{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:48:09Z","timestamp":1760147289543,"version":"build-2065373602"},"reference-count":49,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,1,23]],"date-time":"2023-01-23T00:00:00Z","timestamp":1674432000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Australian Centre for HIV and Viral Hepatitis Research (ACH2)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Virus-like particles (VLPs), composed of the small hepatitis B virus surface antigen (HBsAgS), are the antigenic components of the hepatitis B virus (HBV) vaccine and represent the backbones for a chimeric anti-malaria vaccine and various vaccine candidates. Biological vectors have to face pre-existing anti-vector immune responses due to previous immune exposure. Vector recognition after natural infections or vaccinations can result in unwarranted outcomes, with compromising effects on clinical outcomes. In order to evaluate the impact of a pre-existing anti-HBsAgS immune response, we developed mutant VLPs composed of subunits with reduced HBsAgS-specific antigenicity. The insertion of a Plasmodium falciparum circumsporozoite protein (CSP)-derived epitope as a read-out allowed the assessment of wild type (wt) and mutant VLPs in the context of a pre-existing immune response. Mutant and wt VLP platforms with a CSP-epitope insert are immunogenic and have the ability to generate anti-CSP antibody responses in both na\u00efve BALB\/c mice and mice with a pre-existing anti-HBsAgS immune response, but with superior anti-CSP responses in mice with a pre-existing immunity. The data indicate that previous HBsAgS exposure facilitates enhanced antibody responses against foreign epitopes delivered by the HBsAgS platform, and, in this context, the state of immune sensitization alters the outcome of subsequent vaccinations.<\/jats:p>","DOI":"10.3390\/v15020313","type":"journal-article","created":{"date-parts":[[2023,1,23]],"date-time":"2023-01-23T03:26:41Z","timestamp":1674444401000},"page":"313","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Immunogenicity of Wild Type and Mutant Hepatitis B Surface Antigen Virus-like Particles (VLPs) in Mice with Pre-Existing Immunity against the Wild Type Vector"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7109-6757","authenticated-orcid":false,"given":"Natalie J.","family":"Kingston","sequence":"first","affiliation":[{"name":"Infection and Immunity Program, Monash Biomedicine Discovery Institute, Department of Microbiology, Monash University, Clayton, VIC 3800, Australia"},{"name":"School of Molecular and Cellular Biology, Faculty of Biological Sciences, Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Renae","family":"Walsh","sequence":"additional","affiliation":[{"name":"Victorian Infectious Diseases Reference Laboratory (VIDRL), Melbourne Health, The Peter Doherty Institute, Melbourne, VIC 3000, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachel","family":"Hammond","sequence":"additional","affiliation":[{"name":"Victorian Infectious Diseases Reference Laboratory (VIDRL), Melbourne Health, The Peter Doherty Institute, Melbourne, VIC 3000, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1304-8727","authenticated-orcid":false,"given":"Carina C. D.","family":"Joe","sequence":"additional","affiliation":[{"name":"School of Science, Royal Melbourne Institute of Technology (RMIT) University, Melbourne, VIC 3001, Australia"},{"name":"Commonwealth Scientific and Industrial Research Organisation, Clayton, VIC 3169, Australia"},{"name":"Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"George","family":"Lovrecz","sequence":"additional","affiliation":[{"name":"Commonwealth Scientific and Industrial Research Organisation, Clayton, VIC 3169, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen","family":"Locarnini","sequence":"additional","affiliation":[{"name":"Victorian Infectious Diseases Reference Laboratory (VIDRL), Melbourne Health, The Peter Doherty Institute, Melbourne, VIC 3000, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2808-3923","authenticated-orcid":false,"given":"Hans J.","family":"Netter","sequence":"additional","affiliation":[{"name":"Victorian Infectious Diseases Reference Laboratory (VIDRL), Melbourne Health, The Peter Doherty Institute, Melbourne, VIC 3000, Australia"},{"name":"School of Science, Royal Melbourne Institute of Technology (RMIT) University, Melbourne, VIC 3001, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1146\/annurev-pharmtox-061008-103129","article-title":"Immunodrugs: Therapeutic VLP-based vaccines for chronic diseases","volume":"49","author":"Jennings","year":"2009","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1038\/s41577-020-00479-7","article-title":"A guide to vaccinology: From basic principles to new developments","volume":"21","author":"Pollard","year":"2021","journal-title":"Nat. Rev. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1099\/mic.0.049601-0","article-title":"Pre-existing immunity against vaccine vectors\u2014Friend or foe?","volume":"159","author":"Saxena","year":"2013","journal-title":"Microbiology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2875","DOI":"10.4161\/hv.29594","article-title":"Pre-existing immunity against Ad vectors","volume":"10","author":"Kobinger","year":"2014","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1881","DOI":"10.1016\/S0140-6736(08)61591-3","article-title":"Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step study): A double-blind, randomised, placebo-controlled, test-of-concept trial","volume":"372","author":"Buchbinder","year":"2008","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1038\/s41541-019-0133-5","article-title":"Pre-existing yellow fever immunity impairs and modulates the antibody response to tick-borne encephalitis vaccination","volume":"4","author":"Bradt","year":"2019","journal-title":"NPJ Vaccines"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2319","DOI":"10.4049\/jimmunol.135.4.2319","article-title":"Carrier-induced epitope suppression, a major issue for future synthetic vaccines","volume":"135","author":"Schutze","year":"1985","journal-title":"J. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3116","DOI":"10.1016\/S0264-410X(99)00133-4","article-title":"Prior immunity to a carrier enhances antibody responses to hCG in recipients of an hCG-carrier conjugate vaccine","volume":"17","author":"Shah","year":"1999","journal-title":"Vaccine"},{"key":"ref_9","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_10","doi-asserted-by":"crossref","first-page":"1621","DOI":"10.1586\/erv.11.142","article-title":"Glycoconjugate vaccines and immune reactions, and implications for vaccination schedules","volume":"10","author":"Borrow","year":"2011","journal-title":"Exp. Rev. Vaccines"},{"key":"ref_11","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_12","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.4049\/jimmunol.145.5.1343","article-title":"The in vivo elimination of CD4+ T cells prevents the induction but not the expression of carrier-induced epitopic suppression","volume":"145","author":"LeClerc","year":"1990","journal-title":"J. Immunol."},{"key":"ref_13","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_14","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 CRM197 or Qb-VLP conjugate vaccines","volume":"38","author":"McCluskie","year":"2016","journal-title":"Immunopharmacol. Immunotoxicol."},{"key":"ref_15","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_16","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1038\/nature04721","article-title":"Hexon-chimaeric adenovirus serotype 5 vectors circumvent pre-existing anti-vector immunity","volume":"441","author":"Roberts","year":"2006","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Ho, J.K.T., Jeevan-Raj, B., and Netter, H.J. (2020). Hepatitis B virus (HBV) subviral particles as protective vaccines and vaccine platforms. Viruses, 12.","DOI":"10.3390\/v12020126"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1002\/jmv.20524","article-title":"Protective efficacy, immunotherapeutic potential, and safety of hepatitis B vaccines","volume":"78","author":"Zuckerman","year":"2006","journal-title":"J. Med. Virol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1174","DOI":"10.1016\/S0140-6736(84)92740-5","article-title":"Clinical evaluation of a recombinant hepatitis B vaccine","volume":"2","author":"Jilg","year":"1984","journal-title":"Lancet"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Nishioka, K., Suzuki, H., Mishiro, S., and Oda, T. (1994). Viral Hepatitis and Liver Disease, Springer.","DOI":"10.1007\/978-4-431-68255-4"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2257","DOI":"10.1007\/s007050050240","article-title":"Analysis of intermolecular disulfide bonds and free sufhydryl groups in hepatitis B surface antigen particles","volume":"142","author":"Mangold","year":"1997","journal-title":"Arch. Virol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1576","DOI":"10.1093\/infdis\/171.6.1576","article-title":"Safety, immunogenicity, and efficacy of a recombinantly produced Plasmodium falciparum circumsporozoite protein-hepatitis B surface antigen subunit vaccine","volume":"171","author":"Gordon","year":"1995","journal-title":"J. Infect. Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1080\/21645515.2019.1669415","article-title":"RTS,S\/AS01 vaccine (Mosquirix\u2122): An overview","volume":"16","author":"Laurens","year":"2020","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1126\/science.2425433","article-title":"A poliovirus neutralization epitope expressed on hybrid hepatitis B surface antigen particles","volume":"233","author":"Delpeyroux","year":"1986","journal-title":"Science"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2130","DOI":"10.1128\/JVI.75.5.2130-2141.2001","article-title":"Antigenicity and immunogenicity of novel chimeric hepatitis B surface antigen particles with exposed hepatitis C virus epitopes","volume":"75","author":"Netter","year":"2001","journal-title":"J. Virol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1177\/135965350701200409","article-title":"Immunizations with chimeric hepatitis B virus-like particles to induce potential anti-hepatitis C virus neutralizing antibodies","volume":"12","author":"Vietheer","year":"2007","journal-title":"Antivir. Ther."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2273","DOI":"10.1016\/j.vaccine.2018.03.036","article-title":"Neutralization effects of antibody elicited by chimeric HBV S antigen viral-like particles presenting HCV neutralization epitopes","volume":"36","author":"Wei","year":"2018","journal-title":"Vaccine"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1128\/CVI.05295-11","article-title":"Immunological response to parenteral vaccination with recombinant hepatitis B virus surface antigen virus-like particles expressing Helicobacter pylori KatA epitopes in a murine H. pylori challenge model","volume":"19","author":"Kotiw","year":"2011","journal-title":"Clin. Vaccine Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1674","DOI":"10.1016\/j.vaccine.2019.01.056","article-title":"Hepatitis B virus-like particles expressing Plasmodium falciparum epitopes induce complement-fixing antibodies against the circumsporozoite protein","volume":"37","author":"Kingston","year":"2019","journal-title":"Vaccine"},{"key":"ref_30","unstructured":"World Health Organization (WHO) Fact Sheet (2021). Hepatitis, B., 27 July 2021, WHO."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"11312","DOI":"10.1128\/JVI.01123-15","article-title":"Modification of asparagine-linked glycan density for the design of hepatitis B virus virus-like particles with enhanced immunogenicity","volume":"89","author":"Hyakumura","year":"2015","journal-title":"J. Virol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2066","DOI":"10.1111\/liv.14207","article-title":"Predicting HBsAg clearance in genotype A chronic hepatitis B using HBsAg epitope profiling: A biomarker for functional cure","volume":"39","author":"Walsh","year":"2019","journal-title":"Liver Int."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1006\/viro.2001.1246","article-title":"Reduced antigenicity of the hepatitis B virus HBsAg protein arising as a consequence of sequence changes in the overlapping polymerase gene that are selected by Lamivudine therapy","volume":"293","author":"Torresi","year":"2002","journal-title":"Virology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1111\/j.1365-2893.1997.tb00155.x","article-title":"The clinical significance of surface antigen variants of hepatitis B virus","volume":"4","author":"Carman","year":"1997","journal-title":"J. Viral Hepat."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1002\/hep.26132","article-title":"Chimeric hepatitis B virus\/hepatitis C virus envelope proteins elicit broadly neutralizing antibodies and constitute a potential bivalent prophylactic vaccine","volume":"57","author":"Beaumont","year":"2013","journal-title":"Hepatology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"270","DOI":"10.2174\/1874357901206010270","article-title":"Virus-like particles harbouring CCL19, IL-2 and HPV16 E7 elicit protective T cell responses in HLA-A2 transgenic mice","volume":"6","author":"Juarez","year":"2012","journal-title":"Open Virol. J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e0006191-35","DOI":"10.1371\/journal.pntd.0006191","article-title":"A tetravalent virus-like particle vaccine designed to display domain III of dengue envelope proteins induces multi-serotype neutralizing antibodies in mice and macaques which confer protection against antibody dependent enhancement in AG129 mice","volume":"12","author":"Ramasamy","year":"2018","journal-title":"PloS Negl. Trop. Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.antiviral.2008.10.003","article-title":"Chimeric virus-like particles for the delivery of an inserted conserved influenza A-specific CTL epitope","volume":"81","author":"Cheong","year":"2009","journal-title":"Antivir. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.virol.2007.11.005","article-title":"Analysis of the human immunodeficiency virus type 1 gp41 membrane proximal external region arrayed on hepatitis B surface antigen particles","volume":"373","author":"Phogat","year":"2008","journal-title":"Virology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1901","DOI":"10.1016\/j.vaccine.2006.08.014","article-title":"Optimisation of secretion of recombinant HBsAg virus-like particles: Impact on the development of HIV-1\/HBV bivalent vaccines","volume":"25","author":"Michel","year":"2007","journal-title":"Vaccine"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"46621","DOI":"10.1038\/srep46621","article-title":"Enhancing protective immunity to malaria with a highly immunogenic virus-like particle vaccine","volume":"7","author":"Collins","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1007\/s40267-022-00937-3","article-title":"RTS,S\/AS01 malaria vaccine (Mosquirix\u00ae): A profile of its use","volume":"38","author":"Syed","year":"2022","journal-title":"Drugs Ther. Perspect."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1016\/S0140-6736(21)00943-0","article-title":"Efficacy of a low-dose candidate malaria vaccine, R21, in adjuvant Matrix-M, with seasonal administration to children in Burkina Faso: A randomised controlled trial","volume":"397","author":"Datoo","year":"2021","journal-title":"Lancet"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2692","DOI":"10.1016\/S0264-410X(03)00182-8","article-title":"Immunogenicity of recombinant HBsAg\/HCV particles in mice pre-immunised with hepatitis B virus-specific vaccine","volume":"21","author":"Netter","year":"2003","journal-title":"Vaccine"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1016\/j.vaccine.2015.01.007","article-title":"Chimeric hepatitis B virus (HBV)\/hepatitis C virus (HCV) subviral envelope particles induce efficient anti-HCV antibody production in animals pre-immunized with HBV vaccine","volume":"33","author":"Beaumont","year":"2015","journal-title":"Vaccine"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Lell, B., Agnandji, S., von Glasenapp, I., Haertle, S., Oyakhiromen, S., Issifou, S., Vekemans, J., Leach, A., Lievens, M., and Dubois, M.C. (2009). A randomized trial assessing the safety and immunogenicity of AS01 and AS02 adjuvanted RTS,S malaria vaccine candidates in children in Gabun. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0007611"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3739","DOI":"10.1016\/j.vaccine.2015.05.066","article-title":"Assessing stability and assembly of the hepatitis B surface antigen into virus-like particles during down-stream processing","volume":"33","author":"Zahid","year":"2015","journal-title":"Vaccine"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3892","DOI":"10.1016\/j.vaccine.2020.03.007","article-title":"Glycoengineered hepatitis B virus-like particles with enhanced immunogenicity","volume":"38","author":"Joe","year":"2020","journal-title":"Vaccine"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Al-Barwani, F., Young, S.L., Baird, M.A., Larsen, D.S., and Ward, V.K. (2014). Mannosylation of virus-like particles enhances internalization by antigen presenting cells. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0104523"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/15\/2\/313\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:13:47Z","timestamp":1760120027000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/15\/2\/313"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,23]]},"references-count":49,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["v15020313"],"URL":"https:\/\/doi.org\/10.3390\/v15020313","relation":{},"ISSN":["1999-4915"],"issn-type":[{"type":"electronic","value":"1999-4915"}],"subject":[],"published":{"date-parts":[[2023,1,23]]}}}