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The development of an efficacious vaccine against norovirus is of paramount importance given its potential to reduce the global burden of norovirus-associated morbidity and mortality. Here, we report a detailed immunological analysis of a phase I, double-blind, placebo-controlled clinical trial performed on 60 healthy adults, ages 18 to 40. Total serum immunoglobulin and serum IgA against vaccine strains and cross-reactive serum IgG against non-vaccine strains were measured by enzyme immunoassays, whereas cell-mediated immune responses were quantified using intracellular cytokine staining by flow cytometry. A significant increase in humoral and cellular responses, e.g., IgA and CD4 + polypositive T cells, was triggered by the GI.4 Chiba 407 (1987) and GII.4 Aomori 2 (2006) VLP-based norovirus vaccine candidate rNV-2v, which is formulated without adjuvant. No booster effect was observed after the second administration in the pre-exposed adult study population. Furthermore, a cross-reactive immune response was elicited, as shown by IgG titers against GI.3 (2002), GII.2 OC08154 (2008), GII.4 (1999), GII.4 Sydney (2012), GII.4 Washington (2018), GII.6 Maryland (2018), and GII.17 Kawasaki 308 (2015). Due to viral infection via mucosal gut tissue and the high variety of potentially relevant norovirus strains, a focus should be on IgA and cross-protective humoral and cell-mediated responses in the development of a broadly protective, multi-valent norovirus vaccine., Clinical Trial Registration: https://clinicaltrials.gov, identifier NCT05508178. EudraCT number: 2019-003226-25., Competing Interests: Author GL-R acts as a consultant for 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, VK, and FT 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 Icon Genetics GmbH (Halle, Germany), a wholly owned subsidiary of Denka Ltd. (Tokyo, Japan). 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., (Copyright © 2023 Waerlop, Janssens, Jacobs, Jarczowski, Diessner, Leroux-Roels, Klimyuk, Leroux-Roels and Thieme.)

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 µg + 50 µg and 150 µg + 150 µg) without adjuvant. Overall, 13 subjects (65.0%) in the 50 µg group, 16 subjects (80.0%) in the 150 µg 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 µg 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 µg 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)., Competing Interests: 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., (Copyright © 2022 Leroux-Roels, Maes, Joye, Jacobs, Jarczowski, Diessner, Janssens, Waerlop, Tamminen, Heinimäki, Blazevic, Leroux-Roels, Klimyuk, Adachi, Hiruta and Thieme.)