{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:40:13Z","timestamp":1760146813308,"version":"build-2065373602"},"reference-count":51,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,12,17]],"date-time":"2024-12-17T00:00:00Z","timestamp":1734393600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Ministry of Higher Education, Science, and Innovations of Uzbekistan"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Background: The development of effective and safe vaccines and their timely delivery to the public play a crucial role in preventing and managing infectious diseases. Many vaccines have been produced and distributed globally to prevent COVID-19 infection. However, establishing effective vaccine development platforms and evaluating their safety and immunogenicity remains critical to increasing health security, especially in developing countries. Objectives: Therefore, we developed a local subunit vaccine candidate, RENOVAC, and reported its toxicity and immunogenicity profile in animal models. Methods: First, the synthetic gene-coding tandem RBD linked with the GS linker was cloned into the expression vector and expressed in CHO cells. The protein was then purified and filter sterilized, and 10 \u00b5g\/dose and 25 \u00b5g\/dose formulations were finally examined for the 14-day repeated dose toxicity followed by the immunogenic profile in preclinical studies. Results: When administered to Sprague Dawley rats by intramuscular route, the vaccine was well tolerated up to and including the dose of 25 \u00b5g\/animal, and no toxicologically adverse changes were noted. The observed change in weight of the thymus and spleen might be related to the immunological response to the vaccine. The dimer RBD vaccine demonstrated the ability to generate high levels of specific immunoglobulins (IGs) and neutralization antibodies (NAbs). Finally, changes in the amounts of specific T cells and cytokines after vaccination suggested that the vaccine mainly triggers an immune response by activating CD4+ Th2-cells, which then activate B-cells to provide humoral immunity. Conclusions: The study suggests that, based on its reliable immunogenicity and acceptable safety, the vaccine can be further directed for clinical trials.<\/jats:p>","DOI":"10.3390\/vaccines12121420","type":"journal-article","created":{"date-parts":[[2024,12,17]],"date-time":"2024-12-17T05:26:02Z","timestamp":1734413162000},"page":"1420","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Development, Pre-Clinical Safety, and Immune Profile of RENOVAC\u2014A Dimer RBD-Based Anti-Coronavirus Subunit Vaccine"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-5534-7552","authenticated-orcid":false,"given":"Muzaffar","family":"Muminov","sequence":"first","affiliation":[{"name":"Center for Advanced Technologies, Tashkent 100174, Uzbekistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nargiza","family":"Tsiferova","sequence":"additional","affiliation":[{"name":"Center for Advanced Technologies, Tashkent 100174, Uzbekistan"},{"name":"Institute of Biophysics and Biochemistry, National University of Uzbekistan, Tashkent 100174, Uzbekistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Egor","family":"Pshenichnov","sequence":"additional","affiliation":[{"name":"Center for Advanced Technologies, Tashkent 100174, Uzbekistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Khusnora","family":"Ermatova","sequence":"additional","affiliation":[{"name":"Center for Advanced Technologies, Tashkent 100174, Uzbekistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oksana","family":"Charishnikova","sequence":"additional","affiliation":[{"name":"Center for Advanced Technologies, Tashkent 100174, Uzbekistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8268-7699","authenticated-orcid":false,"given":"Alisher","family":"Abdullaev","sequence":"additional","affiliation":[{"name":"Center for Advanced Technologies, Tashkent 100174, Uzbekistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1737-7941","authenticated-orcid":false,"given":"Yuliya","family":"Levitskaya","sequence":"additional","affiliation":[{"name":"Center for Advanced Technologies, Tashkent 100174, Uzbekistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dilbar","family":"Dalimova","sequence":"additional","affiliation":[{"name":"Center for Advanced Technologies, Tashkent 100174, Uzbekistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandhya","family":"MVS","sequence":"additional","affiliation":[{"name":"PRADO\u2014Preclinical Research and Development Organization, Pvt. Ltd., Pune 410506, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Geetanjali","family":"Tomar","sequence":"additional","affiliation":[{"name":"PRADO\u2014Preclinical Research and Development Organization, Pvt. Ltd., Pune 410506, India"},{"name":"Department of Biotechnology, Savitribai Phule Pune University, Pune 411007, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ankush","family":"Dewle","sequence":"additional","affiliation":[{"name":"PRADO\u2014Preclinical Research and Development Organization, Pvt. Ltd., Pune 410506, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pradhnya","family":"Choudhari","sequence":"additional","affiliation":[{"name":"PRADO\u2014Preclinical Research and Development Organization, Pvt. Ltd., Pune 410506, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aditi","family":"Wangikar","sequence":"additional","affiliation":[{"name":"PRADO\u2014Preclinical Research and Development Organization, Pvt. Ltd., Pune 410506, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6218-0620","authenticated-orcid":false,"given":"Amol","family":"Jadhav","sequence":"additional","affiliation":[{"name":"PRADO\u2014Preclinical Research and Development Organization, Pvt. Ltd., Pune 410506, India"},{"name":"Institute of Applied Biological Research and Development, Pune 411007, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mrunal","family":"Mule","sequence":"additional","affiliation":[{"name":"PRADO\u2014Preclinical Research and Development Organization, Pvt. Ltd., Pune 410506, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1609-9653","authenticated-orcid":false,"given":"Pralhad","family":"Wangikar","sequence":"additional","affiliation":[{"name":"PRADO\u2014Preclinical Research and Development Organization, Pvt. Ltd., Pune 410506, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9563-0686","authenticated-orcid":false,"given":"Ibrokhim","family":"Abdurakhmonov","sequence":"additional","affiliation":[{"name":"Center of Genomics and Bioinformatics, Academy of Sciences of Uzbekistan, Tashkent 111215, Uzbekistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shahlo","family":"Turdikulova","sequence":"additional","affiliation":[{"name":"Center for Advanced Technologies, Tashkent 100174, Uzbekistan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,17]]},"reference":[{"key":"ref_1","unstructured":"(2024, February 23). COVID-19 Cases. WHO COVID-19 Dashboard. Datadot. Available online: https:\/\/data.who.int\/dashboards\/covid19\/cases."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1038\/s41541-021-00292-w","article-title":"SARS-CoV-2 vaccines strategies: A comprehensive review of phase 3 candidates","volume":"6","author":"Kyriakidis","year":"2021","journal-title":"npj Vaccines"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Zhang, Z., Shen, Q., and Chang, H. (2022). Vaccines for COVID-19: A Systematic Review of Immunogenicity, Current Development, and Future Prospects. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.843928"},{"key":"ref_4","unstructured":"(2024, February 23). COVID-19 Vaccine Tracker and Landscape. Available online: https:\/\/www.who.int\/publications\/m\/item\/draft-landscape-of-covid-19-candidate-vaccines."},{"key":"ref_5","first-page":"18","article-title":"Frontier Therapeutics and Vaccine Strategies for SARS-CoV-2 (COVID-19): A Review","volume":"49","author":"Sheikhshahrokh","year":"2020","journal-title":"Iran. J. Public Health"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/s41577-020-00480-0","article-title":"Viral targets for vaccines against COVID-19","volume":"21","author":"Dai","year":"2021","journal-title":"Nat. Rev. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2603","DOI":"10.1056\/NEJMoa2034577","article-title":"Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine","volume":"383","author":"Polack","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1056\/NEJMoa2035389","article-title":"Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine","volume":"384","author":"Baden","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1016\/j.cell.2020.06.035","article-title":"A Universal Design of Betacoronavirus Vaccines against COVID-19, MERS, and SARS","volume":"182","author":"Dai","year":"2020","journal-title":"Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2097","DOI":"10.1056\/NEJMoa2202261","article-title":"Efficacy and Safety of the RBD-Dimer\u2013Based Covid-19 Vaccine ZF2001 in Adults","volume":"386","author":"Dai","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_11","unstructured":"Abdurakhmonov, P.I.Y. (2022). COVID-19 Response in Uzbekistan: From RT-PCR Test System to the Clinical Trial of Subunit Vaccine. COVID-19 Vaccines\u2014Current State and Perspectives, IntechOpen."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1038\/s41587-019-0036-z","article-title":"SignalP 5.0 improves signal peptide predictions using deep neural networks","volume":"37","author":"Tsirigos","year":"2019","journal-title":"Nat. Biotechnol."},{"key":"ref_13","unstructured":"(2023, March 24). Cell-PLoc: A Package of Web Servers for Predicting Subcellular Localization of Proteins in Various Organisms. Nature Protocols. Available online: https:\/\/www.nature.com\/articles\/nprot.2007.494."},{"key":"ref_14","unstructured":"Gibco (2018). For transfection of ExpiCHO-S\u2122 Cells in a defined, serum-free medium. ExpiCHO\u2122 Expression System User Guide, Thermo Fisher Scientific. MAN0014337."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Du Sert, N.P., Ahluwalia, A., Alam, S., Avey, M.T., Baker, M., Browne, W.J., Clark, A., Cuthill, I.C., Dirnagl, U., and Emerson, M. (2020). Reporting animal research: Explanation and elaboration for the ARRIVE guidelines 2.0. PLoS Biol., 18.","DOI":"10.1371\/journal.pbio.3000411"},{"key":"ref_16","unstructured":"Hedrich, H.J., and Bullock, G. (2004). CHAPTER 32\u2014Routes of Administration. The Laboratory Mouse, Academic Press."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.micinf.2014.12.006","article-title":"Advancements in the development of subunit influenza vaccines","volume":"17","author":"Zhang","year":"2015","journal-title":"Microbes Infect."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Mathew, S., Faheem, M., Hassain, N.A., Benslimane, F.M., Al Thani, A.A., Zaraket, H., and Yassine, H.M. (2020). Platforms exploited for SARS-CoV-2 vaccine development. Vaccines, 9.","DOI":"10.3390\/vaccines9010011"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Heidary, M., Kaviar, V.H., Shirani, M., Ghanavati, R., Motahar, M., Sholeh, M., Ghahramanpour, H., and Khoshnood, S. (2022). A Comprehensive Review of the Protein Subunit Vaccines Against COVID-19. Front. Microbiol., 13.","DOI":"10.3389\/fmicb.2022.927306"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"eabc8413","DOI":"10.1126\/sciimmunol.abc8413","article-title":"The receptor-binding domain of the viral spike protein is an immunodominant and highly specific target of antibodies in SARS-CoV-2 patients","volume":"5","author":"Premkumar","year":"2020","journal-title":"Sci. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1038\/s41423-020-0400-4","article-title":"Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: Implication for development of RBD protein as a viral attachment inhibitor and vaccine","volume":"17","author":"Tai","year":"2020","journal-title":"Cell. Mol. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1038\/s41591-020-0913-5","article-title":"A serological assay to detect SARS-CoV-2 seroconversion in humans","volume":"26","author":"Amanat","year":"2020","journal-title":"Nat. Med."},{"key":"ref_23","first-page":"3","article-title":"Toxicological studies. Reference intervals of mass coefficients of internal organs in a sample of 1000 rats","volume":"1","author":"Lugovik","year":"2021","journal-title":"Lab. Zhivotnye Dlya Nauchnych Issled. (Lab. Anim. Sci.)"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"eaau6085","DOI":"10.1126\/sciimmunol.aau6085","article-title":"Structure-function of the immune system in the spleen","volume":"4","author":"Lewis","year":"2019","journal-title":"Sci. Immunol."},{"key":"ref_25","unstructured":"Hsi, E.D. (2018). 7\u2014Small B-Cell Lymphomas. Hematopathology, Elsevier. [3rd ed.]."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"243","DOI":"10.37349\/ei.2021.00016","article-title":"Immune responses induced by different vaccine platforms against coronavirus disease-19","volume":"1","author":"Ahire","year":"2021","journal-title":"Explor. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.pbiomolbio.2023.02.004","article-title":"An overview of the vaccine platforms to combat COVID-19 with a focus on the subunit vaccines","volume":"178","author":"Bayani","year":"2023","journal-title":"Prog. Biophys. Mol. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"eabj9853","DOI":"10.1126\/science.abj9853","article-title":"Low-dose mRNA-1273 COVID-19 vaccine generates durable memory enhanced by cross-reactive T cells","volume":"374","author":"Mateus","year":"2021","journal-title":"Science"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1016\/S1473-3099(21)00127-4","article-title":"Safety and immunogenicity of a recombinant tandem-repeat dimeric RBD-based protein subunit vaccine (ZF2001) against COVID-19 in adults: Two randomised, double-blind, placebo-controlled, phase 1 and 2 trials","volume":"21","author":"Yang","year":"2021","journal-title":"Lancet Infect. Dis."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Kumar, S., Jeong, Y., Ashraf, M.U., and Bae, Y.-S. (2019). Dendritic Cell-Mediated Th2 Immunity and Immune Disorders. Int. J. Mol. Sci., 20.","DOI":"10.20944\/preprints201904.0007.v1"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1038\/nri3254","article-title":"Cross-presentation by dendritic cells","volume":"12","author":"Joffre","year":"2012","journal-title":"Nat. Rev. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.cyto.2016.08.003","article-title":"TNF Activity and T cells","volume":"101","author":"Mehta","year":"2018","journal-title":"Cytokine"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1016\/S0952-7915(02)00335-7","article-title":"Molecular mechanisms of activated T cell death in vivo","volume":"14","author":"Hildeman","year":"2002","journal-title":"Curr. Opin. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Melo, A.K.G., Milby, K.M., Caparroz, A.L.M.A., Pinto, A.C.P.N., Santos, R.R.P., Rocha, A.P., Ferreira, G.A., Souza, V.A., Valadares, L.D.A., and Vieira, R.M.R.A. (2021). Biomarkers of cytokine storm as red flags for severe and fatal COVID-19 cases: A living systematic review and meta-analysis. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0253894"},{"key":"ref_35","unstructured":"Farshi, E. (2021). Cytokine Storm Response to COVID-19 Vaccinations. J. Cytokine Biol., 5."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Ihim, S.A., Abubakar, S.D., Zian, Z., Sasaki, T., Saffarioun, M., Maleknia, S., and Azizi, G. (2022). Interleukin-18 cytokine in immunity, inflammation, and autoimmunity: Biological role in induction, regulation, and treatment. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.919973"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1089\/jir.2013.0052","article-title":"IL-18 Expression Results in a Recombinant Vaccinia Virus That Is Highly Attenuated and Immunogenic","volume":"34","author":"Verardi","year":"2014","journal-title":"J. Interf. Cytokine Res."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Hidalgo-Gajardo, A., Guti\u00e9rrez, N., Lamazares, E., Espinoza, F., Escobar-Riquelme, F., Leiva, M.J., Villavicencio, C., Mena-Ulecia, K., Montesino, R., and Altamirano, C. (2023). Co-Formulation of Recombinant Porcine IL-18 Enhances the Onset of Immune Response in a New Lawsonia intracellularis Vaccine. Vaccines, 11.","DOI":"10.2139\/ssrn.4456794"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1016\/j.vaccine.2005.07.087","article-title":"Interleukin-18 enhances Th1 immunity and tumor protection of a DNA vaccine","volume":"24","author":"Marshall","year":"2006","journal-title":"Vaccine"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2377","DOI":"10.1111\/febs.14467","article-title":"A Guide to IL-1 family cytokines in adjuvanticity","volume":"285","author":"Lavelle","year":"2018","journal-title":"FEBS J."},{"key":"ref_41","unstructured":"Ratcliffe, M.J.H. (2016). Cytokine Regulation of B Cell Activation and Differentiation. Encyclopedia of Immunobiology, Academic Press."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"463","DOI":"10.2183\/pjab.87.463","article-title":"Interleukin-5 and IL-5 receptor in health and diseases","volume":"87","author":"Takatsu","year":"2011","journal-title":"Proc. Jpn. Acad. Ser. B"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1038\/nri.2017.118","article-title":"TH2 cell development and function","volume":"18","author":"Walker","year":"2018","journal-title":"Nat. Rev. Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1111\/j.1365-2567.2011.03413.x","article-title":"Type 2 innate immune responses and the natural helper cell","volume":"132","author":"Koyasu","year":"2011","journal-title":"Immunology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"S20","DOI":"10.1097\/ICO.0b013e318269cb1a","article-title":"Natural Helper Cells and TH2-Type Innate Immunity","volume":"31","author":"Koyasu","year":"2012","journal-title":"Cornea"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1002\/1097-0029(20000801)50:3<184::AID-JEMT2>3.0.CO;2-H","article-title":"TNF alpha and the TNF receptor superfamily: Structure-function relationship(s)","volume":"50","author":"Idriss","year":"2000","journal-title":"Microsc. Res. Tech."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1073\/pnas.87.3.968","article-title":"Prevention of diabetes in nonobese diabetic mice by tumor necrosis factor (TNF): Similarities between TNF-alpha and interleukin 1","volume":"87","author":"Jacob","year":"1990","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"12287","DOI":"10.1073\/pnas.172382999","article-title":"Tumor necrosis factor-\u03b1 regulation of CD4+C25+ T cell levels in NOD mice","volume":"99","author":"Wu","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1016\/0090-1229(89)90157-8","article-title":"Chronic therapy with recombinant tumor necrosis factor-\u03b1 in autoimmune NZB\/NZW F1 mice","volume":"52","author":"Gordon","year":"1989","journal-title":"Clin. Immunol. Immunopathol."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Salomon, B.L., Leclerc, M., Tosello, J., Ronin, E., Piaggio, E., and Cohen, J.L. (2018). Tumor Necrosis Factor \u03b1 and Regulatory T Cells in Oncoimmunology. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.00444"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1038\/35021239","article-title":"Vaccines against intracellular infections requiring cellular immunity","volume":"406","author":"Seder","year":"2000","journal-title":"Nature"}],"container-title":["Vaccines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-393X\/12\/12\/1420\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:53:36Z","timestamp":1760115216000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-393X\/12\/12\/1420"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,17]]},"references-count":51,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["vaccines12121420"],"URL":"https:\/\/doi.org\/10.3390\/vaccines12121420","relation":{},"ISSN":["2076-393X"],"issn-type":[{"type":"electronic","value":"2076-393X"}],"subject":[],"published":{"date-parts":[[2024,12,17]]}}}