Upon stimulation of toll-like receptors with various microbial ligands, induction of a variety of inflammatory genes is elicited by activation of a myeloid differentiation primary-response protein 88 (MyD88)-dependent signaling pathway. Interleukin-1 (IL-1) receptor-associated kinase 1 (IRAK1) plays an essential role in this pathway by activating nuclear factor κB (NF-κB) and mitogen-activated kinases (MAPKs). Here, we identified optineurin (OPTN) as an IRAK1-binding protein by yeast two-hybrid screening using IRAK1 as bait. A C-terminal fragment of OPTN harboring a ubiquitin-binding domain was co-immunoprecipitated with IRAK1. In reporter analyses, overexpression of OPTN inhibited IL-1β-, IRAK1-, and LPS-induced NF-κB activation. Consistently, OPTN deficiency resulted in increased NF-κB activation in response to IL-1β/LPS stimulation. To address the mechanisms underlying the inhibitory effect of OPTN on NF-κB signaling, we focused on tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6), which is an adaptor protein of IRAK1 and upon polyubiquitination plays a crucial role during NF-κB activation. Overexpression of OPTN prevented TRAF6 polyubiquitination. Furthermore, OPTN H486R mutant, which is unable to recruit the deubiquitinase CYLD, failed to inhibit IRAK1-induced NF-κB activation. These results suggest that the IRAK1-binding protein OPTN negatively regulates IL-1β/LPS-induced NF-κB activation by preventing polyubiquitination of TRAF6.
BackgroundIn 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.MethodsIn 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.ResultsA 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.ConclusionKD-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.
Background We have developed an AS03‐adjuvanted H5N1 influenza vaccine produced in an EB66® cell culture platform (KD‐295). Objectives In accordance with Japanese guidelines for development of pandemic prototype vaccines, the phase II study was conducted in a double‐blind, randomized, parallel‐group comparison study and the phase III study was conducted in an open‐label, non‐randomized, uncontrolled study. Methods Healthy adult volunteers aged 20 ‐ 64 years enrolled in the phase II and III studies (N = 248 and N = 369) received KD‐295 intramuscularly twice with a 21‐day interval. After administration, immune response and adverse events were evaluated. In the phase II study, four different vaccine formulations were compared: MA (3.75 μg hemagglutinin [HA] antigen + AS03 adjuvant system), MB (3.75 μg HA + 1/2AS03), HA (7.5 μg HA + AS03), and HB (7.5 μg HA + 1/2AS03). In the phase III study, the MA formulation was further evaluated. Results In the phase II study, all four vaccine formulations were well‐tolerated and no SAE related to vaccination were observed. The MA formulation was slightly more immunogenic and less reactogenic among the vaccine formulations. Therefore, the MA formulation was selected for the phase III study, and it was well‐tolerated and no serious adverse drug reactions were observed. The vaccine fulfilled the three immunogenicity criteria described in the Japanese guidelines. Conclusions These data indicate that the MA formulation of KD‐295 was well‐tolerated and highly immunogenic and it can be considered a useful pandemic and pre‐pandemic influenza vaccine.
Background: In the prolonged COVID-19 pandemic, there remains a high need for the development of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine that can be used more safely and effectively to prevents the disease onset or severe disease. To satisfy such unmet need, we are currently developing the inactivated whole particle SARS-CoV-2 vaccine (KD-414) and conducted a phase 2/3 study in healthy adults in Japan to accumulate more immunogenicity and safety data of KD-414 using the dose selected based on the results of the phase 1/2 study. Methods: In an open-label uncontrolled phase 2/3 study, adults aged 18 years or older without a history of COVID-19 or COVID-19 vaccination received two intramuscular doses of KD-414 at a 28-day intervals, followed by one intramuscular dose 13 weeks after the second dose as the primary immunization. Safety data were collected after the first dose of KD-414 in all participants to evaluate the safety profile. In predetermined immunogenicity analysis subjects, the neutralizing antibody titers against the pseudovirus SARS-CoV-2 (Wuhan) before the first vaccination and after each vaccination with KD-414 were evaluated. Results: A total of 2500 adults aged 18 years or older were enrolled; 2474 of them received the vaccination up to the second dose, and 2081 completed the third vaccination. Regarding the safety, no deaths or serious adverse reactions were recorded from the first vaccination until 28 days after the third vaccination with KD-414. The incidence of adverse reactions (number of participants with onsets/number of participants in the safety analysis set) was 80.6% (2015/2500). Adverse reactions with an incidence of 10% or more included injection site pain, malaise, headache, injection site erythema, myalgia, and injection site induration. A total of 11 events of grade 3 or higher adverse reactions that prevented daily activities in 9 participants. There was no increasing tendency in the incidence of adverse reactions responding to the vaccinations. To evaluate immunogenicity, 295 first comers enrolled from five age ranges were allocated to the immunogenicity analysis subjects; 291 participants received the vaccination up to the second dose, and 249 participants completed the third vaccination. The geometric mean titers (95% confidence interval [CI]) of neutralizing antibody titers against pseudovirus SARS-CoV-2 (Wuhan) 28 days after the second vaccination and 28 days after the third vaccination with KD-414 were 139.6 (118.9 - 164.0) and 285.6 (244.3 - 334.0), respectively, showing an approximately two-fold increase after the third vaccination compared to that after the second vaccination. The geometric mean titers (95% CI) of neutralizing antibody titers after the third vaccination were 327.6 (269.8 - 397.9), 272.2 (211.5 - 350.4) and 128.0 (51.6 - 317.7) in participants aged 18 to 40 years, 41 to 64 years, and 65 years or older, respectively, showing an age-dependency. Conclusion: This study confirmed the favorable safety profile of KD-414 as a result of three vaccinations of KD-414 administered to over 2000 healthy Japanese participants aged 18 years or older. There were no particular differences in the types and incidences of adverse reactions between vaccinations, and no tendency of an increase in adverse reactions with an increase in the number of vaccinations. Similar to the phase 1/2 study, neutralizing antibody responses appeared to be age-dependent and the highest titers were observed in the age group of 18 - 40 years. A phase 3 study in adults aged 18 - 40 years (jRCT2031210679) and a phase 2/3 study in children aged 6 months - 18 years (jRCT2031220032) are currently ongoing.
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