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CVB infections are considered to be prime candidates for environmental triggers of type 1 diabetes. This, together with the significant disease burden of acute CVB infections and their association with chronic diseases other than diabetes, has prompted the development of human CVB vaccines. The current study evaluated the safety and immunogenicity of the first human vaccine designed against CVBs associated with type 1 diabetes in a double-blind randomised placebo-controlled Phase I trial.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The main eligibility criteria for participants were good general health, age between 18 and 45 years, provision of written informed consent and willingness to comply with all trial procedures. Treatment allocation (PRV-101 or placebo) was based on a computer-generated randomisation schedule and people assessing the outcomes were masked to group assignment. In total, 32 participants (17 men, 15 women) aged 18\u201344 years were randomised to receive a low (\n                      <jats:italic>n<\/jats:italic>\n                      =12) or high (\n                      <jats:italic>n<\/jats:italic>\n                      =12) dose of a multivalent, formalin-inactivated vaccine including CVB serotypes 1\u20135 (PRV-101), or placebo (\n                      <jats:italic>n<\/jats:italic>\n                      =8), given by intramuscular injections at weeks 0, 4 and 8 at a single study site in Finland. The participants were followed for another 24 weeks. Safety and tolerability were the primary endpoints. Anti-CVB IgG and virus-neutralising titres were analysed using an ELISA and neutralising plaque reduction assays, respectively.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Among the 32 participants (low dose,\n                      <jats:italic>n<\/jats:italic>\n                      =12; high dose,\n                      <jats:italic>n<\/jats:italic>\n                      =12; placebo,\n                      <jats:italic>n<\/jats:italic>\n                      =8) no serious adverse events or adverse events leading to study treatment discontinuation were observed. Treatment-emergent adverse events considered to be related to the study drug occurred in 37.5% of the participants in the placebo group and 62.5% in the PRV-101 group (injection site pain, headache, injection site discomfort and injection site pruritus being most common). PRV-101 induced dose-dependent neutralising antibody responses against all five CVB serotypes included in the vaccine in both the high- and low-dose groups. Protective titres \u22658 against all five serotypes were seen in &gt;90% of participants over the entire follow-up period.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>The results indicate that the tested multivalent CVB vaccine is well tolerated and immunogenic, supporting its further clinical development.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration<\/jats:title>\n                    <jats:p>ClinicalTrials.gov NCT04690426.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Funding<\/jats:title>\n                    <jats:p>This trial was funded by Provention Bio, a Sanofi company.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Graphical Abstract<\/jats:title>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-024-06092-w","type":"journal-article","created":{"date-parts":[[2024,2,18]],"date-time":"2024-02-18T20:01:51Z","timestamp":1708286511000},"page":"811-821","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Safety, tolerability and immunogenicity of PRV-101, a multivalent vaccine targeting coxsackie B viruses (CVBs) associated with type 1 diabetes: a double-blind randomised placebo-controlled Phase I trial"],"prefix":"10.1007","volume":"67","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0370-4145","authenticated-orcid":false,"given":"Heikki","family":"Hy\u00f6ty","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanna","family":"K\u00e4\u00e4ri\u00e4inen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5443-4651","authenticated-orcid":false,"given":"Jutta E.","family":"Laiho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gail M.","family":"Comer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1068-224X","authenticated-orcid":false,"given":"Taina","family":"H\u00e4rk\u00f6nen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2168-5765","authenticated-orcid":false,"given":"Jussi P.","family":"Lehtonen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3901-6774","authenticated-orcid":false,"given":"Sami","family":"Oikarinen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6677-8654","authenticated-orcid":false,"given":"Leena","family":"Puustinen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Snyder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco","family":"Le\u00f3n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7579-9126","authenticated-orcid":false,"given":"Mika","family":"Scheinin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0474-0033","authenticated-orcid":false,"given":"Mikael","family":"Knip","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Sanjuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,2,19]]},"reference":[{"issue":"10","key":"6092_CR1","doi-asserted-by":"publisher","first-page":"889","DOI":"10.1097\/01.inf.0000237798.07462.32","volume":"25","author":"N Khetsuriani","year":"2006","unstructured":"Khetsuriani N, Lamonte A, Oberste MS, Pallansch M (2006) Neonatal enterovirus infections reported to the national enterovirus surveillance system in the United States, 1983\u20132003. 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Diabetes 53(2):384\u2013392. https:\/\/doi.org\/10.2337\/diabetes.53.2.384","journal-title":"Diabetes"}],"container-title":["Diabetologia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00125-024-06092-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00125-024-06092-w\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00125-024-06092-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,20]],"date-time":"2024-03-20T05:49:06Z","timestamp":1710913746000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00125-024-06092-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,19]]},"references-count":36,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2024,5]]}},"alternative-id":["6092"],"URL":"https:\/\/doi.org\/10.1007\/s00125-024-06092-w","relation":{},"ISSN":["0012-186X","1432-0428"],"issn-type":[{"value":"0012-186X","type":"print"},{"value":"1432-0428","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,19]]},"assertion":[{"value":"18 September 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 November 2023","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 February 2024","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors would like to thank all the participants who agreed to participate in the study. The authors also thank M. Flodstr\u00f6m-Tullberg (Karolinska Institutet, Sweden) for her contribution to preclinical mouse studies, M. Rewers (Barbara Davis Center, University of Colorado, USA), for his contribution to islet autoantibody analyses and J. Lempainen (Department of Clinical Medicine, University of Turku, Finland), for her contribution to the HLA genotyping. We acknowledge the important contribution of Leads to Development Ltd (L2D), Paris, France, in various stages of the development of PRV-101, and Intravacc B.V., Bilthoven, Netherlands, in the GMP manufacturing of PRV-101. We also wish to thank the personnel of CRST Oy, as well as the virus laboratory of Tampere University and autoantibody laboratory of the University of Helsinki, for their skilful work. Statfinn Oy, Espoo, Finland, is acknowledged for the data management and analyses. We appreciate the work of R. Harju, of Vactech Oy, for administrative contribution to the study.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Acknowledgements"}},{"value":"The datasets are available from the corresponding author upon reasonable request.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"Provention Bio, Inc., a Sanofi company, was the study sponsor, responsible for funding and involved in study design, partnership with collaborators and data collection. The sponsor was involved in the analysis and interpretation of data and writing the report, but did not impose restrictions regarding the submission of the report for publication.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"WT, MSa, GMC, FL and MSn are employed by Provention Bio, Inc, a Sanofi company, which is developing PRV-101. Provention Bio was involved in the design and management of the trial, data collection and analysis. MK and HH are board members and stock owners of Vactech Oy, a Finnish biotech company that has contributed to the early-stage development of the vaccine and participated in the trial design and laboratory analyses. SK and MSc are employees of CRST Oy, a clinical contract research organisation that was contracted by Provention Bio to perform the study. The authors declare that there are no other relationships or activities that might bias, or be perceived to bias, their work.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 relationships and activities"}},{"value":"FL, MK, MSc, HH, SK, MSn and GMC were responsible for the overall design of the study and MSa and FL for the overall management of the study. SK and MSc were responsible for the recruitment of study participants and management of the study at CRST Oy. JEL and HH were responsible for project administration in the Tampere virus laboratory and TH and MK in the Helsinki islet autoantibody laboratory. TH was responsible for the autoantibody data analyses, JEL was responsible for the virus-neutralising antibody analyses and SO and LP for the virus PCR and ELISA analyses. WT, MSa and JPL were responsible for the overall data analyses. HH, MSa and JEL were primary contributors in the preparation of the manuscript. All authors reviewed and edited the manuscript and approved the final version. MSc is the guarantor of this work and accepts full responsibility for the work and\/or the conduct of the study, had access to the data and controlled the decision to publish.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}