{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,27]],"date-time":"2025-12-27T07:31:20Z","timestamp":1766820680150,"version":"build-2065373602"},"reference-count":40,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,1,19]],"date-time":"2022-01-19T00:00:00Z","timestamp":1642550400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Background: The need for an updated plague vaccine is highlighted by outbreaks in endemic regions together with the pandemic potential of this disease. There is no easily available, approved vaccine. Methods: Here we have used a murine model of pneumonic plague to examine the factors that maximise immunogenicity and contribute to survival following vaccination. We varied vaccine type, as either a genetic fusion of the F1 and V protein antigens or a mixture of these two recombinant antigens, as well as antigen dose-level and formulation in order to correlate immune response to survival. Results: Whilst there was interaction between each of the variables of vaccine type, dose level and formulation and these all contributed to survival, vaccine formulation in protein-coated microcrystals (PCMCs) was the key contributor in inducing antibody titres. From these data, we propose a cut-off in total serum antibody titre to the F1 and V proteins of 100 \u00b5g\/mL and 200 \u00b5g\/mL, respectively. At these thresholds, survival is predicted in this murine pneumonic model to be &gt;90%. Within the total titre of antibody to the V antigen, the neutralising antibody component correlated with dose level and was enhanced when the V antigen in free form was formulated in PCMCs. Antibody titre to F1 was limited by fusion to V, but this was compensated for by PCMC formulation. Conclusions: These data will enable clinical assessment of this and other candidate plague vaccines that utilise the same vaccine antigens by identifying a target antibody titre from murine models, which will guide the evaluation of clinical titres as serological surrogate markers of efficacy.<\/jats:p>","DOI":"10.3390\/vaccines10020145","type":"journal-article","created":{"date-parts":[[2022,1,19]],"date-time":"2022-01-19T21:02:27Z","timestamp":1642626147000},"page":"145","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Predictors of Survival after Vaccination in a Pneumonic Plague Model"],"prefix":"10.3390","volume":"10","author":[{"given":"Barry D.","family":"Moore","sequence":"first","affiliation":[{"name":"Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow G1 1XQ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clair","family":"Macleod","sequence":"additional","affiliation":[{"name":"Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow G1 1XQ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa","family":"Henning","sequence":"additional","affiliation":[{"name":"Battelle Biomedical Research Center, West Jefferson, OH 43162, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Krile","sequence":"additional","affiliation":[{"name":"Battelle Biomedical Research Center, West Jefferson, OH 43162, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying-Liang","family":"Chou","sequence":"additional","affiliation":[{"name":"Battelle Biomedical Research Center, West Jefferson, OH 43162, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0142-9162","authenticated-orcid":false,"given":"Thomas R.","family":"Laws","sequence":"additional","affiliation":[{"name":"CBR Division, Dstl Porton Down, Salisbury SP4 0JQ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wendy A.","family":"Butcher","sequence":"additional","affiliation":[{"name":"CBR Division, Dstl Porton Down, Salisbury SP4 0JQ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristoffer M.","family":"Moore","sequence":"additional","affiliation":[{"name":"CBR Division, Dstl Porton Down, Salisbury SP4 0JQ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicola J.","family":"Walker","sequence":"additional","affiliation":[{"name":"CBR Division, Dstl Porton Down, Salisbury SP4 0JQ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0322-5972","authenticated-orcid":false,"given":"Ethel Diane","family":"Williamson","sequence":"additional","affiliation":[{"name":"CBR Division, Dstl Porton Down, Salisbury SP4 0JQ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Darrell R.","family":"Galloway","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,19]]},"reference":[{"key":"ref_1","unstructured":"(2021, July 12). WHO Global Plague Statistics. Available online: https:\/\/www.who.int\/health-topics\/plague."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Sagiyev, Z., Berdibekov, A., Bolger, T., Merekenova, A., Ashirova, S., Nurgozhin, Z., and Dalibayev, Z. (2019). Human response to live plague vaccine EV, Almaty region, Kazakhstan, 2014\u20132015. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0218366"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1258\/j.jmb.2007.05-59","article-title":"Waldemar Mordecai Haffkine, CIE (1860\u20131930): Prophylactic vaccination against cholera and bubonic plague in British India","volume":"15","author":"Hawgood","year":"2007","journal-title":"J. Med. Biogr."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1111\/j.1574-695X.1995.tb00196.x","article-title":"A new impoved sub-unit vaccine for plague: The basis of protection","volume":"12","author":"Williamson","year":"1995","journal-title":"FEMS Immunol. Med. Micro."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1016\/S0264-410X(96)00303-9","article-title":"A sub-unit vaccine elicits IgG in serum, spleen cell cultures and bronchial washings and protects immunised animals against pneumonic plague","volume":"15","author":"Stagg","year":"1997","journal-title":"Vaccine"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1551","DOI":"10.1016\/0264-410X(95)00090-N","article-title":"A comparison of Plague vaccine, USP and EV76 vaccine induced protection against Yersinia pestis in a murine model","volume":"13","author":"Russell","year":"1995","journal-title":"Vaccine"},{"key":"ref_7","unstructured":"(2021, July 12). WHO R&D Blueprint: Plague Vaccines Workshop April 2018. Available online: https:\/\/www.who.int\/blueprint\/what\/norms-standards\/Plague_vaccines_workshop-23-april-2018\/en\/."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/s41541-019-0105-9","article-title":"Plague vaccines: Recent progress and prospects","volume":"4","author":"Sun","year":"2019","journal-title":"NPJ Vaccines"},{"key":"ref_9","unstructured":"Williamson, E.D. (2018). Oyston PFC. Plotkin\u2019s Vaccines, Elsevier. [7th ed.]."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/j.micinf.2019.06.007","article-title":"Yersinia pestis and plague: An updated view on evolution, virulence determinants, immune subversion, vaccination and diagnostics","volume":"21","author":"Demeure","year":"2019","journal-title":"Microbes Infect."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"87","DOI":"10.3103\/S089141681303004X","article-title":"Molecular bases of vaccine-prevention of plague","volume":"28","author":"Dentovskaya","year":"2013","journal-title":"Mol. Genet. Microbiol. Virol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"448","DOI":"10.3389\/fcimb.2017.00448","article-title":"Identification of New Virulence Factors and Vaccine Candidates for Yersinia pestis","volume":"7","author":"Andersson","year":"2017","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1586\/erv.13.42","article-title":"Live-attenuatedYersinia pestisvaccines","volume":"12","author":"Wang","year":"2013","journal-title":"Expert Rev. Vaccines"},{"key":"ref_14","unstructured":"WHO (2021, July 12). Plague Outbreak in Madagascar: External Situation Report 14, 4 December 2017. Available online: Afro.who.int\/health-topics\/plague\/plague-outbreak-situation-reports."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1111\/j.1600-065X.2008.00674.x","article-title":"Immune defense against pneumonic plague","volume":"225","author":"Smiley","year":"2008","journal-title":"Immunol. Rev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"25","DOI":"10.3389\/fcimb.2016.00025","article-title":"Environmental Regulation of Yersinia Pathophysiology","volume":"6","author":"Chen","year":"2016","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1007\/s12026-013-8454-3","article-title":"The Yersinia pestis type III secretion system: Expression, assembly and role in the evasion of host defenses","volume":"57","author":"Plano","year":"2013","journal-title":"Immunol. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1038\/nrmicro1526","article-title":"The type III injectisome","volume":"4","author":"Cornelis","year":"2006","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/emi.2012.34","article-title":"Current developments and future prospects","volume":"1","author":"Feodorova","year":"2012","journal-title":"Emerg. Microbes Infect."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.micpath.2006.09.003","article-title":"Immunogenicity of the rF1+rV vaccine with the identification of potential immune correlates of protection","volume":"42","author":"Williamson","year":"2007","journal-title":"Microb. Pathogen."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1016\/S0264-410X(98)80110-2","article-title":"Protection against experimental bubonic and pneumonic plague by a recombinant capsular F1-V antigen fusion protein vaccine","volume":"16","author":"Heath","year":"1998","journal-title":"Vaccine"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4771","DOI":"10.1016\/j.vaccine.2011.04.084","article-title":"Recombinant (F1 + V) vaccine protects cynomolgus macaques against pneumonic plague","volume":"29","author":"Williamson","year":"2011","journal-title":"Vaccine"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1070","DOI":"10.1128\/CVI.00290-15","article-title":"Characterization of a Cynomolgus Macaque Model of Pneumonic Plague for Evaluation of Vaccine Efficacy","volume":"22","author":"Fellows","year":"2015","journal-title":"Clin. Vaccine Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"7748","DOI":"10.1016\/j.vaccine.2010.09.062","article-title":"Protection in mice passively immunized with serum from cynomolgus macaques and humans vaccinated with recombinant plague vaccine (rF1V)","volume":"28","author":"Fellows","year":"2010","journal-title":"Vaccine"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"6572","DOI":"10.1016\/j.vaccine.2011.06.119","article-title":"Prevention of pneumonic plague in mice, rats, guinea pigs and non-human primates with clinical grade rV10, rV10-2 or F1-V vaccines","volume":"29","author":"Quenee","year":"2011","journal-title":"Vaccine"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3598","DOI":"10.1128\/IAI.73.6.3598-3608.2005","article-title":"Human Immune Response to a Plague Vaccine Comprising Recombinant F1 and V Antigens","volume":"73","author":"Williamson","year":"2005","journal-title":"Infect. Immun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3115","DOI":"10.1016\/j.vaccine.2007.01.071","article-title":"Development of a recombinant vaccine against aerosolised plague","volume":"25","author":"Morris","year":"2007","journal-title":"Vaccine"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2012\/731604","article-title":"Advanced Development of the rF1V and rBV A\/B Vaccines: Progress and Challenges","volume":"2012","author":"Hart","year":"2011","journal-title":"Adv. Prev. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4","DOI":"10.4103\/0022-3859.173187","article-title":"The clinical development process for a novel preventive vaccine: An overview","volume":"62","author":"Singh","year":"2016","journal-title":"J. Postgrad. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5210","DOI":"10.1016\/j.vaccine.2018.06.039","article-title":"Dual route vaccination for plague with emergency use applications","volume":"36","author":"Moore","year":"2018","journal-title":"Vaccine"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4234","DOI":"10.1016\/j.vaccine.2013.09.061","article-title":"Protein coated microcrystals formulated with model antigens and modified with calcium phosphate exhibit enhanced phagocytosis and immunogenicity","volume":"32","author":"Jones","year":"2014","journal-title":"Vaccine"},{"key":"ref_32","unstructured":"Food and Drug Administration, HHS (2002). 21CFR 601.90-Evidence needed to demonstrate effectiveness of new drugs when human efficacy studies are not ethical or feasible. Fed. Regist., 67, 37988\u201337998."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1128\/CVI.05591-11","article-title":"Establishment of a Swiss Webster Mouse Model of Pneumonic Plague to Meet Essential Data Elements under the Animal Rule","volume":"19","author":"Fellows","year":"2012","journal-title":"Clin. Vaccine Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1542\/peds.2005-2755","article-title":"Immunogenicity and safety of an inactivated hepatitis A vaccine administered concomitantly with diphtheria\u2013tetanus\u2013acellular pertussis and haemophilus influenzae type B vaccines to children less than 2 years of age","volume":"118","author":"Nolan","year":"2006","journal-title":"Pediatrics"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1016\/S0264-410X(00)00108-0","article-title":"Protection conferred by a fully recombinant sub-unit vaccine against Yer-sinia pestis in male and female mice of four inbred strains","volume":"19","author":"Jones","year":"2001","journal-title":"Vaccine"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1097\/JTO.0b013e3181ec173d","article-title":"ROC curve in diagnostic test assessment","volume":"5","author":"Mandrekar","year":"2010","journal-title":"J. Thorac. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1111\/cei.13284","article-title":"Vaccines for emerging pathogens: Prospects for licensure. Review series on Vaccines for emerging pathogens: From research to the clinic Part 1","volume":"198","author":"Williamson","year":"2019","journal-title":"Clin. Exp. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1038\/nrmicro2129","article-title":"Correlates of protective immunity for Ebola vaccines: Implications for regulatory approval by the animal rule","volume":"7","author":"Sullivan","year":"2009","journal-title":"Nat. Rev. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/j.coviro.2012.01.004","article-title":"Licensure of vaccines using the Animal Rule","volume":"2","author":"Burns","year":"2012","journal-title":"Curr. Opin. Virol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"16013","DOI":"10.1038\/npjvaccines.2016.13","article-title":"First vaccine approval under the FDA Animal Rule","volume":"1","author":"Beasley","year":"2016","journal-title":"NPJ Vaccines"}],"container-title":["Vaccines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-393X\/10\/2\/145\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:03:58Z","timestamp":1760133838000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-393X\/10\/2\/145"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,19]]},"references-count":40,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["vaccines10020145"],"URL":"https:\/\/doi.org\/10.3390\/vaccines10020145","relation":{},"ISSN":["2076-393X"],"issn-type":[{"type":"electronic","value":"2076-393X"}],"subject":[],"published":{"date-parts":[[2022,1,19]]}}}