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While existing medications for managing OUD are proven to be effective, they also present certain challenges. A vaccine offers a promising therapeutic strategy to combat OUD and potentially reduce the risk of overdose death. The TT-6-AmHap heroin conjugate vaccine has effectively reduced heroin-induced pharmacological effects in behavioral assays as well as demonstrated the induction of high titer and high affinity antibody responses in mice and rats. In this GLP study conducted in rabbits, the potential local and systemic toxicity of the TT-6-AmHap heroin vaccine in combination with or without adjuvants ALF43 and Alhydrogel\u00ae (ALFA) was investigated. Methods: Male and female New Zealand White rabbits were administered with vaccines or a saline control intramuscularly at two-week intervals over a 57-day study period. The presence, persistence or reversibility of any toxic effects of the vaccine was determined over a four-week recovery period. Results: Administration of TT-6-AmHap with or without the adjuvants induced high antibody-specific IgG in treatment groups compared to the controls. The study found no TT-6-AmHap-related effects on mortality, physical examinations, dermal Draize observations, body weights, body weight changes, food consumption, ophthalmology, clinical pathology (hematology, coagulation, clinical chemistry, and urinalysis), macroscopic pathology, or organ weights. Conclusions: Under the conditions of this study, these results demonstrate that the TT-6-AmHap vaccine with or without adjuvants was well tolerated, immunogenic, and the effects were not considered adverse in both male and female rabbits.<\/jats:p>","DOI":"10.3390\/vaccines13080792","type":"journal-article","created":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T10:51:14Z","timestamp":1753699874000},"page":"792","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Safety and Toxicology Profile of TT-6-AmHap Heroin Conjugate Vaccine"],"prefix":"10.3390","volume":"13","author":[{"given":"Essie","family":"Komla","sequence":"first","affiliation":[{"name":"Laboratory of Adjuvant and Antigen Research, US Military HIV Research Program, Center for Military Infectious Diseases Research, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910, USA"},{"name":"Henry M. Jackson Foundation for the Advancement of Military Medicine, 6720A Rockledge Drive, Bethesda, MD 20817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erwin G.","family":"Abucayon","sequence":"additional","affiliation":[{"name":"Laboratory of Adjuvant and Antigen Research, US Military HIV Research Program, Center for Military Infectious Diseases Research, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910, USA"},{"name":"Henry M. Jackson Foundation for the Advancement of Military Medicine, 6720A Rockledge Drive, Bethesda, MD 20817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. Steven","family":"Godin","sequence":"additional","affiliation":[{"name":"Inotiv, 13 Firstfield Rd., Suite 110, Gaithersburg, MD 20878, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8849-9736","authenticated-orcid":false,"given":"Agnieszka","family":"Sulima","sequence":"additional","affiliation":[{"name":"Drug Design and Synthesis Section, Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Department of Health and Human Services, 9800 Medical Center Drive, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0011-8354","authenticated-orcid":false,"given":"Arthur E.","family":"Jacobson","sequence":"additional","affiliation":[{"name":"Drug Design and Synthesis Section, Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Department of Health and Human Services, 9800 Medical Center Drive, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenner C.","family":"Rice","sequence":"additional","affiliation":[{"name":"Drug Design and Synthesis Section, Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Department of Health and Human Services, 9800 Medical Center Drive, Bethesda, MD 20892, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2074-2373","authenticated-orcid":false,"given":"Gary R.","family":"Matyas","sequence":"additional","affiliation":[{"name":"Laboratory of Adjuvant and Antigen Research, US Military HIV Research Program, Center for Military Infectious Diseases Research, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,26]]},"reference":[{"key":"ref_1","unstructured":"Ahmad, F.B., Cisewski, J.A., Rossen, L.M., and Sutton, P. 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