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Our study endeavors to elucidate these immunological changes, enhancing our comprehension of maternal and fetal health outcomes. By analyzing immune profiles and cytokine responses, we aim to provide valuable insights into the impact of mRNA\u2010S vaccination on the delicate balance of immune regulation during pregnancy, addressing critical questions in the field of reproductive pharmacology.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objectives<\/jats:title><jats:p>This investigation sought to examine the prospective influence of mRNA\u2010S\u2010based vaccines and extracellular vesicles (EVs) containing the Spike (S) protein at the maternal\u2010fetal interface. Our primary emphasis was on evaluating their effects on maternal decidua cells and fetal chorion trophoblast cells (hFM\u2010CTCs).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We validated the generation of EVs containing the S protein from small human airway epithelial cell lines (HSAECs) following mRNA\u2010S vaccine exposure. We assessed the expression of angiotensin\u2010converting enzyme 2 (ACE2) gene and protein in fetal membranes and the placenta, with specific attention to decidual cells and fetal membrane chorion cells. To assess cellular functionality, these cells were exposed to both recombinant S protein and EVs loaded with S proteins (eSPs).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Our findings revealed that cells and EVs subjected to mRNA\u2010S\u2010based vaccination exhibited altered protein expression levels of S proteins. At the feto\u2010maternal interface, both placental and fetal membrane tissues demonstrated similar ACE\u20102 expression levels. Among individual cellular layers, syncytiotrophoblast cells in the placenta and chorion cells in the fetal membrane exhibited elevated ACE\u20102 expression. Notably, EVs derived from HSAECs activated the MAPK pathway in decidual cells. Additionally, decidual cells displayed a substantial increase in gene expression of chemokines like CXCL\u201010 and CXCL\u201011, as well as proinflammatory cytokines such as IL\u20106 in response to eSPs. However, the levels of Ccl\u20102 and IL\u20101\u03b2 remained unchanged in decidual cells under the same conditions. Conversely, hFM\u2010CTCs demonstrated significant alterations in the proinflammatory cytokines and chemokines with respect to eSPs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>In conclusion, our study indicates that mRNA\u2010S\u2010based maternal vaccination during pregnancy may influence the maternal\u2010fetal interface's COVID\u201019 interaction and immune regulation. Further investigation is warranted to assess safety and implications.<\/jats:p><\/jats:sec>","DOI":"10.1111\/aji.13861","type":"journal-article","created":{"date-parts":[[2024,5,8]],"date-time":"2024-05-08T10:28:17Z","timestamp":1715164097000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["In vitro mRNA\u2010S maternal vaccination induced altered immune regulation at the maternal\u2010fetal interface"],"prefix":"10.1111","volume":"91","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5300-2083","authenticated-orcid":false,"given":"Ananth Kumar","family":"Kammala","sequence":"first","affiliation":[{"name":"Division of Basic Science and Translational Research, Department of Obstetrics &amp; Gynecology The University of Texas Medical Branch at Galveston  Galveston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madhuri","family":"Tatiparthy","sequence":"additional","affiliation":[{"name":"Division of Basic Science and Translational Research, Department of Obstetrics &amp; Gynecology The University of Texas Medical Branch at Galveston  Galveston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tilu Jain","family":"Thomas","sequence":"additional","affiliation":[{"name":"Division of Basic Science and Translational Research, Department of Obstetrics &amp; Gynecology The University of Texas Medical Branch at Galveston  Galveston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Srinivasa Reddy","family":"Bonam","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology University of Texas Medical Branch  Galveston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Istvan","family":"Boldogh","sequence":"additional","affiliation":[{"name":"Director of Cell Biology Core Laboratory, Department of Microbiology University of Texas Medical Branch  Galveston Texas USA"},{"name":"Sealy Institute for Vaccine Sciences University of Texas Medical Branch  Galveston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hu","family":"Haitao","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology University of Texas Medical Branch  Galveston Texas USA"},{"name":"Institute for Human Infections and Immunity University of Texas Medical Branch  Galveston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Surendra","family":"Sharma","sequence":"additional","affiliation":[{"name":"Division of Basic Science and Translational Research, Department of Obstetrics &amp; Gynecology The University of Texas Medical Branch at Galveston  Galveston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9213-6105","authenticated-orcid":false,"given":"Ramkumar","family":"Menon","sequence":"additional","affiliation":[{"name":"Division of Basic Science and Translational Research, Department of Obstetrics &amp; Gynecology The University of Texas Medical Branch at Galveston  Galveston Texas USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,5,8]]},"reference":[{"key":"e_1_2_8_2_1","unstructured":"Prevention. 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