Association between mRNA COVID-19 vaccine boosters and mortality in Japan: The VENUS study.

Although previous studies have shown no increased mortality risk after the primary series of COVID-19 mRNA vaccines, reports on booster doses are lacking. This study aimed to evaluate mortality risk after the mRNA vaccine boosters in addition to the primary series. This nested case-control study included two age-specific cohorts (18-64 and ≥65 years as of February 1, 2021) in two municipalities. All deaths were identified and matched five controls for each case at each date of death (index date) with risk set sampling according to municipality, age, and sex. The adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for mRNA vaccines (first to fifth doses) were estimated by comparing with no vaccination within 21 and 42 days before the index date using a conditional logistic regression model. The 18-64-years cohort comprised 431 cases (mean age, 57.0 years; men, 58.2%) and 2,155 controls (mean age, 56.0; men, 58.2%), whereas the ≥65-years cohort comprised 12,166 cases (84.0; 50.2%) and 60,830 controls (84.0, 50.2%). The aORs (95% CI) in 0-21 days after the third and fourth doses in the 18-64-years cohort were 0.62 (0.24, 1.62) and 0.38 (0.08, 1.84), respectively. The aORs (95% CI) after the third to fifth doses in the ≥65 years cohort were 0.36 (0.31, 0.43), 0.30 (0.25, 0.37), and 0.26 (0.20, 0.33), respectively. In conclusion, booster doses of mRNA vaccines do not increase mortality risk. These findings could help subsequent vaccine campaigns and alleviate vaccine hesitancy.

Development and validation of claims-based algorithms for identifying hospitalized patients with COVID-19 and their severity in 2020 and 2021.

BACKGROUND: This study aimed to develop and validate claims-based algorithms for identifying hospitalized patients with coronavirus disease (COVID-19) and the disease severity. METHODS: We used claims data including all patients at the National Center for Global and Medicine Hospital between January 1, 2020, and December 31, 2021. The claims-based algorithms for three statuses with COVID-19 (hospitalizations, moderate or higher status, and severe status) were developed using diagnosis codes (ICD-10 code: U07.1, B34.2) and relevant medical procedure code. True cases were determined using the COVID-19 inpatient registry and electronic health records. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for each algorithm at 6-month intervals. RESULTS: Of the 75,711 total patients, number of true cases was 1,192 for hospitalizations, 622 for moderate or higher status, and 55 for severe status. The diagnosis code-only algorithm for hospitalization had sensitivities 90.4% to 94.9% and PPVs 9.3% to 19.4%. Among the algorithms consisting of both diagnosis codes and procedure codes, high sensitivity and PPV were observed during the following periods; 93.9% and 97.1% for hospitalization (January-June 2021), 90.4% and 87.5% for moderate or higher status (July-December 2021), and 92.3% and 85.7% for severe status (July-December 2020), respectively. Almost all algorithms had specificities and NPVs of approximately 99%. CONCLUSIONS: The diagnosis code-only algorithm for COVID-19 hospitalization showed low validity throughout the study period. The algorithms for hospitalizations, moderate or higher status, and severe status with COVID-19, consisting of both diagnosis codes and procedure codes, showed high validity in some periods.

Bivalent Vaccine Effectiveness Among Adults Aged ≥65 Years During the BA.5-Predominant Period in Japan: The VENUS Study.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.5 became prevalent in July 2022 in Japan. Bivalent messenger RNA (mRNA) vaccines were approved as booster doses for individuals who received the primary series or booster dose by monovalent vaccines. We aimed to assess the effectiveness of bivalent vaccines in Japanese adults aged ≥65 years. Methods: We conducted a population-based cohort study using data collected from January 2019 to February 2023 in Japan. We included individuals aged ≥65 years in a municipality who received the first or second booster dose of monovalent mRNA vaccines. We estimated the effectiveness of the second or third booster dose of bivalent mRNA vaccines during the Omicron BA.5-predominant period (July-December 2022), compared with ≥90 days after the booster dose of monovalent vaccines. We used a Cox proportional hazard regression model with vaccination status as a time-dependent covariate. Results: A total of 81 977 individuals aged ≥65 years (mean [standard deviation] age, 78.3 [7.4] years; 33 487 male [40.8%]) were included in the study cohort. Among them, 57 396 were vaccinated with the second or third dose of bivalent vaccines (BA.1 or BA.4/5). The effectiveness against coronavirus disease 2019 (COVID-19) was estimated to be 57.9% (95% confidence interval, 52.7%-62.5%) for ≥14 days after the second or third bivalent booster dose, compared with 90 days after the first or second monovalent booster dose. Conclusions: The study showed that the bivalent mRNA vaccines as the second and third doses would provide protection against COVID-19 among adults ≥65 years in Japan.

Effectiveness of BNT162b2 against infection, symptomatic infection, and hospitalization among older adults aged ≥65 years during the Delta variant predominance in Japan: The VENUS Study.

BACKGROUND: We evaluated the effectiveness of the BNT162b2 vaccine against infection, symptomatic infection, and hospitalization in older people during the Delta-predominant period (July 1 to September 30, 2021). METHODS: We performed a population-based cohort study in an older adult population aged ≥65 years using data from the Vaccine Effectiveness, Networking, and Universal Safety Study conducted from January 1, 2019, to September 30, 2021, in Japan. We matched BNT162b2 vaccinated and unvaccinated individuals in a 1:1 ratio on the date of vaccination of the vaccinated individual. We evaluated the effectiveness of the vaccine against infection, symptomatic infection, and COVID-19-related hospitalization by comparing the vaccinated and unvaccinated groups. We estimated the risk ratio and risk difference using the Kaplan-Meier method with inverse probability weighting. The vaccine effectiveness was calculated as (1 - risk ratio) × 100%. RESULTS: The study included 203,574 matched pairs aged ≥65 years. At 7 days after the second dose, the vaccine effectiveness (95% confidence interval) of BNT162b2 against infection, symptomatic infection, and hospitalization was 78.1% (65.2 to 87.8%), 79.1% (64.6 to 88.9%), and 93.5% (83.7 to 100%), respectively. CONCLUSIONS: BNT162b2 was highly effective against infection, symptomatic infection, and hospitalization in Japan's older adult population aged ≥65 years during the Delta-predominant period.

Multiregional Population-Based Cohort Study for Evaluation of the Association Between Herpes Zoster and mRNA Vaccinations for Severe Acute Respiratory Syndrome Coronavirus-2: The VENUS Study.

Background: This study was performed to assess the increased risk of herpes zoster (HZ) associated with mRNA vaccines for coronavirus disease 2019. Methods: This population-based cohort study was conducted in 4 municipalities in Japan. Individuals covered under public health insurance systems without a history of HZ were followed from October 1, 2020 to November 30, 2021. Incidence rates of HZ within 28 days of BNT162b2 or mRNA-1273 vaccination were compared. Adjusted incidence rate ratios (IRR) and 95% confidence intervals (CI) were estimated using a Poisson regression model, including vaccination status as a time-dependent covariate. Subgroup analyses by sex, age, and municipality were also conducted. Results: A total of 339 548 individuals (median age, 74 years) were identified. During follow up, 296 242 individuals (87.2%) completed the primary series, among whom 289 213 and 7019 individuals received homologous BNT162b2 and mRNA-1273 vaccines, respectively. The adjusted IRRs of the first and second BNT162b2 vaccinations were 1.05 (95% CI, 0.84-1.32) and 1.09 (95% CI, 0.90-1.32), respectively. No cases of HZ were observed after mRNA-1273 vaccination. In subgroup analysis, the adjusted IRR of the second BNT162b2 vaccination was 2.94 (95% CI, 1.41-6.13) in individuals aged <50 years old. Conclusions: No increased risk of HZ was found after BNT162b2 vaccination in the overall study population. However, an increased risk was observed in the younger subgroup.

Prescribed daily-dose-based metrics of oral antibiotic use for hospitalized children in Japan.

Objective: Defined daily-dose (DDD)-based metrics are frequently used to measure antibiotic consumption. However, they are unsuitable for the pediatric population because they are defined using the maintenance dose for 70-kg adults. Moreover, children have large body weight variations. We assessed the prescribed daily dose (PDD) and PDD-based metrics of oral antibiotics for children to develop an alternative to DDD-based metrics in Japan. Design: We performed observational study using data from the Japanese administrative claims database between April 2018 and March 2019. Methods: Of 453,001 patients (aged 1 month-15 years), 564,326 admissions to 1,159 hospitals were included. We showed the median PDD (mg/day and mg/kg/day) and PDD-based metrics for 8 antibiotics for each age category (1 month to <1 year old and 1-6, 7-12, and 13-15 years old). We also assessed the relationship between PDD-based metrics and days of therapy (DOT)-based metrics using a scatter plot and correlation. Results: In total, 86,389 patients (19.1%) were prescribed oral antibiotics; amoxicillin, macrolides, and third-generation cephalosporins were the most common. The PDD (mg/day) for each antibiotic increased with age to 7-12 years old, when an adult dose was reached. The PDD (mg/kg/day) decreased with age to 13-15 years old, due to increasing body weight. The relationship between PDD per 1,000 patient days and DOT per 1,000 patient days differed depending on the antibiotic. Conclusions: PDD-based metrics stratified by age could characterize antibiotic consumption, even with body-weight variations. Therefore, PDD-based metrics, in addition to DOT-based metrics, are helpful benchmarks for antibiotic use in children.

Effectiveness of messenger RNA vaccines against infection with SARS-CoV-2 during the periods of Delta and Omicron variant predominance in Japan: the Vaccine Effectiveness, Networking, and Universal Safety (VENUS) study.

OBJECTIVES: We aimed to evaluate COVID-19 messenger RNA vaccine effectiveness during the Delta- and Omicron-predominant periods in Japan. METHODS: We conducted a population-based cohort study among individuals aged 16-64 years during two periods: the Delta-predominant period (July 1-December 31, 2021) and the Omicron-predominant period (January 1-March 29, 2022). RESULTS: When comparing individuals who were vaccinated with those who were unvaccinated, the effectiveness of a second dose against symptomatic infection was 89.8% (95% confidence interval [CI]: 80.5-94.7%) during the Delta-predominant period and 21.2% (95% CI: 11.0-30.3%) during the Omicron-predominant period. The effectiveness of a third dose against symptomatic infection was 71.8% (95% CI: 60.1-80.1%) during the Omicron-predominant period. CONCLUSION: Vaccine effectiveness against symptomatic infection decreased during the Omicron-predominant period but was maintained by a third dose.

Development and application of a Japanese vaccine database for comparative assessments in the post-authorization phase: The Vaccine Effectiveness, Networking, and Universal Safety (VENUS) study.

BACKGROUND: Japan currently lacks a data platform that can support quantitative assessments of the causal relationships between vaccines and adverse events. This study describes the development and application of the Vaccine Effectiveness, Networking, and Universal Safety (VENUS) Study to facilitate such assessments. METHODS: A database was created by linking public insurance enrollees' claims data with vaccination records acquired from participating municipalities. To provide an overview of the study data, we produced descriptive statistics of sex, age, and vaccinations. We also conducted a pilot study using the database to assess influenza vaccine safety during the 2018/2019 season among older persons (≥65 years) residing in a single municipality. RESULTS: Our database was created using data from approximately 1.12 million individuals in 7 municipalities between 2013 and 2020. The data during fiscal year 2018 included 853,016 individuals (male: 363,079, female: 489,937) with a median age of 70 years (interquartile range: 52-79). We obtained information on 17 vaccine types, including the pneumococcal vaccine and influenza vaccine. In the pilot study, we analyzed 48,723 vaccinated persons matched with 48,723 unvaccinated persons. The only adverse event that occurred in both groups was Bell's palsy, which had an adjusted incidence rate ratio of 1.21 (95 % confidence interval: 0.48-3.07). CONCLUSIONS: The VENUS Study is Japan's first healthcare data platform that enables comparative assessments of vaccinated and unvaccinated persons in large samples covering all age groups. Efforts are underway to increase the number of participating municipalities and to generate evidence on vaccine effectiveness and safety.

Influenza vaccine effectiveness against hospitalization during the 2018/2019 season among older persons aged ≥ 75 years in Japan: The LIFE-VENUS Study.

BACKGROUND: Older persons are recommended to receive annual influenza vaccinations due to their increased susceptibility to influenza infections and related complications. Routine assessments of influenza vaccine effectiveness (IVE) in older persons may help to improve vaccine development and vaccination strategies, but there is a lack of consistent epidemiological data from Japan. This study aimed to evaluate IVE against hospitalization during the 2018/2019 season among older persons aged ≥ 75 years in Japan. METHODS: This cohort study was conducted using insurance claims data and vaccination records provided by the Longevity Improvement & Fair Evidence - Vaccine Effectiveness, Networking, and Universal Safety (LIFE-VENUS) Study. The study cohort comprised older persons aged ≥ 75 years residing in an urban municipality in Japan. Vaccinated participants were identified through vaccination records from October 2018 to January 2019, and were matched with unvaccinated participants using a 1:1 ratio. The IVE against hospitalization was calculated as (1-hazard ratio) × 100% while adjusting for covariates such as age, sex, comorbidities, previous vaccinations, and care needs levels. RESULTS: We analyzed 30,881 vaccinated participants matched with 30,881 unvaccinated participants. Among these, 587 (1.9%) vaccinated participants and 644 (2.1%) unvaccinated participants were hospitalized during the 2018/2019 season. The adjusted IVE against hospitalization was estimated to be 28.9% (16.6-39.4%). CONCLUSIONS: The influenza vaccine for the 2018/2019 season showed moderate effectiveness among older persons in Japan. The LIFE-VENUS Study represents a potential platform for the continued monitoring of IVE among the older Japanese population.

Effectiveness of a Third Dose of COVID-19 mRNA Vaccine During the Omicron BA.1- and BA.2-Predominant Periods in Japan: The VENUS Study.

Background: Vaccine effectiveness against the severe acute respiratory syndrome coronavirus 2 Omicron BA.2 sublineage in Japan is unknown. We assessed the effectiveness of a third dose of COVID-19 mRNA vaccine compared with that of 2 doses. Methods: We performed a population-based cohort study using a municipality database located in the Chubu region of Japan during the Omicron BA.1- and BA.2-predominant periods (January 1-March 31, 2022 and April 1-27, 2022, respectively). We included residents aged ≥16 years who received a second vaccine dose at ≥14 days before the start of each period, regardless of the third dose. We compared the data at 14 days after the second and third dose and at 2-week intervals from 14 days to 10 weeks after the third dose using a Cox regression model. Vaccine effectiveness was defined as (1 - hazard ratio) × 100 (%). Results: In total, 295 705 and 288 184 individuals were included in the BA.1- and BA.2-predominant periods, respectively. The effectiveness of a third dose against infection was 62.4% and 48.1% in the BA.1- and BA.2-predominant periods, respectively. Vaccine effectiveness at 2-3 weeks and ≥10 weeks after the third dose decreased from 63.6% (95% confidence interval [CI], 56.4-69.5%) to 52.9% (95% CI, 41.1-62.3%) and from 54.5% (95% CI, 3.0-78.7%) to 40.1% (95% CI, 15.1-57.7%) in the BA.1- and BA.2-predominant periods, respectively. Conclusions: A third dose was moderately effective against BA.1 and BA.2 sublineages, but its effectiveness decreased by approximately 10% age points from 2-3 weeks to ≥10 weeks after the third vaccination.

Interrupted time-series analyses of routine vaccination program for elderly pneumonia patients in Japan; an ecological study using aggregated nationwide inpatient data.

A national routine pneumococcal pneumonia immunization program started in Japan in 2014. It targeted the population aged ≥65 years and used a 23-valent pneumococcal polysaccharide vaccine; PPSV23. However, its effectiveness was not well defined because of the lack of a comprehensive database on the PPSV23 vaccination status of each subject. We used interrupted time-series analyses to assess the changes in the incidence and prognosis of elderly patients hospitalized for pneumonia before and after initiation of the program. First, we estimated the PPSV23 coverage rates in subjects aged ≥65 years based on the number of shipped PPSV23 syringes and the estimated population in each prefecture. The estimated coverage rates reached around 40% in 2014 for the 3 Tohoku prefectures, while those in the other prefectures remained below 20%. After the national routine immunization program started, the estimated coverage rate increased significantly in every prefecture and exceeded 40% in 2017. Next, we aggregated the data extracted from the Japanese Diagnosis Procedure Combination database from April 2011 through February 2017 for hospitalized pneumonia patients aged ≥65 years. The data included data from 655,746 patients, excluding those in the 3 Tohoku prefectures. Interrupted time-series analyses found no change in the incidence of hospitalized pneumonia patients and in-hospital mortality after the vaccination program, but there was a decrease in the in-hospital mortality of pneumonia patients with severe comorbidities defined by the modified Charlson comorbidity index. These results suggest an association between the vaccination program and an improved outcome in hospitalized elderly pneumonia patients with severe comorbidities in Japan.

Antimicrobial utilization and antimicrobial resistance in patients with haematological malignancies in Japan: a multi-centre cross-sectional study.

BACKGROUND: Infection is a major complication for patients with haematological malignancies. It is important to better understand the use of antimicrobial agents and antibiotic resistance for appropriate treatment and prevention of drug resistance. However, very few multi-centre analyses have focused on the use of antimicrobial agents and antibiotic resistance have been carried out in Japan. This study aimed to describe the characteristics of the use of antimicrobial agents and antibiotic resistance in patients with haematological malignancies. METHODS: We conducted a cross-sectional study using administrative claims data and antimicrobial susceptibility data in Japan. We included patients diagnosed with haematological malignancies, who were hospitalized in a haematology ward between 1 April 2015 and 30 September 2017 in 37 hospitals. Descriptive statistics were used to summarize patient characteristics, antimicrobial utilization, bacterial infections, and antibiotic resistance. RESULTS: In total, 8064 patients were included. Non-Hodgkin lymphoma (50.0%) was the most common malignancy. The broad-spectrum antibiotics displayed a following antimicrobial use density (AUD): cefepime (156.7), carbapenems (104.8), and piperacillin/tazobactam (28.4). In particular, patients with lymphoid leukaemia, myeloid leukaemia, or myelodysplastic syndromes presented a higher AUD than those with Hodgkin lymphoma, non-Hodgkin lymphoma, or multiple myeloma. The most frequent bacterial species in our study cohort was Escherichia coli (9.4%), and this trend was also observed in blood specimens. Fluoroquinolone-resistant E. coli (3.6%) was the most frequently observed antibiotic-resistant strain, while other antibiotic-resistant strains were rare. CONCLUSIONS: Broad-spectrum antibiotics were common in patients with haematological malignancies in Japan; however, antibiotic-resistant bacteria including carbapenem-resistant or multidrug-resistant bacteria were infrequent. Our results provide nationwide, cross-sectional insight into the use of antimicrobial agents, prevalence of bacteria, and antibiotic resistance, demonstrating differences in antimicrobial utilization among different haematological diseases.

The Association Between Internet Searches and Moisturizer Prescription in Japan: Retrospective Observational Study.

BACKGROUND: Heparinoid is a medication prescribed in Japan for skin diseases, such as atopic dermatitis and dry skin. Heparinoid prescription has increased with instances of internet blogs recommending its use as a cosmetic. OBJECTIVE: This study aimed to examine the prescription trends in moisturizer use and analyze their association with internet searches. METHODS: We used a claims database to identify pharmacy claims of heparinoid-only prescriptions in Japan. Additionally, we used Google Trends to obtain internet search data for the period between October 1, 2007, and September 31, 2017. To analyze the association between heparinoid prescriptions and internet searches, we performed an autoregressive integrated moving average approach for each time series. RESULTS: We identified 155,733 patients who had been prescribed heparinoid. The number of prescriptions increased from 2011 onward, and related internet searches increased from 2012 onward. Internet searches were significantly correlated with total heparinoid prescription (correlation coefficient=.25, P=.005). In addition, internet searches were significantly correlated with heparinoid prescription in those aged 20-59 years at -1-month lag in Google Trends (correlation coefficient=.30, P=.001). CONCLUSIONS: Google searches related to heparinoid prescriptions showed a seasonal pattern and increased gradually over the preceding several years. Google searches were positively correlated with prescription trends. In addition, in a particular age group (20-59 years), prescriptions increased with the increase in internet searches. These results suggest that people obtained health-related information on the internet and that this affected their behavior and prescription requests.

Patterns of drug treatment in patients with osteoarthritis and chronic low back pain in Japan: a retrospective database study.

Purpose: Musculoskeletal diseases, including osteoarthritis (OA) and low back pain (LBP), are the leading causes of years lived with disability, and are associated with lowered quality-of-life, lost productivity, and increased healthcare costs. However, information publicly available regarding the Japanese real-world usage of prescription medications is limited. This study aimed to describe the clinical characteristics of patients with OA and chronic LBP (CLBP), and to investigate the patterns of medications and opioid use in Japanese real-world settings. Materials and methods: A retrospective study was conducted using a Japanese administrative claims database between 2013 and 2017. The outcomes were patient characteristics and prescription medications, and they were evaluated separately for OA and CLBP. Results: The mean age of 118,996 patients with OA and 256,402 patients with CLBP was 68.8±13.1 years and 64.8±16.4 years, respectively. Approximately 90% of patients with OA and CLBP were prescribed non-steroidal anti-inflammatory drugs (NSAIDs). Other prescriptions included hyaluronate injection (35.6%), acetaminophen (21.4%), and steroid injection (20.0%) in patients with OA, and pregabalin (39.0%) and acetaminophen (22.4%) in patients with CLBP. Weak opioids were prescribed to 10.7% and 20.6% of patients with OA and CLBP, respectively. The prescription of COX-2 inhibitors (OA: +6.5%; CLBP: +6.7%) and acetaminophen (OA: +16.4%; CLBP: +14.4%) increased between 2013 and 2017. The first commonly prescribed medication among patients with OA and CLBP were NSAIDs; hyaluronate injection (patients with OA) and pregabalin (patients with CLBP) were also common first-line medications. Acetaminophen, steroid injection (patients with OA), and weak opioids were prescribed more in the later phases of treatment. Conclusion: Most patients were prescribed limited classes of pain drugs, with NSAIDs being the most common pain medication in Japan for patients with OA and CLBP. Opioid prescription was uncommon, and were weak opioids when prescribed.