{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T21:09:42Z","timestamp":1774559382262,"version":"3.50.1"},"reference-count":64,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,2,15]],"date-time":"2023-02-15T00:00:00Z","timestamp":1676419200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fundo Europeu de Desenvolvimento Regional (FEDER)","award":["IF\/00092\/2014\/CP1255\/CT0004"],"award-info":[{"award-number":["IF\/00092\/2014\/CP1255\/CT0004"]}]},{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia (FCT)","award":["IF\/00092\/2014\/CP1255\/CT0004"],"award-info":[{"award-number":["IF\/00092\/2014\/CP1255\/CT0004"]}]},{"name":"CHAIR in Onco-Innovation from the Faculty of Medicine of the University of Porto (FMUP)","award":["IF\/00092\/2014\/CP1255\/CT0004"],"award-info":[{"award-number":["IF\/00092\/2014\/CP1255\/CT0004"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>The progress that has been made in computer science positioned in silico studies as an important and well-recognized methodology in the drug discovery and development process. It has numerous advantages in terms of costs and also plays a huge impact on the way the research is conducted since it can limit the use of animal models leading to more sustainable research. Currently, human trials are already being partly replaced by in silico trials. EMA and FDA are both endorsing these studies and have been providing webinars and guidance to support them. For instance, PBPK modeling studies are being used to gather data on drug interactions with other drugs and are also being used to support clinical and regulatory requirements for the pediatric population, pregnant women, and personalized medicine. This trend evokes the need to understand the role of in silico studies in vaccines, considering the importance that these products achieved during the pandemic and their promising hope in oncology. Vaccines are safer than other current oncology treatments. There is a huge variety of strategies for developing a cancer vaccine, and some of the points that should be considered when designing the vaccine technology are the following: delivery platforms (peptides, lipid-based carriers, polymers, dendritic cells, viral vectors, etc.), adjuvants (to boost and promote inflammation at the delivery site, facilitating immune cell recruitment and activation), choice of the targeted antigen, the timing of vaccination, the manipulation of the tumor environment, and the combination with other treatments that might cause additive or even synergistic anti-tumor effects. These and many other points should be put together to outline the best vaccine design. The aim of this article is to perform a review and comprehensive analysis of the role of in silico studies to support the development of and design of vaccines in the field of oncology and infectious diseases. The authors intend to perform a literature review of all the studies that have been conducted so far in preparing in silico models and methods to support the development of vaccines. From this point, it was possible to conclude that there are few in silico studies on vaccines. Despite this, an overview of how the existing work could support the design of vaccines is described.<\/jats:p>","DOI":"10.3390\/pharmaceutics15020654","type":"journal-article","created":{"date-parts":[[2023,2,15]],"date-time":"2023-02-15T05:37:46Z","timestamp":1676439466000},"page":"654","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["In Silico Studies to Support Vaccine Development"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1055-3912","authenticated-orcid":false,"given":"Leonor","family":"Saldanha","sequence":"first","affiliation":[{"name":"OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Pl\u00e1cido da Costa, 4200-450 Porto, Portugal"},{"name":"CINTESIS@RISE, Faculty of Medicine, University of Porto, Alameda Professor Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"},{"name":"Department of Community Medicine, Information and Health Decision Sciences (MEDCIDS), Faculty of Medicine, University of Porto, Rua Doutor Pl\u00e1cido da Costa, s\/n, 4200-450 Porto, Portugal"}]},{"given":"\u00dclo","family":"Langel","sequence":"additional","affiliation":[{"name":"Institute of Technology, University of Tartu, Nooruse 1, 50411 Tartu, Estonia"},{"name":"Department of Biochemistry and Biophysics, Stockholm University, 10691 Stockholm, Sweden"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1283-1042","authenticated-orcid":false,"given":"Nuno","family":"Vale","sequence":"additional","affiliation":[{"name":"OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Pl\u00e1cido da Costa, 4200-450 Porto, Portugal"},{"name":"CINTESIS@RISE, Faculty of Medicine, University of Porto, Alameda Professor Hern\u00e2ni Monteiro, 4200-319 Porto, Portugal"},{"name":"Department of Community Medicine, Information and Health Decision Sciences (MEDCIDS), Faculty of Medicine, University of Porto, Rua Doutor Pl\u00e1cido da Costa, s\/n, 4200-450 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"20130433","DOI":"10.1098\/rstb.2013.0433","article-title":"The contribution of vaccination to global health: Past, present and future","volume":"369","author":"Greenwood","year":"2014","journal-title":"Philos Trans. R. Soc. Lond B Biol. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1016\/j.cell.2021.02.030","article-title":"Novel approaches for vaccine development","volume":"184","author":"Gebre","year":"2021","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"120586","DOI":"10.1016\/j.ijpharm.2021.120586","article-title":"mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability","volume":"601","author":"Schoenmaker","year":"2021","journal-title":"Int. J. Pharm."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"627932","DOI":"10.3389\/fimmu.2021.627932","article-title":"Cancer Vaccines, Adjuvants, and Delivery Systems","volume":"12","author":"Paston","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.hoc.2018.12.001","article-title":"Cancer Vaccines","volume":"33","author":"Bilusic","year":"2019","journal-title":"Hematol. Oncol. Clin. N. Am."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1038\/s41392-020-00352-y","article-title":"A systematic review of SARS-CoV-2 vaccine candidates","volume":"5","author":"Dong","year":"2020","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_7","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_8","doi-asserted-by":"crossref","first-page":"612","DOI":"10.3389\/fchem.2020.00612","article-title":"Editorial: In silico Methods for Drug Design and Discovery","volume":"8","author":"Brogi","year":"2020","journal-title":"Front. Chem."},{"key":"ref_9","unstructured":"EMA (2022, January 06). EMA Implements New Measures to Minimise Animal Testing during Medicines Development. Available online: https:\/\/www.ema.europa.eu\/en\/news\/ema-implements-new-measures-minimise-animal-testing-during-medicines-development."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1699","DOI":"10.1093\/bib\/bby043","article-title":"In silico clinical trials: Concepts and early adoptions","volume":"20","author":"Pappalardo","year":"2019","journal-title":"Brief Bioinform."},{"key":"ref_11","unstructured":"EMA (2022, January 13). Guideline on the Reporting of Physiologically Based Pharmacokinetic (PBPK) Modelling and Simulation. Available online: https:\/\/www.ema.europa.eu\/en\/reporting-physiologically-based-pharmacokinetic-pbpk-modelling-simulation-scientific-guideline."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Van Tilbeurgh, M., Lemdani, K., Beignon, A.S., Chapon, C., Tchitchek, N., Cheraitia, L., Marcos-Lopez, E., Pascal, Q., Le Grand, R., and Maisonnasse, P. (2021). Predictive Markers of Immunogenicity and Efficacy for Human Vaccines. Vaccines, 9.","DOI":"10.3390\/vaccines9060579"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2738","DOI":"10.1016\/j.vaccine.2013.03.071","article-title":"Pharmacokinetic modeling as an approach to assessing the safety of residual formaldehyde in infant vaccines","volume":"31","author":"Mitkus","year":"2013","journal-title":"Vaccine"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1007\/s10928-013-9328-y","article-title":"A physiologically-based pharmacokinetic (PBPK) model of squalene-containing adjuvant in human vaccines","volume":"40","author":"Tegenge","year":"2013","journal-title":"J. Pharmacokinet. Pharmacodyn."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.taap.2016.07.017","article-title":"A simple physiologically based pharmacokinetic model evaluating the effect of anti-nicotine antibodies on nicotine disposition in the brains of rats and humans","volume":"307","author":"Saylor","year":"2016","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/j.yrtph.2015.02.005","article-title":"A first-generation physiologically based pharmacokinetic (PBPK) model of alpha-tocopherol in human influenza vaccine adjuvant","volume":"71","author":"Tegenge","year":"2015","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Badhan, R.K.S., Khadke, S., and Perrie, Y. (2017). Application of Pharmacokinetics Modelling to Predict Human Exposure of a Cationic Liposomal Subunit Antigen Vaccine System. Pharmaceutics, 9.","DOI":"10.3390\/pharmaceutics9040057"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"100390","DOI":"10.1016\/j.mtbio.2022.100390","article-title":"Localization of drug biodistribution in a 3D-bioengineered subcutaneous neovascularized microenvironment","volume":"16","author":"Capuani","year":"2022","journal-title":"Mater. Today Bio"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"110193","DOI":"10.1016\/j.jtbi.2020.110193","article-title":"A modeling platform for the lymphatic system","volume":"493","author":"Ziemys","year":"2020","journal-title":"J. Theor. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Pennisi, M., Russo, G., Sgroi, G., Bonaccorso, A., Parasiliti Palumbo, G.A., Fichera, E., Mitra, D.K., Walker, K.B., Cardona, P.J., and Amat, M. (2019). Predicting the artificial immunity induced by RUTI\u00ae vaccine against tuberculosis using universal immune system simulator (UISS). BMC Bioinform., 20.","DOI":"10.1186\/s12859-019-3045-5"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Russo, G., Sgroi, G., Parasiliti Palumbo, G.A., Pennisi, M., Juarez, M.A., Cardona, P.-J., Motta, S., Walker, K.B., Fichera, E., and Viceconti, M. (2020). Moving forward through the in silico modeling of tuberculosis: A further step with UISS-TB. BMC Bioinform., 21.","DOI":"10.1186\/s12859-020-03762-5"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Russo, G., Pappalardo, F., Juarez, M.A., Pennisi, M., Cardona, P.J., Coler, R., Fichera, E., and Viceconti, M. (2019, January 18\u201321). Evaluation of the efficacy of RUTI and ID93\/GLA-SE vaccines in tuberculosis treatment: In silico trial through UISS-TB simulator. Proceedings of the 2019 IEEE International Conference on Bioinformatics and Biomedicine (BIBM), San Diego, CA, USA.","DOI":"10.1109\/BIBM47256.2019.8983060"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Russo, G., Pennisi, M., Fichera, E., Motta, S., Raciti, G., Viceconti, M., and Pappalardo, F. (2020). In silico trial to test COVID-19 candidate vaccines: A case study with UISS platform. BMC Bioinform., 21.","DOI":"10.1186\/s12859-020-03872-0"},{"key":"ref_24","unstructured":"Silva, L.d.L.e., Xavier, M.P., Santos, R.W.d., Lobosco, M., and Reis, R.F. (2020, January 16\u201319). Uncertain Quantification of Immunological Memory to Yellow Fever Virus. Proceedings of the 2020 IEEE International Conference on Bioinformatics and Biomedicine (BIBM), Seoul, Republic of Korea."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.yrtph.2016.08.003","article-title":"Pharmacokinetics and biodistribution of squalene-containing emulsion adjuvant following intramuscular injection of H5N1 influenza vaccine in mice","volume":"81","author":"Tegenge","year":"2016","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"103203","DOI":"10.1016\/j.ebiom.2020.103203","article-title":"Pharmacokinetics and predicted neutralisation coverage of VRC01 in HIV-uninfected participants of the Antibody Mediated Prevention (AMP) trials","volume":"64","author":"Huang","year":"2021","journal-title":"EBioMedicine"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1080\/19466315.2021.1919196","article-title":"Simulation-Based Pharmacokinetics Sampling Design for Evaluating Correlates of Prevention Efficacy of Passive HIV Monoclonal Antibody Prophylaxis","volume":"14","author":"Zhang","year":"2022","journal-title":"Stat. Biopharm. Res."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"L\u0151rincz, O., T\u00f3th, J., Moln\u00e1r, L., Mikl\u00f3s, I., P\u00e1ntya, K., Megyesi, M., Somogyi, E., Csiszovszki, Z., and T\u0151ke, E.R. (2021). In Silico Model Estimates the Clinical Trial Outcome of Cancer Vaccines. Cells, 10.","DOI":"10.3390\/cells10113048"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1039\/c4ib00295d","article-title":"A multi-scale approach to designing therapeutics for tuberculosis","volume":"7","author":"Linderman","year":"2015","journal-title":"Integr. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Maleki, A., Russo, G., Parasiliti Palumbo, G.A., and Pappalardo, F. (2022). In silico design of recombinant multi-epitope vaccine against influenza A virus. BMC Bioinform., 22.","DOI":"10.1186\/s12859-022-04581-6"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1016\/j.apsb.2016.04.004","article-title":"PBPK Modeling and Simulation in Drug Research and Development","volume":"6","author":"Zhuang","year":"2016","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_32","unstructured":"FDA (2022, January 06). How Simulation Can Transform Regulatory Pathways, Available online: https:\/\/www.fda.gov\/science-research\/about-science-research-fda\/how-simulation-can-transform-regulatory-pathways."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1002\/bdd.2257","article-title":"Physiological-based pharmacokinetic modeling trends in pharmaceutical drug development over the last 20-years; in-depth analysis of applications, organizations, and platforms","volume":"42","author":"Burkhill","year":"2021","journal-title":"Biopharm. Drug Dispos."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Kabiri Chimeh, M., Heywood, P., Pennisi, M., Pappalardo, F., and Richmond, P. (2019). Parallelisation strategies for agent based simulation of immune systems. BMC Bioinform., 20.","DOI":"10.1186\/s12859-019-3181-y"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1002\/psp4.12703","article-title":"Step-by-step comparison of ordinary differential equation and agent-based approaches to pharmacokinetic-pharmacodynamic models","volume":"11","author":"Truong","year":"2022","journal-title":"CPT Pharmacomet. Syst. Pharmacol."},{"key":"ref_36","unstructured":"FDA (2022, January 13). Population Pharmacokinetics Guidance for Industry, Available online: https:\/\/www.fda.gov\/regulatory-information\/search-fda-guidance-documents\/population-pharmacokinetics."},{"key":"ref_37","unstructured":"EMA (2022, January 13). Guideline on Reporting the Results of Population Pharmacokinetics Analysis. Available online: https:\/\/www.ema.europa.eu\/en\/documents\/scientific-guideline\/guideline-reporting-results-population-pharmacokinetic-analyses_en.pdf."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"94","DOI":"10.3109\/00498254.2011.627477","article-title":"Application of PBPK modelling in drug discovery and development at Pfizer","volume":"42","author":"Jones","year":"2012","journal-title":"Xenobiotica"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1038\/s41598-022-05108-y","article-title":"A comprehensive physiologically based pharmacokinetic (PBPK) model for nicotine in humans from using nicotine-containing products with different routes of exposure","volume":"12","author":"Rostami","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Pappalardo, F., Russo, G., Pennisi, M., Sgroi, G., Palumbo, G., Motta, S., Maimone, D., and Chiacchio, F. (2018, January 3\u20136). Agent based modeling of relapsing multiple sclerosis: A possible approach to predict treatment outcome. Proceedings of the IEEE International Conference on Bioinformatics and Biomedicine (BIBM), Madrid, Spain.","DOI":"10.1109\/BIBM.2018.8621109"},{"key":"ref_41","first-page":"41","article-title":"The Vaccine Industry","volume":"Volume 4","author":"Plotkin","year":"2018","journal-title":"Plotkin\u2019s Vaccines"},{"key":"ref_42","unstructured":"Abbas, A., Lichtman, H., and Pillai, S. (2022). Cellular and Molecular Immunology, Elsevier. [10th ed.]."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1021\/acsabm.1c01238","article-title":"Peptides for Vaccine Development","volume":"5","author":"Hamley","year":"2022","journal-title":"ACS Appl. Bio Mater."},{"key":"ref_44","first-page":"145","article-title":"Developments in Vaccine Adjuvants. Vaccine Design","volume":"2412","author":"Thomas","year":"2021","journal-title":"Methods in Molecular Biology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/s00253-021-11713-0","article-title":"Current view on novel vaccine technologies to combat human infectious diseases","volume":"106","year":"2022","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref_46","unstructured":"CDC (2021). Varicella, Epidemiology and Prevention of Vaccine-Preventable Diseases."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1038\/s41541-020-0204-7","article-title":"Applying lessons from the Ebola vaccine experience for SARS-CoV-2 and other epidemic pathogens","volume":"5","author":"Wolf","year":"2020","journal-title":"Npj Vaccines"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1636","DOI":"10.1016\/j.immuni.2021.07.017","article-title":"Accelerated COVID-19 vaccine development: Milestones, lessons, and prospects","volume":"54","author":"Bok","year":"2021","journal-title":"Immunity"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1038\/d41586-020-03626-1","article-title":"The lightning-fast quest for COVID vaccines\u2014And what it means for other diseases","volume":"589","author":"Ball","year":"2020","journal-title":"Nature"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1146\/annurev-pharmtox-010510-100540","article-title":"Physiologically-based pharmacokinetics in drug development and regulatory science","volume":"51","author":"Rowland","year":"2011","journal-title":"Annu Rev. Pharm. Toxicol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1002\/cpt.37","article-title":"Physiologically based pharmacokinetic modeling in drug discovery and development: A pharmaceutical industry perspective","volume":"97","author":"Jones","year":"2015","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1093\/infdis\/jiu568","article-title":"Increasing Complexity of Vaccine Development","volume":"212","author":"Plotkin","year":"2015","journal-title":"J. Infec. Dis."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"S67","DOI":"10.1093\/infdis\/jiv070","article-title":"Cancer Immunity: Lessons From Infectious Diseases","volume":"212","author":"Trinchieri","year":"2015","journal-title":"J. Infect. Dis."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1007\/s11523-020-00788-w","article-title":"Vaccine Therapies for Cancer: Then and Now","volume":"16","author":"Morse","year":"2021","journal-title":"Targ Oncol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1111\/j.1751-7915.2011.00321.x","article-title":"Systems biology in vaccine design","volume":"5","author":"Six","year":"2012","journal-title":"Microb. Biotechnol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1111\/j.1600-065X.2006.00492.x","article-title":"Quantitative modeling of immune responses","volume":"216","author":"Cohn","year":"2007","journal-title":"Immunol. Rev."},{"key":"ref_57","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_58","doi-asserted-by":"crossref","first-page":"708299","DOI":"10.3389\/fphar.2021.708299","article-title":"Reviewing Data Integrated for PBPK Model Development to Predict Metabolic Drug-Drug Interactions: Shifting Perspectives and Emerging Trends","volume":"12","author":"Kenza","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1240","DOI":"10.1002\/cpt.1720","article-title":"Evaluation of Current Regulation and Guidelines of Pharmacogenomic Drug Labels: Opportunities for Improvements","volume":"107","author":"Shekhani","year":"2020","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1111\/j.1365-2125.2009.03484.x","article-title":"Proposals for Model-Based Paediatric Medicinal Development within the Current European Union Regulatory Framework","volume":"68","author":"Manolis","year":"2009","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.jconrel.2019.04.025","article-title":"Liposomes used as a vaccine adjuvant-delivery system: From basics to clinical immunization","volume":"303","author":"Wang","year":"2019","journal-title":"J. Control. Release"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Bezbaruah, R., Chavda, V.P., Nongrang, L., Alom, S., Deka, K., Kalita, T., Ali, F., Bhattacharjee, B., and Vora, L. (2022). Nanoparticle-Based Delivery Systems for Vaccines. Vaccines, 10.","DOI":"10.3390\/vaccines10111946"},{"key":"ref_63","unstructured":"WHO (2023, January 22). How Are Vaccines Developed?. Available online: https:\/\/www.who.int\/news-room\/feature-stories\/detail\/how-are-vaccines-developed."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2013","DOI":"10.1093\/bioinformatics\/btr335","article-title":"Immune system simulation online","volume":"27","author":"Rapin","year":"2011","journal-title":"Bioinformatics"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/15\/2\/654\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:36:23Z","timestamp":1760121383000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/15\/2\/654"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,15]]},"references-count":64,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["pharmaceutics15020654"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics15020654","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,15]]}}}