{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T03:18:45Z","timestamp":1783739925526,"version":"3.55.0"},"reference-count":74,"publisher":"American Society for Microbiology","issue":"4","license":[{"start":{"date-parts":[[2025,4,29]],"date-time":"2025-04-29T00:00:00Z","timestamp":1745884800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,4,29]],"date-time":"2025-04-29T00:00:00Z","timestamp":1745884800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"Revabiotech SE","award":["2014"],"award-info":[{"award-number":["2014"]}]},{"DOI":"10.13039\/501100019563","name":"Institute of Microbiology of the Czech Academy of Sciences","doi-asserted-by":"publisher","award":["RVO61388971"],"award-info":[{"award-number":["RVO61388971"]}],"id":[{"id":"10.13039\/501100019563","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ministry of Education Youth and Sports of the Czech Republic","award":["Programme EXCELES ID Project No. LX22NPO5103, LM2023053, CZ.02.01.01\/00\/22_008\/0004597"],"award-info":[{"award-number":["Programme EXCELES ID Project No. LX22NPO5103, LM2023053, CZ.02.01.01\/00\/22_008\/0004597"]}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mSphere"],"published-print":{"date-parts":[[2025,4,29]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:sec>\n            <jats:title\/>\n            <jats:p>\n              Pertussis resurged over the last decade in most countries that replaced the traditional whole-cell pertussis vaccines (wP) by the less reactogenic acellular pertussis vaccines (aP). The aP vaccines induce a Th2-polarized immune response and by a yet unknown mechanism hamper the clearance of\n              <jats:italic>Bordetella pertussis<\/jats:italic>\n              from infected nasopharyngeal mucosa. The aP-induced pertussis toxin-neutralizing antibodies effectively prevent the life-threatening pertussis pneumonia in infants, but aP-elicited immunity fails to prevent infection of nasopharyngeal mucosa and transmission of\n              <jats:italic>B. pertussis<\/jats:italic>\n              . In contrast, the more reactogenic traditional wP vaccines, alike natural infection, elicit a broad antibody response and trigger a Th1\/Th17-polarized T cell immunity. We tackled here the reactogenicity of the conventional wP vaccines by genetic modification of the Fim2 and Fim3-producing\n              <jats:italic>B. pertussis<\/jats:italic>\n              strains used for wP vaccine manufacturing. Mutations were introduced into the genomes of vaccine strains (i) to reduce the TLR4 signaling potency of the lipid A of\n              <jats:italic>B. pertussis<\/jats:italic>\n              lipooligosaccharide (\u0394\n              <jats:italic>lgm<\/jats:italic>\n              B), (ii) eliminate the enzymatic (immunosuppressive) activity of the pertussis toxin (PtxS1-R9K\/E129G), and (iii) ablate the production of the dermonecrotic toxin (\u0394\n              <jats:italic>dnt<\/jats:italic>\n              ). Experimental alum-adjuvanted wP vaccines prepared from such triply modified bacteria exhibited a reduced pyrogenicity in rabbits and a reduced systemic toxicity in mice, while conferring a comparable protection from\n              <jats:italic>B. pertussis<\/jats:italic>\n              infection as the unmodified wP vaccine.\n            <\/jats:p>\n            <jats:sec>\n              <jats:title>IMPORTANCE<\/jats:title>\n              <jats:p>\n                The occasionally severe adverse reactions associated with some lots of the whole-cell pertussis vaccine (wP) led the industrialized nations to switch to the use of less reactogenic acellular pertussis vaccines that confer shorter-lasting protection. This yielded whooping cough resurgence and large whooping cough outbreaks are currently sweeping throughout European countries, calling for the replacement of the pertussis vaccine component of pediatric hexavaccines by an improved wP vaccine. We show that genetic detoxification of the\n                <jats:italic>Bordetella pertussis<\/jats:italic>\n                bacteria used for wP preparation yields a reduced reactogenicity wP vaccine that exhibits a reduced systemic toxicity in mice and reduced pyrogenicity in rabbits, while retaining high immunogenicity and protective potency in the mouse model of pneumonic infection by\n                <jats:italic>B. pertussis<\/jats:italic>\n                . This result has now been confirmed in a nonhuman primate model of\n                <jats:italic>B. pertussis<\/jats:italic>\n                infection of olive baboons, paving the way for the development of the next generation of pertussis vaccines.\n              <\/jats:p>\n            <\/jats:sec>\n          <\/jats:sec>","DOI":"10.1128\/msphere.00639-24","type":"journal-article","created":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T13:00:47Z","timestamp":1741784447000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":5,"title":["Less reactogenic whole-cell pertussis vaccine confers protection from\n            <i>Bordetella pertussis<\/i>\n            infection"],"prefix":"10.1128","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-1645-9286","authenticated-orcid":false,"given":"Karol\u00edna","family":"\u0160kopov\u00e1","sequence":"first","affiliation":[{"name":"Institute of Microbiology of the Czech Academy of Sciences","place":["Prague, Czechia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0829-0976","authenticated-orcid":false,"given":"Jana","family":"Holubov\u00e1","sequence":"additional","affiliation":[{"name":"Institute of Microbiology of the Czech Academy of Sciences","place":["Prague, Czechia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbora","family":"Bo\u010dkov\u00e1","sequence":"additional","affiliation":[{"name":"Institute of Microbiology of the Czech Academy of Sciences","place":["Prague, Czechia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2391-2080","authenticated-orcid":false,"given":"Eva","family":"Sliveneck\u00e1","sequence":"additional","affiliation":[{"name":"Institute of Microbiology of the Czech Academy of Sciences","place":["Prague, Czechia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jo\u00e3o Melo","family":"Santos de Barros","sequence":"additional","affiliation":[{"name":"Institute of Microbiology of the Czech Academy of Sciences","place":["Prague, Czechia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1575-7834","authenticated-orcid":false,"given":"Ond\u0159ej","family":"Stan\u011bk","sequence":"additional","affiliation":[{"name":"Institute of Microbiology of the Czech Academy of Sciences","place":["Prague, Czechia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9755-7715","authenticated-orcid":false,"given":"Peter","family":"\u0160ebo","sequence":"additional","affiliation":[{"name":"Institute of Microbiology of the Czech Academy of Sciences","place":["Prague, Czechia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.18.2.326-382.2005"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1097\/00000441-195109000-00011"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/132.6.707"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1093\/femspd\/ftv050"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.2500\/aap.2021.42.210065"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1080\/21645515.2023.2208514"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(17)30390-0"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1542\/peds.73.1.31"},{"key":"e_1_3_5_10_2","first-page":"423","article-title":"DTP vaccine reactions: effect of prior reactions on rate of subsequent reactions","volume":"61","author":"Baraff LJ","year":"1985","unstructured":"Baraff LJ, Cherry JD, Cody CL, Marcy SM, Manclark CR. 1985. DTP vaccine reactions: effect of prior reactions on rate of subsequent reactions. Dev Biol Stand 61:423\u2013428.","journal-title":"Dev Biol Stand"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.1097\/00006454-198908000-00006"},{"key":"e_1_3_5_12_2","first-page":"789","article-title":"Infants and children with convulsions and hypotonic-hyporesponsive episodes following diphtheria-tetanus-pertussis immunization: follow-up evaluation","volume":"81","author":"Baraff LJ","year":"1988","unstructured":"Baraff LJ, Shields WD, Beckwith L, Strome G, Marcy SM, Cherry JD, Manclark CR. 1988. Infants and children with convulsions and hypotonic-hyporesponsive episodes following diphtheria-tetanus-pertussis immunization: follow-up evaluation. Pediatrics 81:789\u2013794.","journal-title":"Pediatrics"},{"key":"e_1_3_5_13_2","doi-asserted-by":"publisher","DOI":"10.1542\/peds.68.5.650"},{"key":"e_1_3_5_14_2","first-page":"319","article-title":"The past, present, and future of pertussis. the role of adults in epidemiology and future control","volume":"150","author":"Cherry JD","year":"1989","unstructured":"Cherry JD, Baraff LJ, Hewlett E. 1989. The past, present, and future of pertussis. the role of adults in epidemiology and future control. West J Med 150:319\u2013328.","journal-title":"West J Med"},{"key":"e_1_3_5_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro3235"},{"key":"e_1_3_5_16_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0197970"},{"key":"e_1_3_5_17_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2012.6364"},{"key":"e_1_3_5_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2021.04.032"},{"key":"e_1_3_5_19_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cit046"},{"key":"e_1_3_5_20_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cis287"},{"key":"e_1_3_5_21_2","doi-asserted-by":"publisher","DOI":"10.1586\/14760584.2014.946016"},{"key":"e_1_3_5_22_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1314688110"},{"key":"e_1_3_5_23_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.61.2.399-410.1993"},{"key":"e_1_3_5_24_2","doi-asserted-by":"publisher","DOI":"10.1099\/00222615-39-3-163"},{"key":"e_1_3_5_25_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.61.8.3190-3198.1993"},{"key":"e_1_3_5_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.micinf.2014.04.003"},{"key":"e_1_3_5_27_2","doi-asserted-by":"publisher","DOI":"10.1128\/CVI.00314-09"},{"key":"e_1_3_5_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2009.07.075"},{"key":"e_1_3_5_29_2","doi-asserted-by":"publisher","DOI":"10.1155\/2012\/795958"},{"key":"e_1_3_5_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2015.10.136"},{"key":"e_1_3_5_31_2","doi-asserted-by":"publisher","DOI":"10.1093\/femspd\/fty071"},{"key":"e_1_3_5_32_2","first-page":"79","article-title":"An endocrinological test for innocuity of the pertussis vaccine","volume":"3","author":"Pekarek J","year":"1959","unstructured":"Pekarek J, Rezabek K. 1959. An endocrinological test for innocuity of the pertussis vaccine. J Hyg Epidemiol Microbiol Immunol 3:79\u201384.","journal-title":"J Hyg Epidemiol Microbiol Immunol"},{"key":"e_1_3_5_33_2","first-page":"67","article-title":"The investigation of different components of pertussis vaccine obtained by centrifugation","volume":"3","author":"Pekarek J","year":"1959","unstructured":"Pekarek J, Rezabek K. 1959. The investigation of different components of pertussis vaccine obtained by centrifugation. J Hyg Epidemiol Microbiol Immunol 3:67\u201378.","journal-title":"J Hyg Epidemiol Microbiol Immunol"},{"key":"e_1_3_5_34_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.03146-19"},{"key":"e_1_3_5_35_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00033-09"},{"key":"e_1_3_5_36_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01346-09"},{"key":"e_1_3_5_37_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.01875-07"},{"key":"e_1_3_5_38_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.58.5.1308-1315.1990"},{"key":"e_1_3_5_39_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.2683073"},{"key":"e_1_3_5_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijmm.2004.07.007"},{"key":"e_1_3_5_41_2","doi-asserted-by":"publisher","DOI":"10.1586\/14760584.2014.938642"},{"key":"e_1_3_5_42_2","doi-asserted-by":"publisher","DOI":"10.1002\/jat.2720"},{"key":"e_1_3_5_43_2","doi-asserted-by":"publisher","DOI":"10.1006\/biol.1994.1034"},{"key":"e_1_3_5_44_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.06310-11"},{"key":"e_1_3_5_45_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jis443"},{"key":"e_1_3_5_46_2","doi-asserted-by":"publisher","DOI":"10.1128\/msphere.00647-24"},{"key":"e_1_3_5_47_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.02197-14"},{"key":"e_1_3_5_48_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00834-06"},{"key":"e_1_3_5_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.micinf.2007.04.015"},{"key":"e_1_3_5_50_2","doi-asserted-by":"publisher","DOI":"10.4161\/hv.22847"},{"key":"e_1_3_5_51_2","doi-asserted-by":"publisher","DOI":"10.1128\/CVI.00339-08"},{"key":"e_1_3_5_52_2","first-page":"82","article-title":"Alternatives to HIST for acellular pertussis vaccines: progress and challenges in replacement","volume":"2015","author":"Arciniega J","year":"2016","unstructured":"Arciniega J, Wagner L, Prymula R, Sebo P, Isbrucker R, Descampe B, Chapsal JM, Costanzo A, Hendriksen C, Hoonaker M, Nelson S, Lidster K, Casey W, Allen D. 2016. Alternatives to HIST for acellular pertussis vaccines: progress and challenges in replacement. Pharmeur Bio Sci Notes 2015:82\u201396.","journal-title":"Pharmeur Bio Sci Notes"},{"key":"e_1_3_5_53_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41541-020-00270-8"},{"key":"e_1_3_5_54_2","doi-asserted-by":"publisher","DOI":"10.1080\/22221751.2018.1564630"},{"key":"e_1_3_5_55_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01860"},{"key":"e_1_3_5_56_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI121309"},{"key":"e_1_3_5_57_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellimm.2016.05.002"},{"key":"e_1_3_5_58_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.701285"},{"key":"e_1_3_5_59_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1601024"},{"key":"e_1_3_5_60_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41385-021-00407-5"},{"key":"e_1_3_5_61_2","doi-asserted-by":"publisher","DOI":"10.3390\/vaccines8040695"},{"key":"e_1_3_5_62_2","doi-asserted-by":"publisher","DOI":"10.1007\/5584_2019_404"},{"key":"e_1_3_5_63_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiae034"},{"key":"e_1_3_5_64_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiad332"},{"key":"e_1_3_5_65_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12916-015-0382-8"},{"key":"e_1_3_5_66_2","doi-asserted-by":"publisher","DOI":"10.1098\/rspb.2015.2309"},{"key":"e_1_3_5_67_2","doi-asserted-by":"publisher","DOI":"10.1007\/82_2022_260"},{"key":"e_1_3_5_68_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciz840"},{"key":"e_1_3_5_69_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI163121"},{"key":"e_1_3_5_70_2","doi-asserted-by":"publisher","DOI":"10.1099\/00221287-63-2-211"},{"key":"e_1_3_5_71_2","doi-asserted-by":"publisher","DOI":"10.1016\/0076-6879(94)35161-9"},{"key":"e_1_3_5_72_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1010402"},{"key":"e_1_3_5_73_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.67.8.3727-3732.1999"},{"key":"e_1_3_5_74_2","doi-asserted-by":"publisher","DOI":"10.3390\/toxins12090596"},{"key":"e_1_3_5_75_2","first-page":"47","article-title":"Toxicity and immunogenicity of pertussis whole cell vaccine in one animal model","volume":"111","author":"van Straaten I","year":"2002","unstructured":"van Straaten I, Levels L, van der Ark A, Thalen M, Hendriksen C. 2002. Toxicity and immunogenicity of pertussis whole cell vaccine in one animal model. Dev Biol (Basel) 111:47\u201355.","journal-title":"Dev Biol (Basel)"}],"container-title":["mSphere"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/msphere.00639-24","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/msphere.00639-24","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,29]],"date-time":"2025-04-29T13:00:59Z","timestamp":1745931659000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/msphere.00639-24"}},"subtitle":[],"editor":[{"given":"Marcela F.","family":"Pasetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,4,29]]},"references-count":74,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2025,4,29]]}},"alternative-id":["10.1128\/msphere.00639-24"],"URL":"https:\/\/doi.org\/10.1128\/msphere.00639-24","relation":{},"ISSN":["2379-5042"],"issn-type":[{"value":"2379-5042","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,29]]},"assertion":[{"value":"2024-07-27","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-01-31","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-12","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e00639-24"}}