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Development of maternally administered vaccines is under consideration, but to provide adequate protection, an understanding of serotypes causing invasive disease in this population is essential. We describe the genomic characteristics of a collection of neonatal <jats:italic>E. coli<\/jats:italic> isolates from a tertiary hospital in Blantyre, Malawi, with specific reference to potential protection by vaccines under development.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>Neonatal blood or cerebrospinal fluid cultures from 2012 to 2021 identified 208 <jats:italic>E. coli<\/jats:italic> isolates, and 169 could be recovered for sequencing.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Our data shows very high diversity in sequence types, LPS O-antigen-type and flagellar H-type, which all show temporal fluctuations and, as far as we are aware previously undescribed diversity, including ten putative novel O-types. Vaccines in clinical trials target the O-antigen but would only protect against less than half (37.9%) of neonatal sepsis cases in this population (EXPEC9V). An O-antigen-based vaccine would require 30 different O-types to protect against 80% of infections.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>Vaccines against neonatal sepsis in Africa are of considerable potential value, but their development requires larger studies to establish the diversity and stability over time of relevant O-types for this population.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1038\/s43856-025-01007-1","type":"journal-article","created":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T17:38:08Z","timestamp":1752860288000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["High diversity of Escherichia coli causing invasive disease in neonates in Malawi poses challenges for O-antigen based vaccine approach"],"prefix":"10.1038","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-6285-0893","authenticated-orcid":false,"given":"Oliver","family":"Pearse","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2772-5779","authenticated-orcid":false,"given":"Allan","family":"Zuza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edith","family":"Tewesa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Siyabu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice J.","family":"Fraser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Cornick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kondwani","family":"Kawaza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Musicha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4432-8505","authenticated-orcid":false,"given":"Nicholas R.","family":"Thomson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4041-1405","authenticated-orcid":false,"given":"Nicholas A.","family":"Feasey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4413-3756","authenticated-orcid":false,"given":"Eva","family":"Heinz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,18]]},"reference":[{"key":"1007_CR1","unstructured":"United Nations. 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