{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T02:27:11Z","timestamp":1773196031025,"version":"3.50.1"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T00:00:00Z","timestamp":1758067200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"National Institute of Allergy and Infectious Diseases\u2013funded Broad Agency Agreement","award":["272201800043C-P00001-9999-1"],"award-info":[{"award-number":["272201800043C-P00001-9999-1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,9,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The need for effective infectious disease vaccines has become an inescapable topic in recent years. Continued development of next-generation vaccines that provide robust protective immunity is imperative. Such vaccines will likely include adjuvants that avoid excessive adverse reactions while allowing for dose and antigen sparing. Bacterially derived TLR4 agonist, BECC438, has recently emerged as a lead adjuvant candidate across several experimental models of infectious disease, including Yersinia pestis (plague), human papillomavirus, influenza A (flu), SARS-CoV-2 (COVID-19), and Shigella spp (gastrointestinal infection). To confirm that BECC438 is a high-quality immunoadjuvant, even without antigen from an infectious pathogen, studies presented here use the model antigen ovalbumin in a murine prime-boost vaccine model. Durable and more balanced production of antibody isotypes IgG1 and IgG2 is observed when the bacterial enzyme combinatorial chemistry adjuvant is used, as compared with the classic adjuvants aluminum salts (Alhydrogel) and synthetic monophosphorylated lipid A\u2013PHAD (phosphorylated hexaacyl disaccharide). Antibody responses are maintained for at least 18\u2009wk postvaccination. Observed immune metrics maintained similar trends across males, females, and genetic backgrounds, including C57BL\/6, BALB\/c, and CD-1 (outbred) mice, with males overall showing a lower production of IgG2c. In vitro analysis of C57BL\/6 serum showed an increased half-life of ovalbumin-specific antibodies in BECC438 adjuvanted animals, indicative of a higher antigen binding affinity. These studies provide continued evidence to support the development of the BECC438 adjuvant in vaccines for human use.<\/jats:p>","DOI":"10.1093\/immhor\/vlaf038","type":"journal-article","created":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T22:41:43Z","timestamp":1758321703000},"source":"Crossref","is-referenced-by-count":1,"title":["Lipid A mimetic BECC438 potentiates durable and balanced antibody responses in an ovalbumin murine model of vaccination"],"prefix":"10.1093","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9440-5011","authenticated-orcid":false,"given":"Erin M","family":"Harberts","sequence":"first","affiliation":[{"name":"Department of Microbial Pathogenesis, University of Maryland School of Dentistry , Baltimore, MD,","place":["United States"]},{"name":"Department of Biological Sciences, Towson University , Towson, MD,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James K","family":"Fields","sequence":"additional","affiliation":[{"name":"Program in Molecular Microbiology and Immunology, University of Maryland School of Medicine , Baltimore, MD,","place":["United States"]},{"name":"Institute for Human Virology, University of Maryland School of Medicine , Baltimore, MD,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junela Cecille S","family":"Hunat","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Towson University , Towson, MD,","place":["United States"]},{"name":"Bridges to the Doctorate Program, Towson University , Towson, MD,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Danylle M","family":"Otteni","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Towson University , Towson, MD,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca M","family":"Gardner","sequence":"additional","affiliation":[{"name":"Department of Microbial Pathogenesis, University of Maryland School of Dentistry , Baltimore, MD,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David J","family":"Varisco","sequence":"additional","affiliation":[{"name":"Department of Microbial Pathogenesis, University of Maryland School of Dentistry , Baltimore, MD,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric J","family":"Sundberg","sequence":"additional","affiliation":[{"name":"Institute for Human Virology, University of Maryland School of Medicine , Baltimore, MD,","place":["United States"]},{"name":"Present\u00a0address: Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Greg A","family":"Snyder","sequence":"additional","affiliation":[{"name":"Institute for Human Virology, University of Maryland School of Medicine , Baltimore, MD,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert K","family":"Ernst","sequence":"additional","affiliation":[{"name":"Department of Microbial Pathogenesis, University of Maryland School of Dentistry , Baltimore, MD,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,9,17]]},"reference":[{"key":"2025091918413198900_vlaf038-B1","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.1038\/nm.3409","article-title":"Key roles of adjuvants in modern vaccines","volume":"19","author":"Reed","year":"2013","journal-title":"Nat Med"},{"key":"2025091918413198900_vlaf038-B2","doi-asserted-by":"crossref","first-page":"1766","DOI":"10.3390\/pharmaceutics15061766","article-title":"Precision vaccinology approaches for the development of adjuvanted vaccines targeted to distinct vulnerable populations","volume":"15","author":"Lee","year":"2023","journal-title":"Pharmaceutics"},{"key":"2025091918413198900_vlaf038-B3","doi-asserted-by":"crossref","first-page":"S5","DOI":"10.1038\/nm1209","article-title":"Vaccines: past, present and future","volume":"11","author":"Plotkin","year":"2005","journal-title":"Nat Med"},{"key":"2025091918413198900_vlaf038-B4","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1007\/978-1-4419-1603-7_6","article-title":"Lipid A receptor TLR4-mediated signaling pathways","volume":"667","author":"Yamamoto","year":"2010","journal-title":"Adv Exp Med Biol"},{"key":"2025091918413198900_vlaf038-B5","doi-asserted-by":"crossref","first-page":"98","DOI":"10.4049\/jimmunol.1701604","article-title":"Effective combination adjuvants engage both TLR and inflammasome pathways to promote potent adaptive immune responses","volume":"201","author":"Seydoux","year":"2018","journal-title":"J Immunol"},{"key":"2025091918413198900_vlaf038-B6","doi-asserted-by":"crossref","first-page":"1464","DOI":"10.1073\/pnas.1218080110","article-title":"Modulating the innate immune response by combinatorial engineering of endotoxin","volume":"110","author":"Needham","year":"2013","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2025091918413198900_vlaf038-B7","doi-asserted-by":"crossref","first-page":"e00492","DOI":"10.1128\/mBio.00492-17","article-title":"Rationally designed TLR4 ligands for vaccine adjuvant discovery","volume":"8","author":"Gregg","year":"2017","journal-title":"mBio"},{"key":"2025091918413198900_vlaf038-B8","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.vaccine.2020.11.066","article-title":"Optimization of RG1-VLP vaccine performance in mice with novel TLR4 agonists","volume":"39","author":"Zacharia","year":"2021","journal-title":"Vaccine"},{"key":"2025091918413198900_vlaf038-B9","doi-asserted-by":"crossref","first-page":"139","DOI":"10.3109\/10408419609106458","article-title":"The lipooligosaccharides of pathogenic gram-negative bacteria","volume":"22","author":"Preston","year":"1996","journal-title":"Crit Rev Microbiol"},{"key":"2025091918413198900_vlaf038-B10","first-page":"e50623","article-title":"Isolation and chemical characterization of lipid A from gram-negative bacteria","volume":"79","author":"Henderson","year":"2013","journal-title":"J Vis Exp"},{"key":"2025091918413198900_vlaf038-B11","doi-asserted-by":"crossref","first-page":"e18119","DOI":"10.1016\/j.heliyon.2023.e18119","article-title":"Physicochemical characterization of biological and synthetic forms of two lipid A-based TLR4 agonists","volume":"9","author":"Hu","year":"2023","journal-title":"Heliyon"},{"key":"2025091918413198900_vlaf038-B12","doi-asserted-by":"crossref","first-page":"4023","DOI":"10.1016\/j.vaccine.2018.05.101","article-title":"A lipid A-based TLR4 mimetic effectively adjuvants a Yersinia pestis rF-V1 subunit vaccine in a murine challenge model","volume":"36","author":"Gregg","year":"2018","journal-title":"Vaccine"},{"key":"2025091918413198900_vlaf038-B13","doi-asserted-by":"crossref","first-page":"5205","DOI":"10.1016\/j.vaccine.2021.06.085","article-title":"Novel TLR4 adjuvant elicits protection against homologous and heterologous influenza A infection","volume":"39","author":"Haupt","year":"2021","journal-title":"Vaccine"},{"key":"2025091918413198900_vlaf038-B14","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1038\/s41598-023-27965-x","article-title":"Enhancing the protection of influenza virus vaccines with BECC TLR4 adjuvant in aged mice","volume":"13","author":"Haupt","year":"2023","journal-title":"Sci Rep"},{"key":"2025091918413198900_vlaf038-B15","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1038\/s41541-022-00451-7","article-title":"Intranasal administration of BReC-CoV-2 COVID-19 vaccine protects K18-hACE2 mice against lethal SARS-CoV-2 challenge","volume":"7","author":"Wong","year":"2022","journal-title":"NPJ Vaccines"},{"key":"2025091918413198900_vlaf038-B16","doi-asserted-by":"crossref","first-page":"5003","DOI":"10.1016\/j.vaccine.2023.06.080","article-title":"Intranasal VLP-RBD vaccine adjuvanted with BECC470 confers immunity against Delta SARS-CoV-2 challenge in K18-hACE2-mice","volume":"41","author":"Lee","year":"2023","journal-title":"Vaccine"},{"key":"2025091918413198900_vlaf038-B17","doi-asserted-by":"crossref","first-page":"1194912","DOI":"10.3389\/fimmu.2023.1194912","article-title":"Impact of the TLR4 agonist BECC438 on a novel vaccine formulation against Shigella spp","volume":"14","author":"Lu","year":"2023","journal-title":"Front Immunol"},{"key":"2025091918413198900_vlaf038-B18","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1038\/s41541-023-00618-w","article-title":"A protein subunit vaccine elicits a balanced immune response that protects against Pseudomonas pulmonary infection","volume":"8","author":"Howlader","year":"2023","journal-title":"NPJ Vaccines"},{"key":"2025091918413198900_vlaf038-B19","doi-asserted-by":"crossref","first-page":"e0022323","DOI":"10.1128\/iai.00223-23","article-title":"BECC438b TLR4 agonist supports unique immune response profiles from nasal and muscular DTaP pertussis vaccines in murine challenge models","volume":"92","author":"DeJong","year":"2024","journal-title":"Infect Immun"},{"key":"2025091918413198900_vlaf038-B20","doi-asserted-by":"crossref","first-page":"618","DOI":"10.3390\/vaccines12060618","article-title":"Vaccination with a protective Ipa protein-containing nanoemulsion differentially alters the transcriptomic profiles of young and elderly mice following Shigella infection","volume":"12","author":"Lu","year":"2024","journal-title":"Vaccines (Basel)"},{"key":"2025091918413198900_vlaf038-B21","doi-asserted-by":"crossref","first-page":"101224","DOI":"10.1016\/j.mam.2023.101224","article-title":"Vaccines for HPV-associated diseases","volume":"94","author":"Skolnik","year":"2023","journal-title":"Mol Aspects Med"},{"key":"2025091918413198900_vlaf038-B22","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1111\/imr.12098","article-title":"Advances in antiviral vaccine development","volume":"255","author":"Graham","year":"2013","journal-title":"Immunol Rev"},{"key":"2025091918413198900_vlaf038-B23","doi-asserted-by":"crossref","first-page":"2718","DOI":"10.1039\/D4MD00387J","article-title":"Chemical synthesis and immunological evaluation of cancer vaccines based on ganglioside antigens and alpha-galactosylceramide","volume":"15","author":"Romano","year":"2024","journal-title":"RSC Med Chem"},{"key":"2025091918413198900_vlaf038-B24","doi-asserted-by":"crossref","first-page":"6870","DOI":"10.1038\/s41467-024-51315-8","article-title":"A real-world observation of patients with glioblastoma treated with a personalized peptide vaccine","volume":"15","author":"Latzer","year":"2024","journal-title":"Nat Commun"},{"key":"2025091918413198900_vlaf038-B25","doi-asserted-by":"crossref","first-page":"1355","DOI":"10.1126\/science.aar7112","article-title":"Personalized vaccines for cancer immunotherapy","volume":"359","author":"Sahin","year":"2018","journal-title":"Science"},{"key":"2025091918413198900_vlaf038-B26","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.bbi.2024.08.028","article-title":"A pentavalent peptide vaccine elicits Abeta and tau antibodies with prophylactic activity in an Alzheimer's disease mouse model","volume":"122","author":"Song","year":"2024","journal-title":"Brain Behav. Immun"},{"key":"2025091918413198900_vlaf038-B27","doi-asserted-by":"crossref","first-page":"152","DOI":"10.3109\/08916934.2014.1003641","article-title":"Vaccination to modulate atherosclerosis","volume":"48","author":"Kimura","year":"2015","journal-title":"Autoimmunity"},{"key":"2025091918413198900_vlaf038-B28","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1080\/21645515.2018.1527496","article-title":"The effect of antigen dose on T cell-targeting vaccine outcome","volume":"15","author":"Billeskov","year":"2019","journal-title":"Hum Vaccin Immunother"},{"key":"2025091918413198900_vlaf038-B29","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1086\/317537","article-title":"Type 1\/type 2 immunity in infectious diseases","volume":"32","author":"Spellberg","year":"2001","journal-title":"Clin Infect Dis"},{"key":"2025091918413198900_vlaf038-B30","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1038\/nri.2017.106","article-title":"Beyond binding: antibody effector functions in infectious diseases","volume":"18","author":"Lu","year":"2018","journal-title":"Nat Rev Immunol"},{"key":"2025091918413198900_vlaf038-B31","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1126\/science.aad3439","article-title":"Visualizing antibody affinity maturation in germinal centers","volume":"351","author":"Tas","year":"2016","journal-title":"Science"},{"key":"2025091918413198900_vlaf038-B32","doi-asserted-by":"crossref","first-page":"e127882","DOI":"10.1172\/jci.insight.127882","article-title":"New epitopes in ovalbumin provide insights for cancer neoepitopes","volume":"5","author":"Karandikar","year":"2019","journal-title":"JCI Insight"},{"key":"2025091918413198900_vlaf038-B33","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1242\/dmm.000323","article-title":"Mouse models of allergic asthma: acute and chronic allergen challenge","volume":"1","author":"Nials","year":"2008","journal-title":"Dis Model Mech"},{"key":"2025091918413198900_vlaf038-B34","first-page":"29","article-title":"Systemic sensitization with the protein allergen ovalbumin augments local sensitization in atopic dermatitis","volume":"7","author":"Yoo","year":"2014","journal-title":"J Inflamm Res"},{"key":"2025091918413198900_vlaf038-B35","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1021\/acs.molpharmaceut.8b00895","article-title":"Novel hydrogel-forming microneedle array for intradermal vaccination in mice using ovalbumin as a model protein antigen","volume":"16","author":"Courtenay","year":"2019","journal-title":"Mol Pharm"},{"key":"2025091918413198900_vlaf038-B36","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1021\/acsbiomaterials.2c01516","article-title":"Effect of antigen structure in subunit vaccine nanoparticles on humoral immune responses","volume":"9","author":"Park","year":"2023","journal-title":"ACS Biomater Sci Eng"},{"key":"2025091918413198900_vlaf038-B37","doi-asserted-by":"crossref","first-page":"726416","DOI":"10.3389\/fimmu.2021.726416","article-title":"Impact of toll-like receptor-specific agonists on the host immune response to the Yersinia pestis Plague rF1V vaccine","volume":"12","author":"Biryukov","year":"2021","journal-title":"Front Immunol"},{"key":"2025091918413198900_vlaf038-B38","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1177\/1091581813497405","article-title":"Preclinical safety assessment of a recombinant plague vaccine (rF1V)","volume":"32","author":"Price","year":"2013","journal-title":"Int J Toxicol"},{"key":"2025091918413198900_vlaf038-B39","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s12866-018-1186-8","article-title":"Comparative analysis of humoral immune responses and pathologies of BALB\/c and C57BL\/6 wildtype mice experimentally infected with a highly virulent Rodentibacter pneumotropicus (Pasteurella pneumotropica) strain","volume":"18","author":"Fornefett","year":"2018","journal-title":"BMC Microbiol"},{"key":"2025091918413198900_vlaf038-B40","doi-asserted-by":"crossref","first-page":"e4729","DOI":"10.1371\/journal.pone.0004729","article-title":"Genetic variation and population substructure in outbred CD-1 mice: implications for genome-wide association studies","volume":"4","author":"Aldinger","year":"2009","journal-title":"PLoS One"},{"key":"2025091918413198900_vlaf038-B41","doi-asserted-by":"crossref","first-page":"e0020122","DOI":"10.1128\/iai.00201-22","article-title":"Position-specific secondary acylation determines detection of lipid A by murine TLR4 and caspase-11","volume":"90","author":"Harberts","year":"2022","journal-title":"Infect Immun"},{"key":"2025091918413198900_vlaf038-B42","doi-asserted-by":"crossref","first-page":"482","DOI":"10.3390\/v15020482","article-title":"How estrogen, testosterone, and sex differences influence serum immunoglobulin isotype patterns in mice and humans","volume":"15","author":"Surman","year":"2023","journal-title":"Viruses"},{"key":"2025091918413198900_vlaf038-B43","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1038\/nri.2016.90","article-title":"Sex differences in immune responses","volume":"16","author":"Klein","year":"2016","journal-title":"Nat Rev Immunol"},{"key":"2025091918413198900_vlaf038-B44","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1016\/S1567-5769(03)00138-3","article-title":"Yersinia pestis F1 antigen: a correlation between antibody titres and subclass distribution with differential avidity in different inbred mouse strains","volume":"3","author":"Sabhnani","year":"2003","journal-title":"Int Immunopharmacol"},{"key":"2025091918413198900_vlaf038-B45","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1038\/s41541-018-0087-z","article-title":"Targeting of the Yersinia pestis F1 capsular antigen by innate-like B1b cells mediates a rapid protective response against bubonic plague","volume":"3","author":"Levy","year":"2018","journal-title":"NPJ Vaccines"},{"key":"2025091918413198900_vlaf038-B46","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1038\/s41541-024-00958-1","article-title":"Progress on the research and development of plague vaccines with a call to action","volume":"9","author":"Williamson","year":"2024","journal-title":"NPJ Vaccines"},{"key":"2025091918413198900_vlaf038-B47","doi-asserted-by":"crossref","first-page":"6421","DOI":"10.1016\/j.vaccine.2014.09.049","article-title":"H5 N-terminal beta sheet promotes oligomerization of H7-HA1 that induces better antibody affinity maturation and enhanced protection against H7N7 and H7N9 viruses compared with inactivated influenza vaccine","volume":"32","author":"Khurana","year":"2014","journal-title":"Vaccine"},{"key":"2025091918413198900_vlaf038-B48","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1172\/JCI81083","article-title":"Beyond antigens and adjuvants: formulating future vaccines","volume":"126","author":"Moyer","year":"2016","journal-title":"J Clin Invest"},{"key":"2025091918413198900_vlaf038-B49","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/s41573-022-00495-3","article-title":"Antibodies to combat viral infections: development strategies and progress","volume":"21","author":"Pantaleo","year":"2022","journal-title":"Nat Rev Drug Discov"}],"container-title":["ImmunoHorizons"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/immunohorizons\/article-pdf\/9\/10\/vlaf038\/64291461\/vlaf038.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/immunohorizons\/article-pdf\/9\/10\/vlaf038\/64291461\/vlaf038.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T22:41:48Z","timestamp":1758321708000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/immunohorizons\/article\/doi\/10.1093\/immhor\/vlaf038\/8256435"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,17]]},"references-count":49,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2025,9,17]]}},"URL":"https:\/\/doi.org\/10.1093\/immhor\/vlaf038","relation":{},"ISSN":["2573-7732"],"issn-type":[{"value":"2573-7732","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,10]]},"published":{"date-parts":[[2025,9,17]]},"article-number":"vlaf038"}}