Clinical characteristics and COVID-19-related outcomes of immunocompromised patients receiving tixagevimab/cilgavimab pre-exposure prophylaxis in Japan.

OBJECTIVE: Tixagevimab/cilgavimab is a cocktail of two long-acting monoclonal antibodies approved for pre-exposure prophylaxis (PrEP) of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection (cause of coronavirus disease 2019 [COVID-19]) in immunocompromised (IC) or high-risk patients. We investigated the patient characteristics and clinical outcomes of IC patients administered tixagevimab/cilgavimab for PrEP in real-world use in Japan. METHODS: This observational study used anonymous secondary data from Real-World Data Co., Ltd. for IC patients aged ≥12 years administered tixagevimab/cilgavimab between September 2022 and September 2023. We analyzed the baseline characteristics and event-rates of COVID-19-related clinical outcomes within 6 months of administration. RESULTS: Data were analyzed for 397 IC patients. About half (53.4%) were male and the median age was 71.0 (interquartile range 61.0, 77.0) years. Malignancy (97.2%), cardiovascular disease (71.3%), and diabetes (66.5%) were frequent comorbidities. Systemic corticosteroids and immunosuppressants were prescribed to 87.4% and 24.9%, respectively. The two most common target clinical conditions were active therapy for hematologic malignancies (88.2%) and treatment with B cell-depleting therapies (57.4%). The event-rates per 100 person-months (95% confidence interval; number) for medically attended COVID-19, COVID-19 hospitalization, in-hospital mortality due to COVID-19, and all-cause death were 4.14 (3.06-5.48; n=49), 1.74 (1.09-2.64; n=22), 0.07 (0.00-0.42; n=1), and 0.60 (0.26-1.17; n=8), respectively. CONCLUSION: This is the first report using a multicenter database to describe the clinical characteristics and COVID-19-related outcomes of IC patients administered with tixagevimab/cilgavimab in real-world settings in Japan. This cohort of IC patients who received tixagevimab/cilgavimab included many elderly patients with comorbidities.

Factors associated with PPSV23 coverage among older adults in Japan: a nationwide community-based survey.

OBJECTIVES: The 23-valent pneumococcal polysaccharide vaccine (PPSV23) was included in Japan's national immunisation programme for older adults in 2014. While vaccination coverage has increased following the implementation of the national immunisation programme, little is known about the factors that have influenced changes in PPSV23 uptake in Japan. This study aimed to investigate the effects of municipality-level activities implemented to improve vaccine uptake during the fiscal year 2015 (April 2015-March 2016). DESIGN: Community-based national survey. A postal and web-based nationwide survey was sent to all municipalities in Japan in June 2016 (n=1741). The survey included questions regarding PPSV23 coverage, out-of-pocket costs by individuals for vaccination and community-level activities implemented to improve and promote PPSV23 uptake. Municipality-level and prefecture-level variables (eg, unemployment rates, average per capita income) retrieved from published sources were also incorporated to explore the impact of social determinants on vaccine uptake. SETTING: Japan. PARTICIPANTS: Municipal vaccination officers. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary study outcome was PPSV23 coverage among adults aged 65 years in Japanese municipalities. RESULTS: A total of 1010 municipalities (58.0%) responded to the survey. The median PPSV23 coverage among responding municipalities was 41.8%. Vaccine coverage increased by 18.7% (16.7%-20.7%)%) in municipalities that sent a direct mail notification to the target population of adults compared with municipalities that did not send any notification. Vaccine coverage decreased by 3.02% (2.4%-3.6%)%) for every 1000 JPY increase in out-of-pocket costs. Municipality-level unemployment rates and average per capita income were negatively associated with PPSV23 coverage. CONCLUSIONS: This nationwide survey provides insight into factors that may influence PPSV23 coverage in Japanese municipalities. Reduced out-of-pocket costs and direct mail notifications to the target population were associated with higher PPSV23 coverage in Japanese municipalities.

Risk of pneumococcal diseases in adults with underlying medical conditions: a retrospective, cohort study using two Japanese healthcare databases.

OBJECTIVES: To quantify the risk of pneumococcal pneumonia (PP) and invasive pneumococcal disease (IPD) in adults aged ≥19 years with underlying medical conditions compared with healthy adults of the same age in Japan. DESIGN: An observational, retrospective, cohort study using two healthcare claims databases in Japan: Japan Medical Data Center (JMDC) and Medical Data Vision (MDV) databases. PARTICIPANTS: A total of 10.4 million individuals, representing 9.3 million person-years of follow-up, were included in the analysis. Eleven medical conditions as well as PP and IPD were identified by the International Statistical Classification of Diseases and Related Health Problems version 10 diagnostic codes and/or local disease codes used in Japan. PRIMARY OUTCOME MEASURES: Adjusted rate ratios (RRs) for PP and IPD in adults with a medical condition versus adults without any medical condition were calculated using multivariate Poisson regression models with age and/or sex as covariates. RESULTS: In the JMDC and MDV databases, respectively, adults ≥19 years with a medical condition (RRs for PP: 3.3 to 13.4, 1.7 to 5.2; RRs for IPD: 12.6 to 43.3, 4.4 to 7.1), adults with two or more medical conditions (PP: 11.6, 2.8; IPD: 18.7, 5.8) and high-risk adults (PP: 12.9, 1.8; IPD: 29.7, 4.0) were at greater risk of PP and IPD compared with their healthy counterparts. Adults aged 50-64 years with an underlying medical condition (PP rate: 38.6 to 212.1 per 100 000 person-years) had a higher rate of PP than those aged ≥65 years without any condition (PP rate: 13.2 to 93.0 per 100 000 person-years). CONCLUSIONS: Adults of all ages with an underlying medical condition are at greater risk of PP and IPD compared with adults without any medical condition. This risk increases with the number of underlying medical conditions. Our results support extending pneumococcal vaccination to younger adults with an underlying medical condition, especially those aged 50-64 years.

Time interval of revaccination with 23-valent pneumococcal polysaccharide vaccine more than 5 years does not affect the immunogenicity and safety in the Japanese elderly.

In the previous study, revaccination with 23-valent pneumococcal polysaccharide vaccine (PPSV23) in a total of 161 elderly subjects (≥70 years of age) who had received the initial vaccination at least 5 years before (range: 5 to11 years) showed an acceptable safety profile and induction of immune responses to the serotypes in PPSV23. The optimal interval between the initial vaccination and revaccination with PPSV23 is of interest to protect elderly from pneumococcal disease over the long-term. In this post-hoc analysis, we analyzed that the immunogenicity and safety of revaccination with PPSV23 by time interval after the initial vaccination. The level of serotype-specific immunoglobulin G (IgG) geometric mean concentrations (GMCs) and opsonophagocytic killing activity (OPA) geometric mean titers (GMTs) at 4 weeks after revaccination with PPSV23 in each subgroup based on time interval (5, 6, 7, 8 and 9-11 years) after the initial vaccination were comparable to those after the primary vaccination and vaccine-induced serotype-specific IgG and OPA levels were similar regardless of the time interval after the initial vaccination. There was no difference in the safety profiles among the subgroups. In conclusion, administration of a second dose of PPSV23 at least 5 years after the initial vaccination was immunogenic and well-tolerated in the elderly ≥70 years of age regardless of the time interval after the initial vaccination.

Revaccination with 23-valent pneumococcal polysaccharide vaccine in the Japanese elderly is well tolerated and elicits immune responses.

BACKGROUND: Following primary vaccination of adults ⩾65years of age with 23-valent pneumococcal polysaccharide vaccine (PPSV23), immune responses increase and thereafter appear to decrease over time. With increased life expectancy worldwide, revaccination with PPSV23 may be required for continued protection of the elderly population against pneumococcal disease. The present study evaluated the immunogenicity and safety of revaccination with PPSV23 in the Japanese elderly. METHODS: Depending on prior history of PPSV23 vaccination, adults aged ⩾70years were given a first dose (primary group; N=81) or second dose (revaccination group; N=161, at least 5years after first dose) of PPSV23 intramuscularly. Subjects were matched for gender, age, and number and type of comorbidity across both groups. Blood samples were collected before and 4weeks postvaccination to measure serotype-specific immunoglobulin G (IgG) concentrations and opsonophagocytic killing activity (OPA) antibody titers to serotypes included in the vaccine. Injection-site and systemic adverse events (AEs) were collected for 14days postvaccination. RESULTS: Baseline serotype-specific IgG geometric mean concentrations (GMCs) and OPA geometric mean titers (GMTs) were generally higher in subjects with a prior history of PPSV23 vaccination than in PPSV23-naïve subjects. The levels of IgG GMCs and OPA GMTs after revaccination were generally comparable to those observed after primary vaccination. Incidences of systemic AEs were comparable between the 2 groups. Although incidences of injection-site AEs were higher following revaccination than primary vaccination, the difference was not clinically significant as most AEs were mild to moderate in intensity and resolved within 5days after revaccination without treatment. CONCLUSION: Revaccination with PPSV23 was well tolerated and associated with increases in serotype-specific IgG concentrations and OPA titers in the elderly who received a prior PPSV23 dose at least 5years before. Revaccination with PPSV23 can be safely implemented in the elderly for continued prevention against pneumococcal disease. CLINICAL TRIAL REGISTRY NUMBER: NCT02260882.

Phase I and pharmacokinetic study of vorinostat (suberoylanilide hydroxamic acid) in Japanese patients with solid tumors.

Vorinostat (suberoylanilide hydroxamic acid), a potent, oral histone deacetylase inhibitor, has demonstrated clinical activity in non-Japanese patients with various hematological and solid tumors. We sought to determine the maximum tolerated dose and a recommended phase II dose for 18 Japanese patients with solid tumors (median age, 58 years; range, 25-72 years) who failed standard therapy. Patients received vorinostat for 14 days followed by a 7-day rest. The initial dose was 100 mg twice daily escalating by 100 mg twice daily. Once-daily dosing was tested at 400 and 500 mg. A maximum tolerated dose could not be identified. Dose-limiting toxicities (thrombocytopenia, anorexia, and fatigue) were observed in two of six patients receiving 200 mg twice daily and in one of six patients receiving 500 mg once daily. In the 100-500 mg dose range, vorinostat area under the concentration-time curve increased in proportion to dose with a pharmacokinetic profile similar to that established in non-Japanese patients. Vorinostat doses of 200 mg twice daily or 500 mg once daily for 14 days followed by a 7-day rest were well tolerated and are candidate doses for phase II trials, although a maximum tolerated dose for vorinostat was not reached.