Results from a preclinical study in rodents and a Phase 1/2, randomized, double-blind, placebo-controlled, parallel-group study of COVID-19 vaccine S-268019-a in Japanese adults

• Published in: Vaccine Vol. 41; no. 11; pp. 1834 - 1847
• Main Authors: Sonoyama, Takuhiro, Iwata, Satoshi, Shinkai, Masaharu, Iwata-Yoshikawa, Naoko, Shiwa-Sudo, Nozomi, Hemmi, Takuya, Ainai, Akira, Nagata, Noriyo, Matsunaga, Nobuaki, Tada, Yukio, Homma, Tomoyuki, Omoto, Shinya, Yokokawa Shibata, Risa, Igarashi, Kenji, Suzuki, Tadaki, Hasegawa, Hideki, Ariyasu, Mari
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Ltd 10.03.2023; Elsevier Limited
• Subjects: Adjuvants, Immunologic; Adults; Animals; Antibodies; Antibodies, Neutralizing; Antibodies, Viral; Antigens; Clinical trial; Clinical trials; Contingency; Coronaviruses; COVID-19; COVID-19 - prevention & control; COVID-19 vaccine; COVID-19 vaccines; COVID-19 Vaccines - immunology; Double-Blind Method; Double-blind studies; East Asian People; Experiments; Global health; Health care; Histopathology; Humans; IgG antibody; Immunization; Immunogenicity; Immunogenicity, Vaccine; Immunoglobulin G; Infections; Infectious diseases; Intervention; Mice; Neutralizing; Pandemics; Placebos; Preclinical study; Proteins; Recombinant spike protein; Robustness; Safety; SARS-CoV-2; Severe acute respiratory syndrome coronavirus 2; Sodium; Spike protein; Toll-like receptors; Vaccines; Vaccines, Synthetic - immunology; Japan; Preclinical study; COVID-19 vaccine; Clinical trial; Safety; Immunogenicity; Recombinant spike protein
• ISSN: 0264-410X; 1873-2518
• DOI: 10.1016/j.vaccine.2022.12.025

•S-268019-a is a recombinant spike protein vaccine adjuvanted with agatolimod sodium.•S-268019-a elicited immunogenicity and efficacy against SARS-CoV-2 in mice.•S-268019-a was safe but insufficiently immunogenic in humans.•Translating preclinical data to clinical studies is innately challenging.•S-268019-b formulation with a squalene-based adjuvant is in Phase 3 clinical trials. In early 2020, developing vaccines was an urgent need for preventing COVID-19 from a contingency perspective. S-268019-a is a recombinant protein-based vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), comprising a modified recombinant spike protein antigen adjuvanted with agatolimod sodium, a Toll-like receptor-9 agonist. In the preclinical phase, it was administered intramuscularly twice at a 2-week interval in 7-week-old mice. Immunogenicity was assessed, and the mice were challenged intranasally with mouse-adapted SARS-CoV-2 at 2 and 8 weeks, respectively, after the second immunization. After confirming the preclinical effect, a Phase 1/2, randomized, parallel-group clinical study was conducted in healthy adults (aged 20–64 years). All participants received 2 intramuscular injections at various combinations of the antigen and the adjuvant (S-910823/agatolimod sodium, in μg: 12.5/250, 25/250, 50/250, 25/500, 50/500, 100/500, 10/500, 100/100, 200/1000) or placebo (saline) in an equivalent volume at a 3-week interval and were followed up until Day 50 in this interim analysis. In the preclinical studies, S-268019-a was safe and elicited robust immunoglobulin G (IgG) and neutralizing antibody responses in mice. When challenged with SARS-CoV-2, all S-268019-a-treated mice survived and maintained weight until 10 days, whereas all placebo- or adjuvant-treated (without antigen) mice died within 6 days. In the Phase 1/2 trial, although S-268019-a was well tolerated in adult participants, was safe up to Day 50, and elicited robust anti-spike protein IgG antibodies, it did not elicit sufficient neutralizing antibody levels. The S-268019-a vaccine was not sufficiently immunogenic in Japanese adults despite robust immunogenicity and efficacy in mice. Our results exemplify the innate challenges in translating preclinical data in animals to clinical trials, and highlight the need for continued research to overcome such barriers. (jRCT2051200092)