PMID- 36275772 OWN - NLM STAT- MEDLINE DCOM- 20221025 LR - 20221026 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 13 DP - 2022 TI - A randomized, double-blind, placebo-controlled, dose-escalating phase I trial to evaluate safety and immunogenicity of a plant-produced, bivalent, recombinant norovirus-like particle vaccine. PG - 1021500 LID - 10.3389/fimmu.2022.1021500 [doi] LID - 1021500 AB - Noroviruses (NoV) are the leading cause of epidemic acute gastroenteritis in humans worldwide and a safe and effective vaccine is needed. Here, a phase I, double-blind, placebo-controlled clinical trial was performed in 60 healthy adults, 18 to 40 years old. Safety (primary objective) and immunogenicity (secondary and exploratory objectives) of a bivalent (GI.4 and GII.4), plant-produced, virus-like particle (VLP), NoV vaccine candidate formulation were investigated at two dose levels (50 microg + 50 microg and 150 microg + 150 microg) without adjuvant. Overall, 13 subjects (65.0%) in the 50 microg group, 16 subjects (80.0%) in the 150 microg group, and 14 subjects (70.0%) in the placebo group reported at least 1 solicited local or general symptom during the 7-day post-vaccination periods following each dose. Severe solicited adverse events (AEs) were rare (2 events in the 50 microg group). A total of 8 subjects (40.0%) in each group reported at least one unsolicited AE during the 28-day post-vaccination periods. Immunogenicity was assessed on days 1, 8, 29, 57, 183 and 365. All subjects were pre-exposed to norovirus as indicated by baseline levels of the different immunological parameters examined. Vaccine-specific humoral and cellular immune responses increased after the first dose but did not rise further after the second vaccination. Increased GI.4- and GII.4-specific IgG titers persisted until day 365. The vaccine elicited cross-reactive IgG antibodies against non-vaccine NoV VLPs, which was more pronounced for NoV strains of the same genotype as the GII.4 vaccine strain than for non-vaccine genotypes. Significant blocking anti-GI.4 and anti-GII.4 VLP titers were triggered in both dose groups. Lymphoproliferation assays revealed strong cell-mediated immune responses that persisted until day 365. In conclusion, both dose levels were safe and well-tolerated, and no higher incidence of AEs was observed in the higher dose group. The data show that a single dose of the vaccine formulated at 50 microg of each VLP is sufficient to reach a peak immune response after 8 to 28 days. The results of this Phase I study warrant further evaluation of the non-adjuvanted vaccine candidate. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/record/NCT05508178, identifier (NCT05508178). CI - Copyright (c) 2022 Leroux-Roels, Maes, Joye, Jacobs, Jarczowski, Diessner, Janssens, Waerlop, Tamminen, Heinimaki, Blazevic, Leroux-Roels, Klimyuk, Adachi, Hiruta and Thieme. FAU - Leroux-Roels, Isabel AU - Leroux-Roels I AD - Center for Vaccinology (CEVAC), Ghent University and University Hospital, Ghent, Belgium. FAU - Maes, Cathy AU - Maes C AD - Center for Vaccinology (CEVAC), Ghent University and University Hospital, Ghent, Belgium. FAU - Joye, Jasper AU - Joye J AD - Center for Vaccinology (CEVAC), Ghent University and University Hospital, Ghent, Belgium. FAU - Jacobs, Bart AU - Jacobs B AD - Center for Vaccinology (CEVAC), Ghent University and University Hospital, Ghent, Belgium. FAU - Jarczowski, Franziska AU - Jarczowski F AD - Icon Genetics GmbH, a Denka Company, Halle, Germany. FAU - Diessner, Andre AU - Diessner A AD - Icon Genetics GmbH, a Denka Company, Halle, Germany. FAU - Janssens, Yorick AU - Janssens Y AD - Center for Vaccinology (CEVAC), Ghent University and University Hospital, Ghent, Belgium. FAU - Waerlop, Gwenn AU - Waerlop G AD - Center for Vaccinology (CEVAC), Ghent University and University Hospital, Ghent, Belgium. FAU - Tamminen, Kirsi AU - Tamminen K AD - Vaccine Research Center, University of Tampere, Tampere, Finland. FAU - Heinimaki, Suvi AU - Heinimaki S AD - Vaccine Research Center, University of Tampere, Tampere, Finland. FAU - Blazevic, Vesna AU - Blazevic V AD - Vaccine Research Center, University of Tampere, Tampere, Finland. FAU - Leroux-Roels, Geert AU - Leroux-Roels G AD - Center for Vaccinology (CEVAC), Ghent University and University Hospital, Ghent, Belgium. FAU - Klimyuk, Victor AU - Klimyuk V AD - Icon Genetics GmbH, a Denka Company, Halle, Germany. FAU - Adachi, Hiroshi AU - Adachi H AD - Icon Genetics GmbH, a Denka Company, Halle, Germany. AD - Denka Co., Ltd., Tokyo, Japan. FAU - Hiruta, Kazuyuki AU - Hiruta K AD - Icon Genetics GmbH, a Denka Company, Halle, Germany. AD - Denka Co., Ltd., Tokyo, Japan. FAU - Thieme, Frank AU - Thieme F AD - Icon Genetics GmbH, a Denka Company, Halle, Germany. LA - eng SI - ClinicalTrials.gov/NCT05508178 PT - Clinical Trial, Phase I PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20221007 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (Viral Vaccines) RN - 0 (Immunoglobulin G) RN - 0 (Adjuvants, Immunologic) SB - IM MH - Adult MH - Humans MH - Adolescent MH - Young Adult MH - *Norovirus MH - *Caliciviridae Infections MH - *Viral Vaccines MH - *Gastroenteritis MH - Immunoglobulin G MH - Adjuvants, Immunologic PMC - PMC9585308 OTO - NOTNLM OT - adults OT - clinical trial OT - immunogenicity OT - norovirus OT - plant-produced OT - safety OT - vaccine OT - virus-like particle COIS- Author GL-R was retained as a consultant by Icon Genetics GmbH (Halle, Germany) to assist in the design and management of the trial, analysis of results and development of the manuscript. AD, FJ, FT, VK, HA, and KH are employees of Icon Genetics GmbH (Halle, Germany), a wholly owned subsidiary of DENKA Company, Ltd (Tokyo, Japan). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this trial has received funding from DENKA Company, Ltd (Tokyo, Japan), through its wholly owned subsidiary company, Icon Genetics GmbH (Halle, Germany). The funder was involved in the study design, analysis and interpretation of data, the writing of this article, and the decision to submit it for publication. EDAT- 2022/10/25 06:00 MHDA- 2022/10/26 06:00 PMCR- 2022/01/01 CRDT- 2022/10/24 04:04 PHST- 2022/08/17 00:00 [received] PHST- 2022/09/21 00:00 [accepted] PHST- 2022/10/24 04:04 [entrez] PHST- 2022/10/25 06:00 [pubmed] PHST- 2022/10/26 06:00 [medline] PHST- 2022/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2022.1021500 [doi] PST - epublish SO - Front Immunol. 2022 Oct 7;13:1021500. doi: 10.3389/fimmu.2022.1021500. eCollection 2022.