{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T00:52:48Z","timestamp":1760057568843,"version":"build-2065373602"},"reference-count":43,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,2,13]],"date-time":"2025-02-13T00:00:00Z","timestamp":1739404800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"USA NIH, National Institute on Drug Abuse (NIDA)","award":["R01-DA025223"],"award-info":[{"award-number":["R01-DA025223"]}]},{"name":"John O\u2019Quinn Foundation","award":["R01-DA025223"],"award-info":[{"award-number":["R01-DA025223"]}]},{"name":"Waggoner Chair Endowment","award":["R01-DA025223"],"award-info":[{"award-number":["R01-DA025223"]}]},{"name":"Toomim Foundation","award":["R01-DA025223"],"award-info":[{"award-number":["R01-DA025223"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Background: Cocaine and illicit amphetamines (disguised as \u201cAdderall\u201d) are being laced with fentanyl and producing accidental and intentional fatal overdoses. Vaccines can prevent these overdoses, but 33% of humans generate insufficient anti-drug antibody (AB) levels. Plasma microRNAs (miRs) can be used to predict non-responders. We have plasma stored from 152 cocaine vaccine trial participants following three vaccinations over 9 weeks and examined miRs as potential response biomarkers. Methods: We compared 2517 miRs before anti-cocaine vaccination in participants with the highest (n = 25) to the lowest (n = 23) antibody levels. False Discovery Rates (FDRs) were applied to identify differentially expressed (DE) miRs. We used miR target prediction pipelines to identify the miR-regulated genes. Results: Using a DE-FDR &lt; 0.05 and a &gt;3-fold difference between high- and low-AB responders yielded 12 miRs down and 3 miRs up compared to low-AB patients. Furthermore, 11 among 1673 genes were targeted by 3 or more of the 12 down DE-miRs. Conclusions: A significant DE-miR for identifying optimal antibody responders replicated previous vaccine study predictors (miR-150), and several more miRs appear to be strong candidates for future consideration in replications based upon significance of individual DE-miRs and upon multiple miRs converging on individual genes.<\/jats:p>","DOI":"10.3390\/vaccines13020181","type":"journal-article","created":{"date-parts":[[2025,2,13]],"date-time":"2025-02-13T05:10:22Z","timestamp":1739423422000},"page":"181","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Plasma microRNAs to Select Optimal Patients for Antibody Production from Anti-Addiction Vaccines"],"prefix":"10.3390","volume":"13","author":[{"given":"Thomas R.","family":"Kosten","sequence":"first","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, Department of Pharmacology, Department of Neuroscience, Department of Immunology, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amrit","family":"Koirala","sequence":"additional","affiliation":[{"name":"Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David A.","family":"Nielsen","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Coreen B.","family":"Domingo","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3120-6397","authenticated-orcid":false,"given":"Ynhi T.","family":"Thomas","sequence":"additional","affiliation":[{"name":"Henry J.N. Taub Hospital Department of Emergency Medicine, Baylor College of Medicine, Houston, TX 77030, USA"},{"name":"Michael E. DeBakey VA Medical Center, Center for Innovations in Quality, Effectiveness, and Safety, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Preethi H.","family":"Gunaratne","sequence":"additional","affiliation":[{"name":"Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristian","family":"Coarfa","sequence":"additional","affiliation":[{"name":"Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1001\/jamapsychiatry.2020.4148","article-title":"The Hidden Epidemic of Opioid Overdoses During the Coronavirus Disease 2019 Pandemic","volume":"78","author":"Kosten","year":"2021","journal-title":"JAMA Psychiatry"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"110985","DOI":"10.1016\/j.drugalcdep.2023.110985","article-title":"Prevalence of fentanyl in methamphetamine and cocaine samples collected by community-based drug checking services","volume":"252","author":"Wagner","year":"2023","journal-title":"Drug Alcohol Depend."},{"key":"ref_3","unstructured":"Substance Abuse and Mental Health Services Administration (2025, February 02). Results from the 2022 National Survey on Drug Use and Health: A Companion Infographic (SAMHSA Publication No. PEP23-07-01-007). Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration, Available online: https:\/\/www.samhsa.gov\/data\/report\/2022-nsduh-infographic."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"120098","DOI":"10.1016\/j.jns.2021.120098","article-title":"Current Status of Vaccines for Substance Use Disorders: A Brief Review of Human Studies","volume":"434","author":"Truong","year":"2021","journal-title":"J. Neurol. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1038\/s41541-022-00439-3","article-title":"Circulating extracellular vesicle microRNAs associated with adverse reactions, proinflammatory cytokine, and antibody production after COVID-19 vaccination","volume":"7","author":"Miyashita","year":"2022","journal-title":"NPJ Vaccines"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1016\/j.immuni.2010.10.002","article-title":"Vaccine Adjuvants: Putting Innate Immunity to Work","volume":"33","author":"Coffman","year":"2010","journal-title":"Immunity"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1176\/appi.ajp.20230828","article-title":"Vaccine as Immunotherapies for Substance Use Disorders","volume":"181","author":"Kosten","year":"2024","journal-title":"Am. J. Psychiatry"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Kosten, T.R., Domingo, C.B., Haile, C.N., and Nielsen, D.A. (2022). A clinical trial of Entolimod a TLR-5 adjuvant for anti-drug vaccines using diphtheria or tetanus carrier proteins. Vaccines, 10.","DOI":"10.3390\/vaccines10101592"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2286","DOI":"10.1002\/eji.201546178","article-title":"Aging of the Immune System: Focus on Inflammation and Vaccination","volume":"46","author":"Pinti","year":"2016","journal-title":"Eur. J. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1007\/s10522-015-9578-8","article-title":"Inflammaging Decreases Adaptive and Innate Immune Responses in Mice and Humans","volume":"17","author":"Frasca","year":"2016","journal-title":"Biogerontology"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Agarwal, K., Manza, P., Chapman, M., Nawal, N., Biesecker, E., McPherson, K., Dennis, E., Johnson, A., Volkow, N.D., and Joseph, P.V. (2022). Inflammatory Markers in Substance Use and Mood Disorders: A Neuroimaging Perspective. Front. Psychiatry, 13.","DOI":"10.3389\/fpsyt.2022.863734"},{"key":"ref_12","first-page":"3913","article-title":"Upregulation of miRNA-140-5p Inhibits Inflammatory Cytokines in Acute Lung Injury Through the MyD88\/NFkappaB Signaling Pathway by Targeting TLR4","volume":"16","author":"Yang","year":"2018","journal-title":"Exp. Ther. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1016\/j.bbrc.2018.04.146","article-title":"Activation of TLR3 and Its Adaptor TICAM-1 Increases miR-21 Levels in Extracellular Vesicles Released From Human Cells","volume":"500","author":"Fukushima","year":"2018","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1946","DOI":"10.1002\/hep.25873","article-title":"Circulating microRNAs in Exosomes Indicate Hepatocyte Injury and Inflammation in Alcoholic, Drug-Induced, and Inflammatory Liver Diseases","volume":"56","author":"Bala","year":"2012","journal-title":"Hepatology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"7321","DOI":"10.1038\/ncomms8321","article-title":"Exosome-Delivered microRNAs Modulate the Inflammatory Response to Endotoxin","volume":"6","author":"Alexander","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1038\/nri2708","article-title":"Physiological and pathological roles for microRNAs in the immune system","volume":"10","author":"Rao","year":"2010","journal-title":"Nat. Rev. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3362","DOI":"10.4049\/jimmunol.1101235","article-title":"MicroRNA-21 Limits In Vivo Immune Response-Mediated Activation of the IL-12\/IFN-gamma Pathway, Th1 Polarization, and the Severity of Delayed-Type Hypersensitivity","volume":"187","author":"Lu","year":"2011","journal-title":"J. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"103849","DOI":"10.1016\/j.dci.2020.103849","article-title":"MicroRNA-21-5p Targets PDCD4 to Modulate Apoptosis and Inflammatory Response to Clostridium Perfringens Beta2 Toxin Infection in IPEC-J2 Cells","volume":"114","author":"Gao","year":"2021","journal-title":"Dev. Comp. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.trsl.2011.01.007","article-title":"MicroRNA, a new paradigm for understanding immunoregulation, inflammation, and autoimmune diseases","volume":"157","author":"Dai","year":"2011","journal-title":"Transl. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1002\/jcp.25056","article-title":"MicroRNA as Biomarkers and Diagnostics","volume":"231","author":"Wang","year":"2016","journal-title":"J. Cell Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Haralambieva, I.H., Ratishvili, T., Goergen, K.M., Grill, D.E., Simon, W.L., Chen, J., Ovsyannikova, I.G., Poland, G.A., and Kennedy, R.B. (2024). Effect of Lymphocyte miRNA Expression on Influenza Vaccine-Induced Immunity. medRxiv.","DOI":"10.2139\/ssrn.5012025"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"108574","DOI":"10.1016\/j.isci.2023.108574","article-title":"Global blood miRNA profiling unravels early signatures of immunogenicity of Ebola vaccine rVSV\u0394G-ZEBOV-GP","volume":"26","author":"Vianello","year":"2023","journal-title":"iScience"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1007\/s10753-018-0896-2","article-title":"Mir-410-3p suppresses cytokine release from fibroblast-like synoviocytes by regulating NF-kappaB signaling in rheumatoid arthritis","volume":"42","author":"Wang","year":"2019","journal-title":"Inflammation"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1111\/1756-185X.14160","article-title":"Downregulation of miR-98-5p expression induces interleukin-6 expression in rheumatoid fibroblast-like synoviocytes","volume":"24","author":"Wang","year":"2021","journal-title":"Int. J. Rheum. Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"101520","DOI":"10.1016\/j.isci.2020.101520","article-title":"Aging-associated extracellular vesicles contain immune regulatory microRNAs alleviating hyperinflammatory state and immune dysfunction in the elderly","volume":"23","author":"Tsukamoto","year":"2020","journal-title":"iScience"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.drugalcdep.2014.04.003","article-title":"Vaccine for cocaine dependence: A randomized double-blind placebo-controlled efficacy trial","volume":"140","author":"Kosten","year":"2014","journal-title":"Drug Alcohol Depend."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1111\/j.1521-0391.2013.00314.x","article-title":"Spontaneous development of IgM anti-cocaine antibodies in habitual cocaine users: Effect on IgG antibody responses to a cocaine cholera toxin B conjugate vaccine","volume":"22","author":"Orson","year":"2013","journal-title":"Am. J. Addict."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Kosten, T.R., Domingo, C.B., Haile, C.N., and Norton, E.B. (2022). Anti-cocaine IgA rather than IgG mediates vaccine protection from cocaine use. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14112368"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: Ultrafast universal RNA-seq aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"D155","DOI":"10.1093\/nar\/gky1141","article-title":"miRBase: From microRNA sequences to function","volume":"47","author":"Kozomara","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Matias-Garcia, P.R., Wilson, R., Mussack, V., Reischl, E., Waldenberger, M., Gieger, C., Anton, G., Peters, A., and Kuehn-Steven, A. (2020). Impact of long-term storage and freeze-thawing on eight circulating microRNAs in plasma samples. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0227648"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"D127","DOI":"10.1093\/nar\/gkz757","article-title":"miRDB: An online database for prediction of functional microRNA targets","volume":"48","author":"Chen","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/75556","article-title":"Gene ontology: Tool for the unification of biology","volume":"25","author":"Ashburner","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.jgg.2021.01.007","article-title":"Pathway analysis for genome-wide genetic variation data: Analytic principles, latest developments, and new opportunities","volume":"48","author":"Silberstein","year":"2021","journal-title":"J. Genet. Genom."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1038\/cmi.2012.62","article-title":"The role of microRNAs in B-cell development and function","volume":"10","author":"Li","year":"2013","journal-title":"Cell. Mol. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1631\/jzus.B1200292","article-title":"MicroRNAs in the regulation of immune response against infections","volume":"14","author":"Zhang","year":"2013","journal-title":"J. Zhejiang Univ. Sci. B."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Chandan, K., Gupta, M., and Sarwat, M. (2020). Role of Host and Pathogen-Derived MicroRNAs in Immune Regulation During Infectious and Inflammatory Diseases. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.03081"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Girardi, C., De Pitt\u00e0, C., Casara, S., Calura, E., Romualdi, C., Celotti, L., and Mognato, M. (2014). Integration analysis of microRNA and mRNA expression profiles in human peripheral blood lymphocytes cultured in modeled microgravity. BioMed Res. Int., 2014.","DOI":"10.1155\/2014\/296747"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"de Candia, P., Torri, A., Gorletta, T., Fedeli, M., Bulgheroni, E., Cheroni, C., Marabita, F., Crosti, M., Moro, M., and Pariani, E. (2013). Intracellular modulation, extracellular disposal and serum increase of MiR-150 mark lymphocyte activation. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0075348"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"7080","DOI":"10.1073\/pnas.0702409104","article-title":"miR-150, a microRNA expressed in mature B and T cells, blocks early B cell development when expressed prematurely","volume":"104","author":"Zhou","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1093\/intimm\/dxad017","article-title":"cell differentiation from germinal centers","volume":"35","author":"Inoue","year":"2023","journal-title":"Int. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1111\/imr.12055","article-title":"Role of microRNAs and long-non-coding RNAs in CD4(+) T-cell differentiation","volume":"253","author":"Pagani","year":"2013","journal-title":"Immunol. Rev."},{"key":"ref_43","first-page":"43","article-title":"Serum microRNAs as Biomarkers of Human Lymphocyte Activation in Health and Disease","volume":"5","author":"Torri","year":"2014","journal-title":"Front Immunol."}],"container-title":["Vaccines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-393X\/13\/2\/181\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:32:55Z","timestamp":1760027575000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-393X\/13\/2\/181"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,13]]},"references-count":43,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["vaccines13020181"],"URL":"https:\/\/doi.org\/10.3390\/vaccines13020181","relation":{},"ISSN":["2076-393X"],"issn-type":[{"type":"electronic","value":"2076-393X"}],"subject":[],"published":{"date-parts":[[2025,2,13]]}}}