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Although vaccines currently in use in humans have robust safety records, historical examples show that some vaccines have resulted in adverse outcomes, including vaccine-associated enhanced respiratory disease (VAERD). VAERD occurs when preexisting vaccine-induced immunity worsens respiratory disease, rather than conferring protection during infection. Enhanced disease in the lower respiratory tract characteristic of VAERD includes worsened clinical manifestations such as pneumonia and bronchiolitis, as well as increased pulmonary pathology in vaccinated, infected individuals compared with their unvaccinated, infected counterparts. Mechanistically, VAERD has been associated with TH2-mediated immunopathology or antibody-dependent enhancement and is primarily associated with specific virus families, including Pneumoviridae, Orthomyxoviridae and Coronaviridae. Notable cases of VAERD have been associated with a respiratory syncytial virus vaccine candidate evaluated in clinical trials in the 1960s, experimental coronavirus vaccines in animal models, and in veterinary vaccines for influenza virus in swine. Existing approved vaccines are safe and highly effective tools for protecting both humans and animals against respiratory pathogens. However, as new respiratory vaccines are developed, they must also undergo careful testing for VAERD or other adverse outcomes. This review aims to provide the field with an overview of VAERD as a resource to support vaccine development and safety studies.<\/jats:p>","DOI":"10.3390\/vaccines14090799","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T14:11:22Z","timestamp":1789049482000},"page":"799","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Vaccine-Associated Enhanced Respiratory Disease: From Animal Models to Human Health"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6560-1494","authenticated-orcid":false,"given":"Jacob A.","family":"Dillard","sequence":"first","affiliation":[{"name":"Department of Microbiology & Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7573-8818","authenticated-orcid":false,"given":"Reina A.","family":"Saldivar","sequence":"additional","affiliation":[{"name":"Texas Biomedical Research Institute, San Antonio, TX 78227, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark T.","family":"Heise","sequence":"additional","affiliation":[{"name":"Department of Microbiology & Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"},{"name":"Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0916-360X","authenticated-orcid":false,"given":"Victoria K.","family":"Baxter","sequence":"additional","affiliation":[{"name":"Texas Biomedical Research Institute, San Antonio, TX 78227, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"eabe0948","DOI":"10.1126\/scitranslmed.abe0948","article-title":"Prospects for a Safe COVID-19 Vaccine","volume":"12","author":"Haynes","year":"2020","journal-title":"Sci. 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