{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T15:47:29Z","timestamp":1791388049136,"version":"4.3.3"},"reference-count":162,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T00:00:00Z","timestamp":1774310400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000199","name":"U.S. Department of Agriculture\u2019s National Institute of Food and Agriculture","doi-asserted-by":"publisher","award":["2026-67015-45733"],"award-info":[{"award-number":["2026-67015-45733"]}],"id":[{"id":"10.13039\/100000199","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Bio and Agro-Defense Facility Transition Fund"},{"DOI":"10.13039\/100000199","name":"USDA National Institute of Food and Agriculture","doi-asserted-by":"publisher","award":["1021491"],"award-info":[{"award-number":["1021491"]}],"id":[{"id":"10.13039\/100000199","id-type":"DOI","asserted-by":"publisher"}]},{"name":"USDA ARS Non-Assistance Cooperative Agreements","award":["58-8064-8-011"],"award-info":[{"award-number":["58-8064-8-011"]}]},{"name":"USDA ARS Non-Assistance Cooperative Agreements","award":["58-8064-9-007"],"award-info":[{"award-number":["58-8064-9-007"]}]},{"name":"USDA ARS Non-Assistance Cooperative Agreements","award":["58-3020-9-020"],"award-info":[{"award-number":["58-3020-9-020"]}]},{"name":"USDA NIFA Subaward","award":["#25-6226-0633-002"],"award-info":[{"award-number":["#25-6226-0633-002"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathogens"],"abstract":"<jats:p>Porcine reproductive and respiratory syndrome (PRRS) remains one of the most economically devastating diseases in global swine production. The causative agent, PRRS virus (PRRSV), comprises two genetically distinct species\u2014PRRSV-1 and PRRSV-2\u2014that differ substantially in antigenic composition and immune recognition. Despite widespread use of modified live vaccines (MLVs), protection against heterologous and cross-species strains remains inconsistent and difficult to predict. This review synthesizes current knowledge of homologous, heterologous, and cross-species protection, with emphasis on humoral and cellular immune responses and the viral determinants that constrain breadth of immunity. Neutralizing antibodies can confer near-sterilizing homologous protection under controlled conditions; however, their delayed induction and narrow specificity limit efficacy against heterologous strains. T-cell-mediated responses are generally broader but remain highly strain- and context-dependent. Structural features of PRRSV envelope glycoproteins, including glycan shielding and immunodominant decoy epitopes, further restrict antibody-mediated cross-protection while providing targets for rational vaccine design. We also examine potential drawbacks of preexisting immunity, including antigenic mismatch and non-neutralizing antibody-dominated responses that may contribute to suboptimal outcomes following heterologous exposure. Collectively, these findings highlight the multifactorial nature of PRRSV protection and the need for next-generation vaccines capable of inducing broader and more durable immunity.<\/jats:p>","DOI":"10.3390\/pathogens15040345","type":"journal-article","created":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T08:02:49Z","timestamp":1774339369000},"page":"345","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Cross-Protection in PRRSV: Mechanisms, Limitations, and Implications for Vaccine Design"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8823-2513","authenticated-orcid":false,"given":"Sergei A.","family":"Raev","sequence":"first","affiliation":[{"name":"Center on Biologics Development and Evaluation, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA"},{"name":"Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Limeng","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Muro","sequence":"additional","affiliation":[{"name":"Center on Biologics Development and Evaluation, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA"},{"name":"Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6809-6956","authenticated-orcid":false,"given":"Rachel","family":"Madera","sequence":"additional","affiliation":[{"name":"Center on Biologics Development and Evaluation, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA"},{"name":"Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7951-4175","authenticated-orcid":false,"given":"Lihua","family":"Wang","sequence":"additional","affiliation":[{"name":"Center on Biologics Development and Evaluation, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA"},{"name":"Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7177-9280","authenticated-orcid":false,"given":"Jishu","family":"Shi","sequence":"additional","affiliation":[{"name":"Center on Biologics Development and Evaluation, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA"},{"name":"Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.virusres.2010.08.014","article-title":"Molecular epidemiology of PRRSV: A phylogenetic perspective","volume":"154","author":"Shi","year":"2010","journal-title":"Virus Res."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Zhou, L., Ge, X., and Yang, H. 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