{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,20]],"date-time":"2025-12-20T21:53:26Z","timestamp":1766267606329,"version":"build-2065373602"},"reference-count":41,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2021,1,22]],"date-time":"2021-01-22T00:00:00Z","timestamp":1611273600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/M009513\/1"],"award-info":[{"award-number":["BB\/M009513\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/P002404\/1"],"award-info":[{"award-number":["MR\/P002404\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000865","name":"Bill and Melinda Gates Foundation","doi-asserted-by":"publisher","award":["OPP1084276\/OPP1135288","OPP1160830","OPP1137034\/OPP1151915"],"award-info":[{"award-number":["OPP1084276\/OPP1135288","OPP1160830","OPP1137034\/OPP1151915"]}],"id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"publisher"}]},{"name":"UNITAID","award":["4214-LSHTM-Sept15; PO 8477-0-600"],"award-info":[{"award-number":["4214-LSHTM-Sept15; PO 8477-0-600"]}]},{"DOI":"10.13039\/501100000269","name":"Economic and Social Research Council","doi-asserted-by":"publisher","award":["ES\/P008011\/1"],"award-info":[{"award-number":["ES\/P008011\/1"]}],"id":[{"id":"10.13039\/501100000269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Developing a vaccine against the global pandemic SARS-CoV-2 is a critical area of active research. Modelling can be used to identify optimal vaccine dosing; maximising vaccine efficacy and safety and minimising cost. We calibrated statistical models to published dose-dependent seroconversion and adverse event data of a recombinant adenovirus type-5 (Ad5) SARS-CoV-2 vaccine given at doses 5.0 \u00d7 1010, 1.0 \u00d7 1011 and 1.5 \u00d7 1011 viral particles. We estimated the optimal dose for three objectives, finding: (A) the minimum dose that may induce herd immunity, (B) the dose that maximises immunogenicity and safety and (C) the dose that maximises immunogenicity and safety whilst minimising cost. Results suggest optimal dose [95% confidence interval] in viral particles per person was (A) 1.3 \u00d7 1011 [0.8\u20137.9 \u00d7 1011], (B) 1.5 \u00d7 1011 [0.3\u20135.0 \u00d7 1011] and (C) 1.1 \u00d7 1011 [0.2\u20131.5 \u00d7 1011]. Optimal dose exceeded 5.0 \u00d7 1010 viral particles only if the cost of delivery exceeded \u00a30.65 or cost per 1011 viral particles was less than \u00a36.23. Optimal dose may differ depending on the objectives of developers and policy-makers, but further research is required to improve the accuracy of optimal-dose estimates.<\/jats:p>","DOI":"10.3390\/vaccines9020078","type":"journal-article","created":{"date-parts":[[2021,1,25]],"date-time":"2021-01-25T12:28:31Z","timestamp":1611577711000},"page":"78","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Optimising Vaccine Dose in Inoculation against SARS-CoV-2, a Multi-Factor Optimisation Modelling Study to Maximise Vaccine Safety and Efficacy"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0537-5437","authenticated-orcid":false,"given":"John","family":"Benest","sequence":"first","affiliation":[{"name":"Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sophie","family":"Rhodes","sequence":"additional","affiliation":[{"name":"Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9291-1511","authenticated-orcid":false,"given":"Matthew","family":"Quaife","sequence":"additional","affiliation":[{"name":"Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas G.","family":"Evans","sequence":"additional","affiliation":[{"name":"Vaccitech Ltd., The Schrodinger Building, Heatley Road, The Oxford Science Park, Oxford OX4 4GE, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard G.","family":"White","sequence":"additional","affiliation":[{"name":"Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"106054","DOI":"10.1016\/j.ijantimicag.2020.106054","article-title":"Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2): A Global Pandemic and Treatment Strategies","volume":"56","author":"Sharma","year":"2020","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.ijsu.2020.04.018","article-title":"The Socio-Economic Implications of the Coronavirus Pandemic (COVID-19): A Review","volume":"78","author":"Nicola","year":"2020","journal-title":"Int. J. Surg."},{"key":"ref_3","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. B Biol. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"198114","DOI":"10.1016\/j.virusres.2020.198114","article-title":"COVID-19 Vaccine: A Comprehensive Status Report","volume":"288","author":"Kaur","year":"2020","journal-title":"Virus Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.jtbi.2019.01.017","article-title":"Dose Finding for New Vaccines: The Role for Immunostimulation\/Immunodynamic Modelling","volume":"465","author":"Rhodes","year":"2019","journal-title":"J. Theor. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Handel, A., Li, Y., McKay, B., Pawelek, K.A., Zarnitsyna, V., and Antia, R. (2018). Exploring the Impact of Inoculum Dose on Host Immunity and Morbidity to Inform Model-Based Vaccine Design. PLoS Comput. Biol., 14.","DOI":"10.1101\/328559"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"6285","DOI":"10.1016\/j.vaccine.2016.10.060","article-title":"The TB Vaccine H56+IC31 Dose-Response Curve Is Peaked Not Saturating: Data Generation for New Mathematical Modelling Methods to Inform Vaccine Dose Decisions","volume":"34","author":"Rhodes","year":"2016","journal-title":"Vaccine"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Benest, J., Rhodes, S., Afrough, S., Evans, T., and White, R. (2020). Response Type and Host Species May Be Sufficient to Predict Dose-Response Curve Shape for Adenoviral Vector Vaccines. Vaccines, 8.","DOI":"10.3390\/vaccines8020155"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Fraz\u00e3o, T.D.C., Camilo, D.G.G., Cabral, E.L.S., and Souza, R.P. (2018). Multicriteria Decision Analysis (MCDA) in Health Care: A Systematic Review of the Main Characteristics and Methodological Steps. BMC Med. Inform. Decis. Mak., 18.","DOI":"10.1186\/s12911-018-0663-1"},{"key":"ref_10","unstructured":"World Health Organisation (2020, September 09). DRAFT Landscape of COVID-19 Candidate Vaccines. Available online: https:\/\/www.who.int\/publications\/m\/item\/draft-landscape-of-covid-19-candidate-vaccines."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"108634","DOI":"10.1016\/j.clim.2020.108634","article-title":"COVID-19: A Review of Therapeutic Strategies and Vaccine Candidates","volume":"222","author":"Izda","year":"2020","journal-title":"Clin. Immunol."},{"key":"ref_12","unstructured":"(2020, November 30). Oxford University Breakthrough on Global COVID-19 Vaccine | University of Oxford. Available online: https:\/\/www.ox.ac.uk\/news\/2020-11-23-oxford-university-breakthrough-global-covid-19-vaccine."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"m4347","DOI":"10.1136\/bmj.m4347","article-title":"COVID-19: Vaccine Candidate May Be More than 90% Effective, Interim Results Indicate","volume":"371","author":"Mahase","year":"2020","journal-title":"BMJ"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1751","DOI":"10.1016\/S0140-6736(20)31252-6","article-title":"COVID-19 Vaccine Development Pipeline Gears Up","volume":"395","author":"Mullard","year":"2020","journal-title":"Lancet"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1845","DOI":"10.1016\/S0140-6736(20)31208-3","article-title":"Safety, Tolerability, and Immunogenicity of a Recombinant Adenovirus Type-5 Vectored COVID-19 Vaccine: A Dose-Escalation, Open-Label, Non-Randomised, First-in-Human Trial","volume":"395","author":"Zhu","year":"2020","journal-title":"Lancet"},{"key":"ref_16","first-page":"e8399","article-title":"Protective Adaptive Immunity Against Severe Acute Respiratory Syndrome Coronaviruses 2 (SARS-CoV-2) and Implications for Vaccines","volume":"12","author":"Manners","year":"2020","journal-title":"Cureus"},{"key":"ref_17","unstructured":"US Food and Drug Administration (2007). Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1111\/j.1365-2125.2010.03741.x","article-title":"A Safety Grading Scale to Support Dose Escalation and Define Stopping Rules for Healthy Subject First-Entry-into-Man Studies","volume":"70","author":"Sibille","year":"2010","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_19","unstructured":"Grothendieck, G. (2019, January 05). Nls2: Non-Linear Regression with Brute Force, R package version 0.2."},{"key":"ref_20","unstructured":"R Core Team (2018). R: A Language and Environment for Statistical Computing, R Foundation for Statistical Computing."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Afrough, S., Rhodes, S., Evans, T., White, R., and Benest, J. (2020). Immunologic Dose-Response to Adenovirus-Vectored Vaccines in Animals and Humans: A Systematic Review of Dose-Response Studies of Replication Incompetent Adenoviral Vaccine Vectors When Given via an Intramuscular or Subcutaneous Route. Vaccines, 8.","DOI":"10.3390\/vaccines8010131"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1002\/sim.8021","article-title":"A Bayesian Design for Phase I Cancer Therapeutic Vaccine Trials","volume":"38","author":"Wang","year":"2019","journal-title":"Stat. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1007\/s12561-019-09245-3","article-title":"Flexible Phase I\u2013II Design for Partially Ordered Regimens with Application to Therapeutic Cancer Vaccines","volume":"12","author":"Wages","year":"2020","journal-title":"Stat. Biosci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1093\/jnci\/djp079","article-title":"Dose Escalation Methods in Phase I Cancer Clinical Trials","volume":"101","author":"Lee","year":"2009","journal-title":"JNCI J. Natl. Cancer Inst."},{"key":"ref_25","unstructured":"(2020, October 15). Safety Information by Vaccine | CDC, Available online: https:\/\/www.cdc.gov\/vaccinesafety\/vaccines\/index.html."},{"key":"ref_26","unstructured":"(2020, October 16). Average for the Year to 31 March 2020\u2014GOV.UK, Available online: https:\/\/assets.publishing.service.gov.uk\/government\/uploads\/system\/uploads\/attachment_data\/file\/885947\/Spot.csv\/preview."},{"key":"ref_27","unstructured":"(2020, October 16). Inflation Calculator. Available online: http:\/\/www.bankofengland.co.uk\/monetary-policy\/inflation\/inflation-calculator."},{"key":"ref_28","unstructured":"(2020, October 16). Agenda for Change\u2014Pay Rates. Available online: https:\/\/www.healthcareers.nhs.uk\/working-health\/working-nhs\/nhs-pay-and-benefits\/agenda-change-pay-rates."},{"key":"ref_29","unstructured":"(2020, October 16). Annual Leave and Holiday | Advice Guides | Royal College of Nursing. Available online: \/get-help\/rcn-advice\/annual-leave-and-holiday-pay."},{"key":"ref_30","unstructured":"(2017). Vaccinating Adults: A Step-by-Step Guide, Centers for Disease Control and Prevention."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1586\/erv.10.129","article-title":"Vaccine Presentation in the USA: Economics of Prefilled Syringes versus Multidose Vials for Influenza Vaccination","volume":"9","author":"Pereira","year":"2010","journal-title":"Expert Rev. Vaccines"},{"key":"ref_32","unstructured":"GE Healthcare (2020, October 15). Scalable Process for Adenovirus Production 2018. Available online: https:\/\/cdn.cytivalifesciences.com\/dmm3bwsv3\/AssetStream.aspx?mediaformatid=10061&destinationid=10016&assetid=27018."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e32","DOI":"10.1016\/j.jinf.2020.03.027","article-title":"Herd Immunity\u2014Estimating the Level Required to Halt the COVID-19 Epidemics in Affected Countries","volume":"80","author":"Kwok","year":"2020","journal-title":"J. Infect."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1743","DOI":"10.1016\/j.jsps.2020.10.019","article-title":"Current COVID-19 Vaccine Candidates: Implications in the Saudi Population","volume":"28","author":"Raja","year":"2020","journal-title":"Saudi Pharm. J. SPJ"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1038\/s41541-018-0075-3","article-title":"Using Vaccine Immunostimulation\/Immunodynamic Modelling Methods to Inform Vaccine Dose Decision-Making","volume":"3","author":"Rhodes","year":"2018","journal-title":"NPJ Vaccines"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1111\/irv.12510","article-title":"WHO Guide on the Economic Evaluation of Influenza Vaccination","volume":"12","author":"Newall","year":"2018","journal-title":"Influenza Other Respir. Viruses"},{"key":"ref_37","unstructured":"World Health Organistaion (2002). Guidelines for Estimating Costs of Introducing New Vaccines into the National Immunization System, World Health Organisation."},{"key":"ref_38","first-page":"429","article-title":"Quantifying the Burden of Disease: The Technical Basis for Disability-Adjusted Life Years","volume":"72","author":"Murray","year":"1994","journal-title":"Bull. World Health Organ."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41586-020-2607-z","article-title":"Single-Shot Ad26 Vaccine Protects against SARS-CoV-2 in Rhesus Macaques","volume":"586","author":"Mercado","year":"2020","journal-title":"Nature"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.1016\/S0140-6736(20)32137-1","article-title":"SARS-CoV-2 Immunity: Review and Applications to Phase 3 Vaccine Candidates","volume":"396","author":"Oland","year":"2020","journal-title":"Lancet"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"818","DOI":"10.1126\/science.abc5343","article-title":"Primary Exposure to SARS-CoV-2 Protects against Reinfection in Rhesus Macaques","volume":"369","author":"Deng","year":"2020","journal-title":"Science"}],"container-title":["Vaccines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-393X\/9\/2\/78\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:14:11Z","timestamp":1760159651000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-393X\/9\/2\/78"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,22]]},"references-count":41,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["vaccines9020078"],"URL":"https:\/\/doi.org\/10.3390\/vaccines9020078","relation":{},"ISSN":["2076-393X"],"issn-type":[{"type":"electronic","value":"2076-393X"}],"subject":[],"published":{"date-parts":[[2021,1,22]]}}}