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BackgroundIn 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.MethodsIn 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.ResultsA 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.ConclusionThis 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.

An effective dengue vaccine should induce a long-lasting immune response against all four serotypes simultaneously with a minimum number of immunizations. Our live attenuated tetravalent dengue vaccine candidate, KD-382, was developed using a classical host range mutation strategy (no addition of artificial genetic modification). In our previous study, cynomolgus monkeys immunized with a single dose of KD-382 seroconverted to all four serotypes. However, it is important to determine if neutralizing antibodies (NAbs) induced by KD-382 can work as a long-lasting immune response to prevent dengue. In this study, a single dose of KD-382 induced a strong NAb response against all four serotypes in cynomolgus monkeys. We also confirmed that NAb titers against all four serotypes persist for at least five years, indicating its high potential as a dengue vaccine candidate. Next, we evaluated the effect of pre-existing dengue immunity on NAb responses induced by KD-382. We administered KD-382 to cynomolgus monkeys pre-administered one of the monovalent parental wild-type strains 60 days before vaccination. Regardless of the pre-immunized serotype, all the monkeys showed sufficient tetravalent NAb responses, which lasted for over two years. All the KD-382 vaccinated monkeys were then challenged with different parental wild-type viruses than that used for pre-administration; viral RNA in the serum was less than the lower limit of quantification, indicating complete protection against secondary heterologous dengue infection without any harmful disease enhancement. Consequently, KD-382 successfully induced a long-lasting and protective tetravalent NAb response in monkeys, suggesting that KD-382 is a promising vaccine candidate usable for both dengue seronegative and seropositive individuals.

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.

Concerns about bioterrorism and outbreaks of zoonotic orthopoxvirus require safe and efficacious smallpox vaccines. We previously reported the clinical efficacy and safety profiles of LC16m8, a live, attenuated, cell culture-derived, smallpox vaccine, examined in over 3000 healthy Japanese adults with various vaccination histories. In this study, serum of approximately 200 subjects pre and post LC16m8 vaccination were subjected to a vaccinia virus-specific protein array to evaluate the proteome-wide immunogenicity. The relationships between antigen-specific antibodies and plaque reduction neutralization titers were analyzed. LC16m8 induced antibodies to multiple vaccinia antigens in primary-vaccinated individuals and yielded effective booster responses in previously vaccinated individuals, demonstrating similar antibody profiles to those reported for other vaccinia virus strains. Several immunodominant antigens were indicated to be important for neutralization of the intracellular mature virion. The similarity of antibody profiles between LC16m8 and other smallpox vaccine strains supports the immunogenicity and protective efficacy of LC16m8.

Background: Evolocumab is the first monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9) approved in Japan for the treatment of patients with familial hypercholesterolemia (FH) and hypercholesterolemia (HC). This study assessed the 12-week effectiveness and safety of low-density lipoprotein cholesterol (LDL-C)-lowering therapy by PCSK9 inhibition in patients with FH (homozygous [HoFH] or heterozygous [HeFH]) and HC by analyzing evolocumab data collected in the real-world setting in Japan. Methods and Results: Overall, 427 patients (mean±SD age, 61.6±13.8 years; female, 38.4%; 28 HoFH, 320 HeFH, 79 HC), enrolled from 299 clinical sites, were included in the safety analysis set. The major cardiovascular risk factors were coronary artery disease (77.3%), diabetes mellitus/impaired glucose tolerance (38.6%), and hypertension (65.1%). Median follow-up duration was 85.0 days. After 12 weeks of evolocumab treatment, the mean±SD percent change from baseline in LDL-C was −45.5%±27.0% (n=23) in HoFH (P

The safety and efficacy of adalimumab were evaluated over 24 weeks in Japanese patients with psoriasis in routine clinical practice. In this multicenter, observational, open‐label, postmarketing study, primary efficacy measures included the Psoriasis Area and Severity Index (PASI) and the Dermatology Life Quality Index (DLQI) in all patients with psoriasis. In patients with psoriatic arthritis (PsA), the 28‐joint Disease Activity Score (DAS28) and the visual analog scale (VAS) pain were also evaluated. Safety was assessed based on the frequency of adverse drug reactions (ADR). Among patients with psoriasis evaluated for efficacy (n = 604), significant improvements from baseline were observed in mean PASI and DLQI scores at weeks 16 and 24 (all P < 0.0001). Furthermore, in psoriasis patients without PsA, the PASI 75/90 response rates were 55.9%/28.4% at week 16 (n = 306) and 65.6%/43.3% at week 24 (n = 270), respectively. In patients with PsA evaluable for effectiveness, significant improvements from baseline were observed in PASI, DAS28 erythrocyte sedimentation rate, DAS28 C‐reactive protein and VAS pain at weeks 16 and 24 (all P < 0.0001). ADR and serious ADR were reported by 26.1% and 3.3%, respectively, of 731 safety evaluable patients with psoriasis; no unexpected safety findings were noted. The safety profile and effectiveness of adalimumab for the treatment of psoriasis in a routine clinical setting were as expected in Japanese patients.

Background and Aims: Data from an all-cases post-marketing study were used to evaluate the safety and effectiveness of adalimumab in Japanese patients with Crohn’s disease [CD]. Methods: Patients received adalimumab for 24 weeks. Data from all patients [ n = 1693] were used for the safety assessment. Data from patients with CD activity index [CDAI] ≥ 150 at baseline were used for the effectiveness assessment. Results: The most frequent serious adverse drug reaction [ADR] was infection and infestations [6.6 events/100 patient-years]. The risk of serious infections increased in patients who had a history of malignancy and those with concomitant corticosteroid use. Of 415 patients who had switched from another anti-tumour necrosis factor alpha [TNFα] agent to adalimumab due to ADRs, 7.2% discontinued due to ADRs to adalimumab. Ten of 13 patients with a history of tuberculosis [TB] received prophylactic medication, and none developed TB. TB developed in one patient with no history of TB or anti-TB prophylaxis. Remission rates were 41.3% and 32.4% at 4 and 24 weeks, respectively. Remission rates did not differ between patients with and without concomitant use of immunomodulators. Predictive variables for increased effectiveness were CDAI ≤ 220 and disease duration of ≤ 2 years. Perianal lesions and loss of response to previous anti-TNFα agents affected effectiveness. Conclusions: The most frequent serious ADR was infection. Adalimumab significantly reduced disease activity, without any unexpected ADRs. Development of active TB during adalimumab therapy can be prevented through TB screening and prophylaxis. In patients who switched from another anti-TNFα agent to adalimumab due to ADRs, adalimumab was well tolerated.

One of the challenges developing a live attenuated tetravalent dengue vaccine (TDV) is to overcome the presumed viral interference that may be preventing the induction of a balanced immune response to all 4 serotypes of the dengue virus (DENV1–4). Our live attenuated TDV candidate was developed from wild-type (wt) parental strains (DENV1/03135, DENV2/99345, DENV3/16562, and DENV4/1036, respectively) using a classical host range mutation strategy: the same strategy used for the approved live attenuated smallpox, polio, and MMR vaccines. Our vaccine candidate is expected to mimic natural dengue virus infection, as it provides all the components of dengue virus, including both structural and nonstructural proteins. Therefore, induction of more solid and comprehensive immune responses against pathogenic dengue viruses is also expected. In this study, we evaluated the neutralizing antibody responses for each serotype induced by a single subcutaneous administration of 6 formulations, which were composed of different combinations of vaccine strains and were all of different dosages. These formulations were tested in dengue-naïve cynomolgus macaques. As a result, regardless of the TDV formulation, all the monkeys immunized with TDVs seroconverted to all the 4 serotypes at day 30. Next, we evaluated protection ability of the selected formulations of TDV candidate, no RNAemia was detected from any of the immunized monkeys upon s.c. challenge with wtDENV. The findings of this non-human primate study indicate that our vaccine candidate is very promising; it can be further evaluated for safety and efficacy in human clinical studies., Microbiology; Virology; Antibody; Immune response; Vaccination; Vaccines; Viral disease; Live attenuated tetravalent dengue vaccine; Protective efficacy; KD-382

To investigate the relationship between changes in patient characteristics over time and the effectiveness and safety of adalimumab in the treatment of rheumatoid arthritis (RA) in clinical practice.Patients enrolled in the post-marketing registry study in Japan were divided into 5 subgroups based on the time adalimumab treatment was initiated. Demographic and baseline characteristics and responses to adalimumab were compared among the 5 subgroups to detect any time-course trend. Multiple logistic regression analysis was performed to identify characteristics that were significantly associated with the effectiveness or safety of adalimumab and to estimate response rates and the incidence of adverse drug reactions in individual subgroups.During the study period, patient characteristics changed significantly over time, in particular with regard to prior biologic use and concomitant methotrexate therapy. There was a significant trend toward higher response rates and lower incidence of infections and injection-site reactions in patients initiating adalimumab later in the study. Patient characteristics, such as concomitant methotrexate therapy and early stage RA, were significant predictors of the effectiveness and safety of adalimumab.Patient characteristics have changed since adalimumab became available for the treatment of RA; several of these characteristics were significant predictors of adalimumab effectiveness and safety.

Freeze-dried live attenuated smallpox vaccine LC16m8 prepared in cell culture has been the sole smallpox vaccine licensed in Japan since 1975 and was recently recommended as a WHO stockpile vaccine. We evaluated the safety of recently remanufactured lots of LC16m8 using a series of immunodeficient mouse models. These models included suckling mice, severe combined immunodeficiency disease (SCID) mice, and wild-type mice treated with cyclosporine. LC16m8 showed extremely low virulence in each of the three mouse models compared with that of its parental strains, Lister and LC16mO. These results provide further evidence that LC16m8 is one of the safest replication-competent smallpox vaccines in the world and may be considered for use in immunodeficient patients.

The effects of nine methylsulfonyl (MeSO 2 ) metabolites of tetra-, penta- and hexachlorinated biphenyls (tetra-, penta- and hexaCBs; 20 μmol/kg once daily for 4 days) on the hepatic microsomal UDP-glucuronosyltransferase (UDP-GT) were investigated in male Sprague–Dawley rats. Each of the seven 3-MeSO 2 -PCBs, 3-MeSO 2 -2,2′,4′,5-tetraCB (3-MeSO 2 -CB49), 3-MeSO 2 -2,3′,4′,5-tetraCB (3-MeSO 2 -CB70), 3-MeSO 2 -2,2′,3′,4′,5-pentaCB (3-MeSO 2 -CB87), 3-MeSO 2 -2,2′,4′,5,5′-pentaCB (3-MeSO 2 -CB101), 3-MeSO 2 -2,2′,3′,4′,5,6-hexaCB (3-MeSO 2 -CB132), 3-MeSO 2 -2,2′,3′,4′,5,5′-hexaCB (3-MeSO 2 -CB141), 3-MeSO 2 -2,2′,4′,5,5′,6-hexaCB (3-MeSO 2 -CB149) and 4-MeSO 2 -2,2′,4′,5,5′-pentaCB (4-MeSO 2 -CB101) increased the activities of UDP-GT toward chloramphenicol, 4-nitrophenol and 4-methylumbelliferone. 4-MeSO 2 -2,2′,4′,5,5′,6-hexaCB (4-MeSO 2 -CB149) increased the activity of UDP-GT toward chloramphenicol (UGT2B1) but not toward 4-nitrophenol (UGT1A6) and 4-methylumbelliferone (UGT1A6). The activity of UDP-GT toward thyroxine (T 4 ) significantly increased after the administration of each of the seven 3-MeSO 2 -PCBs and 4-MeSO 2 -CB101. Significant correlation was found between the activity of UDP-GT toward T 4 and serum total T 4 concentration after the administration of each of the MeSO 2 derivatives except 4-MeSO 2 -CB149. In conclusion, seven 3-MeSO 2 -PCBs and 4-MeSO 2 -CB101 induce both UGT2B1 and UGT1A6, and 4-MeSO 2 -CB149 induces UGT 2B1. The results from the present study indicate that increase in the hepatic T 4 glucuronidation after the administration of the seven 3-MeSO 2 -PCBs and 4-MeSO 2 -CB101 possibly because of the induction of both UGT1A1 and UGT1A6 caused the reduction of serum T 4 levels.

International audience; (See the editorial commentary by Bray, on pages 1037-9.) The licensed smallpox vaccine, ACAM2000, is a cell culture derivative of Dryvax. Both ACAM2000 and Dryvax are administered by skin scarification and can cause progressive vaccinia, with skin lesions that disseminate to distal sites. We have investigated the immunologic basis of the containment of vaccinia in the skin with the goal to identify safer vaccines for smallpox. Macaques were depleted systemically of T or B cells and vaccinated with either Dryvax or an attenuated vaccinia vaccine, LC16m8. B cell depletion did not affect the size of skin lesions induced by either vaccine. However, while depletion of both CD4(+) and CD8(+) T cells had no adverse effects on LC16m8-vaccinated animals, it caused progressive vaccinia in macaques immunized with Dryvax. As both Dryvax and LC16m8 vaccines protect healthy macaques from a lethal monkeypox intravenous challenge, our data identify LC16m8 as a safer and effective alternative to ACAM2000 and Dryvax vaccines for immunocompromised individuals.

We read with some concern the report by Yokote et al. ([1][1]), in which the authors recommend that LC16m8, a replicating smallpox vaccine licensed in Japan, be considered for use in persons who are immunocompromised. The authors presented new data from mouse models comparing the virulence of LC16m8

Background Attenuated vaccinia virus strain, LC16m8, defective in the B5R envelope protein gene, is used as a stockpile smallpox vaccine strain in Japan against bioterrorism: the defect in the B5R gene mainly contributes to its highly attenuated properties. Methods The protective activity of LC16m8 vaccine against challenge with a lethal dose of vaccinia Western Reserve strain was assessed in wild-type and immunodeficient mice lacking CD4, MHC class I, MHC class II or MHC class I and II antigens. Results The immunization with LC16m8 induced strong protective activity comparable to that of its parent strain, Lister (Elstree) strain, in wild-type mice from 2 days to 1 year after vaccination, as well as in immunodeficient mice at 2 or 3 weeks after vaccination. These results implicated that the defect in the B5R gene hardly affected the potential activity of LC16m8 to induce innate, cell-mediated and humoral immunity, and that LC16m8 could be effective in immunodeficient patients. Conclusion LC16m8 with truncated B5 protein has an activity to induce immunity, such as innate immunity and subsequent cell-mediated and humoral immunity almost completely comparable to the activity of its parental strain Lister.