{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T02:02:25Z","timestamp":1760234545918,"version":"build-2065373602"},"reference-count":31,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T00:00:00Z","timestamp":1622505600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000026","name":"National Institute on Drug Abuse","doi-asserted-by":"publisher","award":["UG3DA048351","1DP1DA034787-01"],"award-info":[{"award-number":["UG3DA048351","1DP1DA034787-01"]}],"id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Opioid use disorder (OUD) is a serious health problem that has dramatically increased over the last decade. Although current therapies for the management of OUD can be effective, they have limitations. The complementary strategy to combat the opioid crisis is the development of a conjugate vaccine to generate high affinity antibodies in order to neutralize opioids in circulation before reaching the brain. The components of an opioid vaccine include an opioid hapten (6-AmHap) that is conjugated to a carrier protein (tetanus toxoid) with the addition of adjuvants (Army Liposome Formulation adsorbed to aluminum hydroxide-ALFA). There is no consensus in the literature as to whether preexisting immunity to the carrier protein may impact the immunogenicity of the conjugate vaccine by inducing an enhanced or suppressed immune response to the hapten. Here, we investigated whether pre-exposure to tetanus toxoid would affect the immunogenicity and efficacy of the heroin vaccine, TT-6-AmHap. Mice were primed with diphtheria, tetanus, and acellular pertussis (DTaP) vaccine at weeks -4 and -2, then immunized with TT-6-AmHap vaccine at weeks 0, 3, and 6. Using ELISA and behavioral assays, we found that preexisting immunity to tetanus toxoid had no influence on the immunogenicity and efficacy of the TT-6-AmHap vaccine.<\/jats:p>","DOI":"10.3390\/vaccines9060573","type":"journal-article","created":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T23:07:03Z","timestamp":1622588823000},"page":"573","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Effect of Preexisting Immunity to Tetanus Toxoid on the Efficacy of Tetanus Toxoid-Conjugated Heroin Vaccine in Mice"],"prefix":"10.3390","volume":"9","author":[{"given":"Essie","family":"Komla","sequence":"first","affiliation":[{"name":"Laboratory of Adjuvant and Antigen Research, US Military HIV Research Program, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910, USA"},{"name":"U.S. Military HIV Research Program, Henry M. Jackson Foundation for the Advancement of Military Medicine, 6720A Rockledge Drive, Bethesda, MD 20817, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oscar B.","family":"Torres","sequence":"additional","affiliation":[{"name":"Laboratory of Adjuvant and Antigen Research, US Military HIV Research Program, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910, USA"},{"name":"U.S. Military HIV Research Program, Henry M. Jackson Foundation for the Advancement of Military Medicine, 6720A Rockledge Drive, Bethesda, MD 20817, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rashmi","family":"Jalah","sequence":"additional","affiliation":[{"name":"Laboratory of Adjuvant and Antigen Research, US Military HIV Research Program, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910, USA"},{"name":"U.S. Military HIV Research Program, Henry M. Jackson Foundation for the Advancement of Military Medicine, 6720A Rockledge Drive, Bethesda, MD 20817, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Agnieszka","family":"Sulima","sequence":"additional","affiliation":[{"name":"Drug Design and Synthesis Section, Molecular Targets and Medications Discovery Branch, Intramural Research Program, Department of Health and Human Services, National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 9800 Medical Center Drive, Bethesda, MD 20892-3373, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zoltan","family":"Beck","sequence":"additional","affiliation":[{"name":"Laboratory of Adjuvant and Antigen Research, US Military HIV Research Program, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910, USA"},{"name":"U.S. Military HIV Research Program, Henry M. Jackson Foundation for the Advancement of Military Medicine, 6720A Rockledge Drive, Bethesda, MD 20817, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carl R.","family":"Alving","sequence":"additional","affiliation":[{"name":"Laboratory of Adjuvant and Antigen Research, US Military HIV Research Program, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"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, Department of Health and Human Services, National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 9800 Medical Center Drive, Bethesda, MD 20892-3373, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenner C.","family":"Rice","sequence":"additional","affiliation":[{"name":"Drug Design and Synthesis Section, Molecular Targets and Medications Discovery Branch, Intramural Research Program, Department of Health and Human Services, National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 9800 Medical Center Drive, Bethesda, MD 20892-3373, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"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, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.15585\/mmwr.mm675152e1","article-title":"Drug and Opioid-Involved Overdose Deaths\u2014United States, 2013\u20132017","volume":"67","author":"Scholl","year":"2018","journal-title":"MMWR Morb. Mortal. Wkly. Rep."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"290","DOI":"10.15585\/mmwr.mm6911a4","article-title":"Drug and Opioid-Involved Overdose Deaths\u2014United States, 2017\u20132018","volume":"69","author":"Wilson","year":"2020","journal-title":"MMWR Morb. Mortal. Wkly. Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1126\/scitranslmed.aan2595","article-title":"Medication development in opioid addiction: Meaningful clinical end points","volume":"10","author":"Volkow","year":"2018","journal-title":"Sci. Transl. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1128\/CVI.05438-11","article-title":"Effect of Increased CRM 197 Carrier Protein Dose on Meningococcal C Bactericidal Antibody Response","volume":"19","author":"Lee","year":"2012","journal-title":"Clin. Vaccine Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"4827","DOI":"10.1016\/j.vaccine.2013.07.078","article-title":"Comparison of CRM197, diphtheria toxoid and tetanus toxoid as protein carriers for meningococcal glycoconjugate vaccines","volume":"31","author":"Tontini","year":"2013","journal-title":"Vaccine"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4881","DOI":"10.1016\/j.vaccine.2011.04.053","article-title":"Comparative effects of carrier proteins on vaccine-induced immune response","volume":"29","author":"Knuf","year":"2011","journal-title":"Vaccine"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1674","DOI":"10.1016\/j.vaccine.2009.01.005","article-title":"The influence of carrier protein on the immunogenicity of simultaneously administered conjugate vaccines in infants","volume":"27","author":"Petermann","year":"2009","journal-title":"Vaccine"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1016\/j.vaccine.2014.01.047","article-title":"Carrier priming or suppression: Understanding carrier priming enhancement of anti-polysaccharide antibody response to conjugate vaccines","volume":"32","author":"Pobre","year":"2014","journal-title":"Vaccine"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2334","DOI":"10.1016\/j.vaccine.2016.03.055","article-title":"Carrier priming effect of CRM 197 is related to an enhanced B and T cell activation in meningococcal serogroup A conjugate vaccination. Immunological comparison between CRM 197 and diphtheria toxoid","volume":"34","author":"Pecetta","year":"2016","journal-title":"Vaccine"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5503","DOI":"10.1016\/j.vaccine.2010.02.103","article-title":"Carrier induced epitopic suppression of antibody responses induced by virus-like particles is a dynamic phenomenon caused by carrier-specific antibodies","volume":"28","author":"Jegerlehner","year":"2010","journal-title":"Vaccine"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1016\/S0140-6736(96)06392-1","article-title":"Vaccine failures after primary immunisation with Haemophilus influenzae type-b conjugate vaccine without booster","volume":"349","author":"Booy","year":"1997","journal-title":"Lancet"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/S0022-3476(95)70545-7","article-title":"Effect of neonatal immunization with diphtheria and tetanus toxoids on antibody responses to Haemophilus influenzae type b conjugate vaccines","volume":"126","author":"Lieberman","year":"1995","journal-title":"J. Pediatr."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1128\/iai.59.3.1057-1064.1991","article-title":"Influence of prevaccination immunity on the human B-lymphocyte response to a Haemophilus influenzae type b conjugate vaccine","volume":"59","author":"Barington","year":"1991","journal-title":"Infect. Immun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1128\/iai.61.2.432-438.1993","article-title":"Non-epitope-specific suppression of the antibody response to Haemophilus influenzae type b conjugate vaccines by preimmunization with vaccine components","volume":"61","author":"Barington","year":"1993","journal-title":"Infect. Immun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1021\/acs.bioconjchem.5b00085","article-title":"Efficacy, but Not Antibody Titer or Affinity, of a Heroin Hapten Conjugate Vaccine Correlates with Increasing Hapten Densities on Tetanus Toxoid, but Not on CRM 197 Carriers","volume":"26","author":"Jalah","year":"2015","journal-title":"Bioconjug. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5927","DOI":"10.1007\/s00216-014-8035-x","article-title":"Characterization and optimization of heroin hapten-BSA conjugates: Method development for the synthesis of reproducible hapten-based vaccines","volume":"406","author":"Torres","year":"2014","journal-title":"Anal. Bioanal. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/S0076-6879(03)73003-1","article-title":"Oil-in-Water Liposomal Emulsions for Vaccine Delivery","volume":"373","author":"Matyas","year":"2003","journal-title":"Methods Enzymol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1016\/j.vaccine.2014.01.028","article-title":"Facial recognition of heroin vaccine opiates: Type 1 cross-reactivities of antibodies induced by hydrolytically stable haptenic surrogates of heroin, 6-acetylmorphine, and morphine","volume":"32","author":"Matyas","year":"2014","journal-title":"Vaccine"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"8.9.1","DOI":"10.1002\/0471142301.ns0809s41","article-title":"Models of Nociception: Hot-Plate, Tail-Flick, and Formalin Tests in Rodents","volume":"41","author":"Bannon","year":"2007","journal-title":"Curr. Protoc. Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2093","DOI":"10.1128\/IAI.66.5.2093-2098.1998","article-title":"Reduced Response to Multiple Vaccines Sharing Common Protein Epitopes That Are Administered Simultaneously to Infants","volume":"66","author":"Dagan","year":"1998","journal-title":"Infect. Immun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3504","DOI":"10.1128\/iai.59.10.3504-3510.1991","article-title":"Effect of Carrier Priming on Immunogenicity of Saccharide-Protein Conjugate Vaccines","volume":"59","author":"Peeters","year":"1991","journal-title":"Infect. Immun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1016\/j.micinf.2007.07.010","article-title":"Pre-existing anti-Salmonella vector immunity prevents the development of protective antigen-specific CD8 T-cell frequencies against murine listeriosis","volume":"9","author":"Panthel","year":"2007","journal-title":"Microbes Infect."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.coi.2011.03.006","article-title":"Viral vectors as vaccine platforms: Deployment in sight","volume":"23","author":"Rollier","year":"2011","journal-title":"Curr. Opin. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1099\/mic.0.049601-0","article-title":"Pre-existing immunity against vaccine vectors\u2013friend or foe?","volume":"159","author":"Saxena","year":"2013","journal-title":"Microbiology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2319","DOI":"10.4049\/jimmunol.135.4.2319","article-title":"Carrier-induced epitopic suppression, a major issue for future synthetic vaccines","volume":"135","author":"Schutze","year":"1985","journal-title":"J. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/S0165-2478(98)00073-X","article-title":"Effect of pre-existing carrier immunity on the efficacy of synthetic influenza vaccine","volume":"64","author":"Arnon","year":"1998","journal-title":"Immunol. Lett."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1021\/acs.jmedchem.7b01427","article-title":"A Stable Heroin Analogue That Can Serve as a Vaccine Hapten to Induce Antibodies That Block the Effects of Heroin and Its Metabolites in Rodents and That Cross-React Immunologically with Related Drugs of Abuse","volume":"61","author":"Sulima","year":"2018","journal-title":"J. Med. Chem"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2635","DOI":"10.4049\/jimmunol.142.8.2635","article-title":"Carrier-induced epitopic suppression is initiated through clonal dominance","volume":"142","author":"Schutze","year":"1989","journal-title":"J. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"184","DOI":"10.3109\/08923973.2016.1165246","article-title":"The effect of preexisting anti-carrier immunity on subsequent responses to CRM 197 or Qb-VLP conjugate vaccines","volume":"38","author":"McCluskie","year":"2016","journal-title":"Immunopharmacol. Immunotoxicol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/j.vaccine.2014.11.026","article-title":"Carrier priming with CRM197 or diphtheria toxoid has a different impact on the immunogenicity of the respective glycoconjugates: Biophysical and immunochemical interpretation","volume":"33","author":"Pecetta","year":"2015","journal-title":"Vaccine"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3208","DOI":"10.1016\/j.vaccine.2015.04.094","article-title":"Moderate PEGylation of the carrier protein improves the polysaccharide-specific immunogenicity of meningococcal group A polysaccharide conjugate vaccine","volume":"33","author":"Zhang","year":"2015","journal-title":"Vaccine"}],"container-title":["Vaccines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-393X\/9\/6\/573\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:09:44Z","timestamp":1760162984000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-393X\/9\/6\/573"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,1]]},"references-count":31,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2021,6]]}},"alternative-id":["vaccines9060573"],"URL":"https:\/\/doi.org\/10.3390\/vaccines9060573","relation":{},"ISSN":["2076-393X"],"issn-type":[{"type":"electronic","value":"2076-393X"}],"subject":[],"published":{"date-parts":[[2021,6,1]]}}}