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This co-evolutionary process poses a fundamental challenge to the development of broadly effective vaccines and diagnostics against a diversifying pathogen. Based on surveys of natural allele frequencies and experimental immunization of mice, we show high antigenic specificities of natural variants of the outer surface protein C (OspC), a dominant antigen of a Lyme Disease-causing bacterium (Borrelia burgdorferi). To overcome the challenge of OspC antigenic diversity to clinical development of preventive measures, we implemented a number of evolution-informed strategies to broaden OspC antigenic reactivity. In particular, the centroid algorithm\u2014a genetic algorithm to generate sequences that minimize amino-acid differences with natural variants\u2014generated synthetic OspC analogs with the greatest promise as diagnostic and vaccine candidates against diverse Lyme pathogen strains co-existing in the Northeast United States. Mechanistically, we propose a model of maximum antigen diversification (MAD) mediated by amino-acid variations distributed across the hypervariable regions on the OspC molecule. Under the MAD hypothesis, evolutionary centroids display broad cross-reactivity by occupying the central void in the antigenic space excavated by diversifying natural variants. In contrast to vaccine designs based on concatenated epitopes, the evolutionary algorithms generate analogs of natural antigens and are automated. The novel centroid algorithm and the evolutionary antigen designs based on consensus and ancestral sequences have broad implications for combating diversifying pathogens driven by pathogen\u2013host co-evolution.<\/jats:p>","DOI":"10.1038\/s41396-021-01089-4","type":"journal-article","created":{"date-parts":[[2021,8,19]],"date-time":"2021-08-19T15:04:41Z","timestamp":1629385481000},"page":"447-464","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Maximum antigen diversification in a lyme bacterial population and evolutionary strategies to overcome pathogen diversity"],"prefix":"10.1093","volume":"16","author":[{"given":"Lia","family":"Di","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, Hunter College, City University of New York , New York, NY,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9084-9379","authenticated-orcid":false,"given":"Saymon","family":"Akther","sequence":"additional","affiliation":[{"name":"Graduate Center, City University of New York , New York, NY,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1250-1027","authenticated-orcid":false,"given":"Edgaras","family":"Bezrucenkovas","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Hunter College, City University of New York , New York, NY,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larisa","family":"Ivanova","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center , Memphis, TN,","place":["USA"]},{"name":"Present address: Pediatrics Department, New York Medical College, Valhalla, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Sulkow","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Hunter College, City University of New York , New York, NY,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Hunter College, City University of New York , New York, NY,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saad","family":"Mneimneh","sequence":"additional","affiliation":[{"name":"Graduate Center, City University of New York , New York, NY,","place":["USA"]},{"name":"Department of Computer Science, Hunter College, City University of New York , New York, NY,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3715-4543","authenticated-orcid":false,"given":"Maria","family":"Gomes-Solecki","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center , Memphis, TN,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4585-1872","authenticated-orcid":false,"given":"Wei-Gang","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Hunter College, City University of New York , New York, NY,","place":["USA"]},{"name":"Graduate Center, City University of New York , New York, NY,","place":["USA"]},{"name":"Department of Physiology and Biophysics & Institute for Computational Biomedicine, Weil Cornell Medical College , New York, NY,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,8,19]]},"reference":[{"key":"2026011505114218700_CR1","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1111\/j.1095-8312.1984.tb00802.x","article-title":"Frequency dependent selection: homage to E. 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