| Abstract |
Background: In the current protracted COVID-19 pandemic, SARS-CoV-2 vaccines that have the ability to be used safely and to prevent onset or severe disease are still highly needed. A Phase 1/2 study was conducted in healthy adults and the elderly in Japan to evaluate the immunogenicity, safety, and tolerability of an inactivated whole-virus vaccine (KD-414) that is under development. Methods: In this double-blind, randomized, placebo-controlled, Phase 1/2 study, adults aged 20 to 64 years and elderly participants aged 65 years or older without a history of COVID-19 were randomly allocated to the following groups: the L group (2.5 μg/dose), M group (5 μg/dose), or H group (10 μg/dose) with KD-414, or the placebo group (2:2:2:1). The participants received KD-414 or the placebo intramuscularly twice at intervals of 28 days. To determine the go-forward dose, safety after the first dosing and neutralizing antibody titers against SARS-CoV-2 at 28 days after the second dosing were evaluated for each group. Additionally, after unblinding, participants in the H group received a third dose of KD-414 (H) approximately 6 months after the second dosing for an exploratory evaluation of the safety and neutralizing antibody titers to be conducted. Results: A total of 210 participants were enrolled: 105 adults aged 20 to 64 years, and 105 elderly participants aged 65 years or older. Of these participants, 105 adults and 104 elderly participants completed the second dosing, and 28 adults and 31 elderly participants in the H group received a third dose of KD-414 (H). The incidence of adverse reactions from the first dosing to 28 days after the second dosing was 19 of 30 (63.3%), 22 of 31 (71.0%), 22 of 29 (75.9%), and six of 15 (40.0%) for adults, and 14 of 30 (46.7%), 14 of 29 (48.3%), 15 of 31 (48.4%), and six of 15 (40.0%) for elderly participants in the L, M, H, and placebo groups, respectively. No differences in incidence were shown among the KD-414 groups. The most common adverse reaction was injection site pain. Fever that resolved the following day was observed in only 1 adult in the H group after the second dosing; this was a sole Grade 3 or higher adverse reaction. For immunogenicity, the neutralizing antibody seroconversion rate (95% confidence intervals [CI]) against SARS-CoV-2 (vaccine strain) 28 days after the second dosing was 36.7% (19.9-56.1), 38.7% (21.8-57.8), and 72.4% (52.8-87.3) in adults, and 33.3% (17.3-52.8), 31.0% (15.3-50.8), and 45.2% (27.3-64.0) in elderly participants in the L, M, and H groups, respectively, showing a dose response by KD-414. The stratified analysis by age-range for the H group, which observed the highest immunogenicity, also showed an age dependency in the neutralizing antibody responses. Based on these results up to the second dosing, the H (10 μg/dose) dosage was determined as the recommended dosage for further clinical development of KD-414. In addition, there was no particular difference between the incidence of adverse reactions after the third dosing and that after the second dosing with KD-414 (H) in participants. Moreover, the geometric mean neutralizing antibody titers (GMTs) against SARS-CoV-2 (vaccine strain) 28 days after the third dosing were 2-fold higher than those at 28 days after the second dosing, and the GMTs 13 weeks after the third dosing were 3-fold higher than those at 13 weeks after the second dosing. The stratified analysis by age-range of Pseudovirus SARS-CoV-2 (D614) spike protein neutralizing antibody titers showed 100.0% neutralizing antibody seroconversion rate and high neutralizing antibody titers in participants aged ≤40 years. Conclusion: KD-414 was well tolerated in healthy adults and the elderly at all doses evaluated. In view of the dose-response and age-dependency of the immunogenicity of KD-414 (H) (10 μg/dose), it is expected to induce high neutralizing antibody titers, particularly in the age range of 20 to 40 years. A Phase 2/3 study (Japan Registry of Clinical Trials [jRCT] 2071210081), a Phase 3 study (jRCT 2031210679), and a Phase 2/3 study in pediatric participants aged 6 months to 17 years (jRCT 2031220032) using KD-414 (H) are ongoing.
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