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Here, we report a POC-compatible serologic test for Lyme disease (LD), leveraging synthetic peptides specific to LD antibodies and a paper-based platform for rapid, and cost-effective diagnosis. Antigenic epitopes conserved across <jats:italic>Borrelia burgdorferi<\/jats:italic> genospecies, targeted by IgG and IgM antibodies, are selected to develop a multiplexed panel for detection of LD antibodies from patient sera. Multiple peptide epitopes, when combined synergistically with a machine learning-based diagnostic model achieve high sensitivity without sacrificing specificity. Blinded validation with 15 LD-positive and 15 negative samples shows 95.5% sensitivity and 100% specificity. Blind testing with the CDC\u2019s LD repository samples confirms the test accuracy, matching lab-based two-tier results, correctly differentiating between LD and look-alike diseases. This LD diagnostic test could potentially replace the cumbersome two-tier testing, improving diagnosis and enabling earlier treatment while facilitating immune monitoring and surveillance.<\/jats:p>","DOI":"10.1038\/s41467-024-51067-5","type":"journal-article","created":{"date-parts":[[2024,8,20]],"date-time":"2024-08-20T10:02:39Z","timestamp":1724148159000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Rapid single-tier serodiagnosis of Lyme disease"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7408-8944","authenticated-orcid":false,"given":"Rajesh","family":"Ghosh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5106-4459","authenticated-orcid":false,"given":"Hyou-Arm","family":"Joung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Artem","family":"Goncharov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barath","family":"Palanisamy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Ngo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7802-3993","authenticated-orcid":false,"given":"Katarina","family":"Pejcinovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1693-1120","authenticated-orcid":false,"given":"Nicole","family":"Krockenberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth J.","family":"Horn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omai B.","family":"Garner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ezdehar","family":"Ghazal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"O\u2019Kula","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul M.","family":"Arnaboldi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1983-1301","authenticated-orcid":false,"given":"Raymond J.","family":"Dattwyler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0717-683X","authenticated-orcid":false,"given":"Aydogan","family":"Ozcan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3942-4284","authenticated-orcid":false,"given":"Dino","family":"Di Carlo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,8,20]]},"reference":[{"key":"51067_CR1","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1016\/j.cca.2019.03.008","volume":"493","author":"H Chen","year":"2019","unstructured":"Chen, H., Liu, K., Li, Z. & Wang, P. 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Some of the peptides described in this study are protected under US patent number 7887815B2 and US provisional patent application nos. 14376409 and 15102002, all owned by Biopeptides, Corp. R.J.D. is a shareholder in Biopeptides, Corp. P.M.A. has a research appointment with Biopeptides Corp. The remaining authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"7124"}}