomics and Molecular Aspects","author":"Kuhnert P","year":"2008"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.epirev.a036066"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/165.Supplement_1-S2"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2249.2000.01109.x"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1469-0691.2003.00530.x"},{"key":"e_1_2_10_7_1","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1128\/IAI.67.2.789-793.1999","article-title":"Regulatory T cells in the antibody response to Haemophilus influenzae type b polysaccharide","volume":"67","author":"Breukels MA","year":"1999","journal-title":"Infect Immun."},{"key":"e_1_2_10_8_1","unstructured":"HillemanMR TaiJY TolmanRL VellaPP.CoupledH. influenzaetype B vaccine. 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