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This study investigated the immunogenicity and efficacy of a maternal ORF\u2010<jats:italic>B2L<\/jats:italic> genetic vaccine in a pregnant rat model, focusing on maternal\u2013neonatal immune modulation, placental and neonatal spleen transcriptomics and the underlying mechanisms contributing to neonatal immune development. Female rats received intramuscular injections of either a gene vaccine (GV) containing 200\u2009\u03bcg of recombinant ORF\u2010<jats:italic>B2L<\/jats:italic> DNA and 50\u2009\u03bcg of a subunit protein or an empty plasmid as a control. Results showed significantly higher levels of specific anti\u2010<jats:italic>B2L<\/jats:italic> antibodies and Th1 and Th2 cytokine levels in both maternal and neonatal sera from the GV group compared to the control group (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). Transcriptome analysis identified 1295 differentially expressed genes (DEGs) in the placenta and 998 DEGs in the neonatal spleen, with upregulated pathways associated with immune cell recruitment, cytokine signalling and hormone regulation in the GV group. Notably, upregulated DEGs such as <jats:italic>TLR4<\/jats:italic>, <jats:italic>ESR1<\/jats:italic> and various cytokine\/chemokine\u2010related genes in the placenta suggest enhanced immune regulation and foetal protection. In the neonatal spleen, increased expression of <jats:italic>IL\u20101\u03b2<\/jats:italic>, <jats:italic>IL\u20106<\/jats:italic>, <jats:italic>IL\u201010<\/jats:italic> and <jats:italic>CD69<\/jats:italic> indicates enhanced T and B cell development and pathogen defence. The upregulation of <jats:italic>IL\u20101\u03b2<\/jats:italic> suggests a Th1 response, while elevated <jats:italic>IL\u201010<\/jats:italic> indicates a potential Th2\u2010biased immunity, reflecting a balanced Th1\/Th2 response that is crucial for effective adaptive immunity. Overall, maternal ORF\u2010<jats:italic>B2L<\/jats:italic> genetic vaccination induces a robust immune response, enhancing maternal\u2010foetal protection and shaping neonatal immune responses, offering valuable insights for optimizing maternal vaccination strategies.<\/jats:p>","DOI":"10.1111\/imm.13880","type":"journal-article","created":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T03:59:00Z","timestamp":1736222340000},"page":"322-339","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integration of Immune Responses and Transcriptomic Signatures Reveals the Efficacy of Maternal Genetic Vaccination in a Pregnant Model and Its Neonates"],"prefix":"10.1111","volume":"174","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0611-8558","authenticated-orcid":false,"given":"Sohail","family":"Ahmed","sequence":"first","affiliation":[{"name":"Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of 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