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Our group has identified extracellular loops (ECLs) of\n                      <jats:italic toggle=\"yes\">TPA<\/jats:italic>\n                      BamA (TP0326) and members of the FadL family (TP0548, TP0856, TP0858, TP0859, and TP0865) as potential components of a multivalent vaccine cocktail. As part of a consortium to explore\n                      <jats:italic toggle=\"yes\">TPA<\/jats:italic>\n                      strain diversity, we mapped the variability of BamA and FadL orthologs in 186\n                      <jats:italic toggle=\"yes\">TPA<\/jats:italic>\n                      strains from Malawi, China, and Colombia onto predicted 3D structures. The 186 genomes fell into eight subclades (five Nichols- and three SS14-lineage) with substantial geographic restriction. Single nucleotide variants accounted for the large majority of proteoforms, with variability notably higher within the Nichols-lineage strains. Most mutations were in regions of the proteins predicted to be extracellular and harboring B cell epitopes. We observed a striking difference in the degree of variability between the six OMPs, suggesting that these proteins are following divergent evolutionary paths. Concatenation of OMP sequences recapitulated the phylogenetic structure of the\n                      <jats:italic toggle=\"yes\">TPA<\/jats:italic>\n                      strains, effectively segregating within clades and largely clustering by subclades. Finally, we noted that BamA and FadL candidate ECL vaccinogens, previously shown to elicit antibodies that kill treponemes during\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      cultivation, are well conserved. Taken as a whole, our study establishes a structural-phylogenetic approach for analyzing the forces shaping the host-pathogen interface in syphilis within endemic populations while informing the selection of vaccine targets.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        Syphilis remains a major global health concern, reinforcing the need for a safe and effective vaccine. Understanding the variability of\n                        <jats:italic toggle=\"yes\">TPA<\/jats:italic>\n                        OMPs is essential for tracking pathogen evolution and informing vaccine design. Here, we analyzed the variability of six\n                        <jats:italic toggle=\"yes\">TPA<\/jats:italic>\n                        OMPs in 186 strains from Malawi, China, and Colombia, identifying protein-specific evolutionary patterns. Most mutations were localized in extracellular regions and, notably, appeared to correlate with the phylogenetic structure of\n                        <jats:italic toggle=\"yes\">TPA<\/jats:italic>\n                        . Despite OMP heterogeneity, several candidate vaccinogens remained highly conserved, reinforcing their potential as globally effective vaccine targets. Our study establishes a structural-phylogenetic framework for dissecting the forces shaping the host-spirochete interface within endemic populations and provides a foundation for designing a globally effective syphilis vaccine.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/jb.00159-25","type":"journal-article","created":{"date-parts":[[2025,7,14]],"date-time":"2025-07-14T13:00:47Z","timestamp":1752498047000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":7,"title":["Sequence variability of BamA and FadL candidate vaccinogens suggests divergent evolutionary paths of\n                    <i>Treponema pallidum<\/i>\n                    outer membrane proteins"],"prefix":"10.1128","volume":"207","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5095-2198","authenticated-orcid":true,"given":"Everton 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