{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"submitter":["Brangulis K"],"funding":["NIAID NIH HHS"],"pubmed_abstract":["The quality of protective immunity plays a critical role in modulating vaccine efficacy, with native antigens often not able to trigger sufficiently strong immune responses for pathogen killing. This warrants creation of structure-based vaccine design, leveraging high-resolution antigen structures for mutagenesis to improve protein stability and efficient immunization strategies. Here, we investigated the mechanisms underlying structure-based vaccine design using CspZ-YA, a vaccine antigen from <i>Borrelia burgdorferi</i>, the bacteria causing Lyme disease (LD), the most common vector-borne disease in the Northern Hemisphere. Compared to wild-type CspZ-YA, we found CspZ-YA<sub>I183Y</sub> and CspZ-YA<sub>C187S</sub> required lower immunization frequency to protect mice from LD-associated manifestations and bacterial colonization. We observed indistinguishable human and mouse antigenicity between wild-type and mutant CspZ-YA proteins after native infection or active immunization. This supports our newly generated, high-resolution structures of CspZ-YA<sub>I183Y</sub> and CspZ-YA<sub>C187S</sub>, showing no altered surface epitopes after mutagenesis. However, CspZ-YA<sub>I183Y</sub> and CspZ-YA<sub>C187S</sub> favored the interactions between helices H and I, consistent with their elevated thermostability. Such findings are further strengthened by increasing ability of protective CspZ-YA monoclonal antibodies in binding to CspZ-YA at a physiological temperature (37°C). Overall, this study demonstrated enhanced intramolecular interactions improved long-term stability of antigens while maintaining protective epitopes, providing a mechanism for structure-based vaccine design. These findings can ultimately be extended to other vaccine antigens against newly emerging pathogens for the improvement of protective immunity."],"journal":["bioRxiv : the preprint server for biology"],"pagination":["2024.10.23.619738"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11565809"],"repository":["biostudies-literature"],"pubmed_title":["Mechanistic insights into structure-based design of a Lyme disease subunit vaccine."],"pmcid":["PMC11565809"],"funding_grant_id":["R01 AI154542","R21 AI144891","R01 AI181746","R44 AI152954"],"pubmed_authors":["Wang A","Pal U","Hsieh CL","Lee J","Bottazzi ME","Malfetano J","Lin YP","Marcinkiewicz AL","Yang X","Liu Z","Brangulis K","Strych U","Chen WH","Chen YL"],"additional_accession":[]},"is_claimable":false,"name":"Mechanistic insights into structure-based design of a Lyme disease subunit vaccine.","description":"The quality of protective immunity plays a critical role in modulating vaccine efficacy, with native antigens often not able to trigger sufficiently strong immune responses for pathogen killing. This warrants creation of structure-based vaccine design, leveraging high-resolution antigen structures for mutagenesis to improve protein stability and efficient immunization strategies. Here, we investigated the mechanisms underlying structure-based vaccine design using CspZ-YA, a vaccine antigen from <i>Borrelia burgdorferi</i>, the bacteria causing Lyme disease (LD), the most common vector-borne disease in the Northern Hemisphere. Compared to wild-type CspZ-YA, we found CspZ-YA<sub>I183Y</sub> and CspZ-YA<sub>C187S</sub> required lower immunization frequency to protect mice from LD-associated manifestations and bacterial colonization. We observed indistinguishable human and mouse antigenicity between wild-type and mutant CspZ-YA proteins after native infection or active immunization. This supports our newly generated, high-resolution structures of CspZ-YA<sub>I183Y</sub> and CspZ-YA<sub>C187S</sub>, showing no altered surface epitopes after mutagenesis. However, CspZ-YA<sub>I183Y</sub> and CspZ-YA<sub>C187S</sub> favored the interactions between helices H and I, consistent with their elevated thermostability. Such findings are further strengthened by increasing ability of protective CspZ-YA monoclonal antibodies in binding to CspZ-YA at a physiological temperature (37°C). Overall, this study demonstrated enhanced intramolecular interactions improved long-term stability of antigens while maintaining protective epitopes, providing a mechanism for structure-based vaccine design. These findings can ultimately be extended to other vaccine antigens against newly emerging pathogens for the improvement of protective immunity.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Oct","modification":"2026-05-26T20:09:53.972Z","creation":"2025-04-21T21:43:46.393Z"},"accession":"S-EPMC11565809","cross_references":{"pubmed":["39554036"],"doi":["10.1101/2024.10.23.619738"]}}