Safety and immunogenicity studies in animal models support clinical development of a bivalent norovirus-like particle vaccine produced in plants

• Published in: Vaccine Vol. 40; no. 7; pp. 977 - 987
• Main Authors: Tusé, Daniel, Malm, Maria, Tamminen, Kirsi, Diessner, André, Thieme, Frank, Jarczowski, Franziska, Blazevic, Vesna, Klimyuk, Victor
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 11-02-2022; Elsevier Limited
• Subjects: Age groups; Animal models; Animal welfare; Animals; Antibodies; Antibodies, Viral; Antigens; Blocking antibodies; Body temperature; Caliciviridae Infections; Disease; Epidemics; Gastroenteritis; Gene expression; Genetics; Genotypes; Hematology; Histopathology; Immune response; Immunization; Immunogenicity; Infections; Irritation; Laboratory animals; Manufacturers; Models, Animal; Mortality; Norovirus; Plant; Plant diseases; Proteins; Rabbits; Route selection; Safety; Serology; Toxicity; Vaccines; Vaccines, Virus-Like Particle; Variance analysis; Viral Vaccines; Virus-like particle (VLP); Virus-like particles; United States > US; Germany; FDA; MHLW; Norovirus; GI.4; rNV-2v; SC; Plant; NoV; EMA; Safety; VLP; HPLC; CGE; Virus-like particle (VLP); BCA; IM; GII.4; PEG; Immunogenicity; HBGA; LAL; NOAEL; PGM; MTD; USDA
• ISSN: 0264-410X; 1873-2518
• DOI: 10.1016/j.vaccine.2022.01.009

•Noroviruses (NoV) are the leading cause of epidemic acute gastroenteritis in humans.•There is currently no safe and effective preventative NoV vaccine on the market.•A plant-based manufacturing system was used to express a divalent NoV VLP vaccine.•The vaccine showed preclinical safety and potent NoV-specific immunogenicity.•Results of these studies support initiation of clinical development of the vaccine.
Noroviruses (NoV) are the leading cause of epidemic acute gastroenteritis in humans worldwide. A safe and effective vaccine that prevents NoV infection or minimizes NoV disease burden is needed, especially for children and the elderly who are particularly susceptible to NoV disease. A plant-based expression system (magnICON®) was used to manufacture two different virus-like particle (VLP) immunogens derived from human NoV genogroups I and II, genotype 4 (GI.4 and GII.4), which were subsequently blended 1:1 (w/w) into a bivalent vaccine composition (rNV-2v). Here, we report on the safety and immunogenicity of rNV-2v from one pilot and two GLP-compliant toxicity studies in New Zealand White rabbits administered the vaccine subcutaneously (SC) or intramuscularly (IM). Strong genogroup-specific immune responses were induced by vaccination without adjuvant at various doses (200 to 400 μg VLP/administration) and administration schedules (Days 1 and 7; or Days 1, 15 and 29). The results showed sporadic local irritation at the injection site, which resolved over time, and was non-adverse and consistent with expected reactogenicity. There were no signs of systemic toxicity related to vaccine administration relative to vehicle-treated controls with respect to clinical chemistry, haematology, organ weights, macroscopic examinations, or histopathology. In a 3-administration regimen (n + 1 the clinical regimen), the NOAEL for rNV-2v via the SC or IM route was initially determined to be 200 μg. An improved GI.4 VLP variant mixed 1:1 (w/w) with the wild-type GII.4 VLP was subsequently evaluated via the IM route at a higher dose in the same 3-administration model, and the NOAEL was raised to 300 µg. Serology performed in samples of both toxicity studies showed significant and substantial anti-VLP-specific antibody titers for rNV-2v vaccines administered via the IM or SC route, as well as relevant NoV blocking antibody responses. These results support initiation of clinical development of the plant-made NoV vaccine.