Modeling and predicting individual variation in COVID-19 vaccine-elicited antibody response in the general population.

As we learned during the COVID-19 pandemic, vaccines are one of the most important tools in infectious disease control. To date, an unprecedentedly large volume of high-quality data on COVID-19 vaccinations have been accumulated. For preparedness in future pandemics beyond COVID-19, these valuable datasets should be analyzed to best shape an effective vaccination strategy. We are collecting longitudinal data from a community-based cohort in Fukushima, Japan, that consists of 2,407 individuals who underwent serum sampling two or three times after a two-dose vaccination with either BNT162b2 or mRNA-1273. Using the individually reconstructed time courses of the vaccine-elicited antibody response based on mathematical modeling, we first identified basic demographic and health information that contributed to the main features of the antibody dynamics, i.e., the peak, the duration, and the area under the curve. We showed that these three features of antibody dynamics were partially explained by underlying medical conditions, adverse reactions to vaccinations, and medications, consistent with the findings of previous studies. We then applied to these factors a recently proposed computational method to optimally fit an "antibody score", which resulted in an integer-based score that can be used as a basis for identifying individuals with higher or lower antibody titers from basic demographic and health information. The score can be easily calculated by individuals themselves or by medical practitioners. Although the sensitivity of this score is currently not very high, in the future, as more data become available, it has the potential to identify vulnerable populations and encourage them to get booster vaccinations. Our mathematical model can be extended to any kind of vaccination and therefore can form a basis for policy decisions regarding the distribution of booster vaccines to strengthen immunity in future pandemics.

Categorization of disaster-related deaths in Minamisoma city after the Fukushima nuclear disaster using clustering analysis.

The medical situation during disasters often differs from that at usual times. Disasters can lead to significant mortality that can be difficult to monitor. The types of disaster-related deaths are largely unknown. In this study, we conducted a survey to categorize the disaster-related deaths caused by a radiation disaster. A total of 520 people living in Minamisoma City, Fukushima Prefecture, at the time of the Fukushima Daiichi Nuclear Power Plant accident, who were certified to have died due to disaster-related causes were surveyed. We divided the participants into those who were at home at the time of the earthquake and those who were in hospitals or facilities when the disaster struck and conducted a hierarchical cluster analysis of the two groups. Disaster-related deaths could be divided into seven groups for those who were at home at the time of the disaster and five groups for those who were in hospitals or facilities at the time of the disaster. Each group showed different characteristics, such as "the group with disabilities," "the group receiving care," and "the group with depression," and it became evident that not only uniform post-disaster support, but support tailored to the characteristics of each group is necessary.

Antibody Profiling of Microbial Antigens in the Blood of COVID-19 mRNA Vaccine Recipients Using Microbial Protein Microarrays.

Although studies have demonstrated that infections with various viruses, bacteria, and parasites can modulate the immune system, no study has investigated changes in antibodies against microbial antigens after the COVID-19 mRNA vaccination. IgG antibodies against microbial antigens in the blood of vaccinees were comprehensively analyzed using microbial protein microarrays that carried approximately 5000 microbe-derived proteins. Changes in antibodies against microbial antigens were scrutinized in healthy participants enrolled in the Fukushima Vaccination Community Survey conducted in Fukushima Prefecture, Japan, after their second and third COVID-19 mRNA vaccinations. Antibody profiling of six groups stratified by antibody titer and the remaining neutralizing antibodies was also performed to study the dynamics of neutralizing antibodies against SARS-CoV-2 and the changes in antibodies against microbial antigens. The results showed that changes in antibodies against microbial antigens other than SARS-CoV-2 antigens were extremely limited after COVID-19 vaccination. In addition, antibodies against a staphylococcal complement inhibitor have been identified as microbial antigens that are associated with increased levels of neutralizing antibodies against SARS-CoV-2. These antibodies may be a predictor of the maintenance of neutralizing antibodies following the administration of a COVID-19 mRNA vaccine.

Varying Cellular Immune Response against SARS-CoV-2 after the Booster Vaccination: A Cohort Study from Fukushima Vaccination Community Survey, Japan.

Booster vaccination reduces the incidence of severe cases and mortality related to COVID-19, with cellular immunity playing an important role. However, little is known about the proportion of the population that has achieved cellular immunity after booster vaccination. Thus, we conducted a Fukushima cohort database and assessed humoral and cellular immunity in 2526 residents and healthcare workers in Fukushima Prefecture in Japan through continuous blood collection every 3 months from September 2021. We identified the proportion of people with induced cellular immunity after booster vaccination using the T-SPOT.COVID test, and analyzed their background characteristics. Among 1089 participants, 64.3% (700/1089) had reactive cellular immunity after booster vaccination. Multivariable analysis revealed the following independent predictors of reactive cellular immunity: age < 40 years (adjusted odds ratio: 1.81; 95% confidence interval: 1.19-2.75; p-value: 0.005) and adverse reactions after vaccination (1.92, 1.19-3.09, 0.007). Notably, despite IgG(S) and neutralizing antibody titers of ≥500 AU/mL, 33.9% (349/1031) and 33.5% (341/1017) of participants, respectively, did not have reactive cellular immunity. In summary, this is the first study to evaluate cellular immunity at the population level after booster vaccination using the T-SPOT.COVID test, albeit with several limitations. Future studies will need to evaluate previously infected subjects and their T-cell subsets.

Cross-sectional analysis of pharmaceutical payments to Japanese board-certified gastroenterologists between 2016 and 2019.

OBJECTIVES: Limited evidence is available regarding the financial relationships between gastroenterologists and pharmaceutical companies in Japan. This study analysed the magnitude, prevalence and trends of personal payments made by major pharmaceutical companies to board-certified gastroenterologists in Japan in recent years. DESIGN: Cross-sectional analysis SETTING AND PARTICIPANTS: Using payment data publicly disclosed by 92 major pharmaceutical companies, this study examined the non-research payments made to all board-certified gastroenterologists by the Japanese Society of Gastroenterology. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcomes were payment amounts, the prevalence of gastroenterologists receiving payments, yearly trends in per-gastroenterologist payment values and the number of gastroenterologists with payments. Additionally, we evaluated the differences in payments among influential gastroenterologists, including clinical practice guideline authors, society board member gastroenterologists and other general gastroenterologists. RESULTS: Approximately 52.8% of all board-certified gastroenterologists received a total of US$89 151 253, entailing 134 249 payment contracts as the reimbursement for lecturing, consulting and writing, from 84 pharmaceutical companies between 2016 and 2019. The average and median payments per gastroenterologist were US$7670 (SD: US$26 842) and US$1533 (IQR: US$582-US$4781), respectively. The payment value per gastroenterologist did not significantly change during the study period, while the number of gastroenterologists with payments decreased by -1.01% (95% CI: -1.61% to -0.40%, p<0.001) annually. Board member gastroenterologists (median: US$132 777) and the guideline authoring gastroenterologists (median: US$106 069) received 29.9 times and 17.3 times higher payments, respectively, than general gastroenterologists (median: US$284). CONCLUSION: Most gastroenterologists received personal payments from pharmaceutical companies, but only very few influential gastroenterologists with authority accepted substantial amounts in Japan. There should be transparent and rigorous management strategies for financial conflicts of interest among gastroenterologists working in influential positions.

Antibody and T-Cell Responses against SARS-CoV-2 after Booster Vaccination in Patients on Dialysis: A Prospective Observational Study.

Intensive vaccination is recommended for populations more vulnerable to COVID-19 infection, although data regarding the built of immunity after vaccination for dialysis patients are lacking. This prospective, observational cohort study of maintenance hemodialysis patients examined IgG antibody levels against the SARS-CoV-2 spike (S1) protein, neutralizing activity, and interferon gamma levels after the third dose of the BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) vaccine. Humoral immunity was repeatedly measured for up to two months. The study includes 58 patients on hemodialysis. Median neutralizing antibodies reached a maximum at 56 and 9 days after booster vaccination with BNT162b2 and mRNA-1273, respectively. The median IgG antibody titer reached a maximum of 3104.38 and 7209.13 AU/mL after 16 days of booster dose, and cellular immunity was positive in 61.9% and 100% of patients with BNT162b2 and mRNA-1273 vaccination, respectively. By repeating the measurements over a period of two months, we clarified the chronological aspects of the acquisition of humoral immunity in dialysis patients after a booster COVID-19 vaccination; most dialysis patients acquired not only humoral immunity, but also cellular immunity against SARS-CoV-2. Future research should investigate the continued long-term dynamics of antibody titers and cellular immunity after the third or further vaccinations, evaluating the need for additional vaccinations for hemodialysis patients.

Disaster-related deaths with alcohol-related diseases after the Fukushima Daiichi nuclear power plant accident: case series.

Introduction: The health of patients with mental disorders, such as alcohol-related diseases, often deteriorates after disasters. However, the causes of death among those with alcohol-related diseases during and after radiation disasters remain unclear. Methods: To minimize and prevent alcohol-related deaths in future radiation disasters, we analyzed and summarized six cases of alcohol-related deaths in Minamisoma City, a municipality near the Fukushima Daiichi nuclear power plant. Results: Patients were generally treated for alcohol-related diseases. In one case, the patient was forced to evacuate because of hospital closure, and his condition worsened as he was repeatedly admitted and discharged from the hospital. In another case, the patient's depression worsened after he returned home because of increased medication and drinking for insomnia and loss of appetite. Discussion: The overall findings revealed that, in many cases, evacuation caused diseases to deteriorate in the chronic phase, which eventually resulted in death sometime after the disaster. To mitigate loss of life, alcohol-related diseases must be addressed during the chronic phases of future large-scale disasters, including nuclear disasters.

Humoral response to SARS-CoV-2 vaccination in haemodialysis patients and a matched cohort.

OBJECTIVES: SARS-CoV-2 vaccination is a crucial intervention for infection control; however, the immune response to vaccination in dialysis patients has been reported to be moderate compared with healthy adults. There are few studies available on humoral response in immunised dialysis patients compared with well-matched control group, we conducted a prospective cohort study measuring SARS-CoV-2 antibody titres in Fukushima Prefecture, Japan since September 2021. PARTICIPANTS: We compared the titres of both anti-SARS-CoV-2 S1 IgG and neutralising antibodies of 65 haemodialysis patients (dialysis group) with 500 residents in Soma, Fukushima (control group). METHODS: Coarsened exact matching was used to balance sex, age and days from the second dose between dialysis and control groups. RESULTS: Significant differences in the titres of anti-SARS-CoV-2 S1 IgG and neutralising antibodies were observed between the dialysis and control groups; anti-SARS-CoV-2 S1 IgG: 168.35 (4.48-1074.29) AU/mL and 269.81 (4.72-945.96) AU/mL in dialysis and control groups, p=0.02, neutralising antibodies: 35.77 (2.94-826.06) AU/mL and 62.22 (0.00-535.57) AU/mL, p=0.007, respectively). CONCLUSIONS: We observed significantly reduced anti-SARS-CoV-2 S1 antibody and neutralising antibodies in haemodialysis patients compared with cohorts matched for duration after vaccination. Patients receiving haemodialysis should be carefully monitored for immunological responses to the vaccination and COVID-19 infection.

Humoral immunity after second dose of BNT162b2 vaccine in Japanese communities: an observational cross-sectional study, Fukushima Vaccination Community Survey.

To reveal waning humoral immunity after second dose BNT162b2 vaccinations in a rural Japanese community and determine factors affecting antibody titers. We aimed to report Immunoglobulin G (IgG) antibody against the SARS-CoV-2 spike (S1) protein levels and neutralizing activity in a large scale community based cohort. METHODS: Participants in the observational cross-sectional study received a second dose of vaccination with BNT162b2 (Pfizer/BioNTech) and were not previously infected with COVID-19. Questionnaire-collected data on sex, age, adverse vaccine reactions, and medical history was obtained. RESULTS: Data from 2496 participants revealed that older age groups reached a low antibody titer 90-120 days after the second vaccination. Neutralizing activity decreased with age; 35 (13.3%) of those aged ≥ 80 years had neutralizing activity under the cut-off value. Neutralizing activity > 179 days from the second vaccination was 11.6% compared to that at < 60 days from the second vaccination. Significantly lower IgG antibody titers and neutralizing activity were associated with age, male sex, increased time from second vaccination, smoking, steroids, immunosuppression, and comorbidities. CONCLUSIONS: Antibody titer decreased substantially over time. Susceptible populations, older people, men, smokers, steroid users, immunosuppression users, and people with three or more comorbidities may require a special protection strategy.

Nature and Trends in Personal Payments Made to the Respiratory Physicians by Pharmaceutical Companies in Japan between 2016 and 2019.

BACKGROUND: Financial relationships between healthcare professionals and pharmaceutical companies have historically caused conflicts of interest and unduly influenced patient care. However, little was known about such relationship and its effect in clinical practice among specialists in respiratory medicine. METHODS: Based on the retrospective analysis of payment data made available by all 92 pharmaceutical companies in Japan, this study evaluated the magnitude and trend of financial relationships between all board-certified Japanese respiratory specialists and pharmaceutical companies between 2016 and 2019. Magnitude and prevalence of payments for specialists were analyzed descriptively. The payment trends were assessed using the generalized estimating equations for the payment per specialist and the number of specialists with payments. RESULTS: Among all 7,114 respiratory specialists certified as of August 2021, 4,413 (62.0%) received a total of USD 53,547,391 and 74,195 counts from 72 (78.3%) pharmaceutical companies between 2016 and 2019. The median (interquartile range) 4-year combined payment values per specialist were USD 2,210 (USD 715-8,178). At maximum, one specialist received USD 495,332 personal payments over the 4 years. Both payments per specialist and number of specialists with payments significantly increased during the 4-year period, with 7.8% (95% CI: 5.5-9.8; p < 0.001) in payments and 1.5% (95% CI: 0.61-2.4; p = 0.001) in number of specialists with payments, respectively. CONCLUSION: The majority of respiratory specialists had increasingly received more personal payments from pharmaceutical companies for the reimbursement of lecturing, consulting, and writing between 2016 and 2019. These increasing financial relationships with pharmaceutical companies might cause conflicts of interest among respiratory physicians.

Pharmaceutical Payments to Japanese Board-Certified Infectious Disease Specialists: A Four-Year Retrospective Analysis of Payments from 92 Pharmaceutical Companies between 2016 and 2019.

BACKGROUNDS: Conflict of interest with pharmaceutical companies is one of the most concerned issues in infectious diseases. However, there is a lack of whole picture of detailed payments in Japan. METHODS: This retrospective study assessed financial relationships between pharmaceutical companies and all infectious disease specialists board-certified by the Japanese Association for Infectious Disease, using publicly disclosed payment data from 92 major pharmaceutical companies. Descriptive analyses were conducted for the payments. Payment trends were examined by the generalized estimating equations. RESULTS: Of 1614 board-certified infection disease specialists, 1055 (65.4%) received a total of $17,784,070 payments, corresponding to 21,680 contracts between 2016 and 2019. The mean ± SD and median (interquartile range: IQR) were $16,857 ± $45,010 and $3183 ($938-$11,250) in payments. All board executive members of Japanese Association of Infectious Disease received higher payments averaging $163,792. There were no significant changes in payments per specialist (annual change rate: -1.4% [95% CI: -4.7-2.3%], p = 0.48) and prevalence of specialists with payments (annual change rate: -1.4% [95% CI: -3.1-0.2%], p = 0.093) over the four years. CONCLUSION: There were substantial financial relationships between pharmaceutical companies and board-certified infectious disease specialists in Japan. Furthermore, high ranked specialists such as those in the executive board had stronger financial ties with the companies.

Factors Associated with COVID-19 Vaccine Booster Hesitancy: A Retrospective Cohort Study, Fukushima Vaccination Community Survey.

This was a retrospective cohort study, which aimed to investigate the factors associated with hesitancy to receive a third dose of a coronavirus disease 2019 (COVID-19) vaccine. A paper-based questionnaire survey was administered to all participants. This study included participants who provided answers in the questionnaire about whether they had an intent to receive a third dose of a vaccine. Data on sex, age, area of residence, adverse reactions after the second vaccination, whether the third vaccination was desired, and reasons to accept or hesitate over the booster vaccination were retrieved. Among the 2439 participants, with a mean (±SD) age of 52.6 ± 18.9 years, and a median IgG-S antibody titer of 324.9 (AU/mL), 97.9% of participants indicated their intent to accept a third vaccination dose. The logistic regression revealed that participants of a younger age (OR = 0.98; 95% CI: 0.96-1.00) and with a higher antibody level (OR = 2.52; 95% CI: 1.27-4.99) were positively associated with hesitancy over the third vaccine. The efficacy of the COVID-19 vaccine and concerns about adverse reactions had a significant impact on behavior regarding the third vaccination. A rapid increase in the booster dose rate is needed to control the pandemic, and specific approaches should be taken with these groups that are likely to hesitate over the third vaccine, subsequently increasing booster contact rate.

Slowly Progressive Male Alport Syndrome Evaluated by Serial Biopsy: Importance of Type IV Collagen Staining.

A slowly progressive middle-aged man initially diagnosed with thin basement membrane nephropathy based on extensive thinning of the glomerular basement membrane (GBM) was subsequently diagnosed with Alport syndrome (AS) by a serial renal biopsy eight years later. The ultrastructural analysis of the second biopsy indicated thickening and wrinkling with mild reticulation in the GBM, consistent with AS. However, a retrospective analysis of the first biopsy revealed mild attenuation of type IV collagen α5 chain staining, suggesting a potential diagnosis of AS, despite the lack of ultrastructural features of AS. We herein report the clinical usefulness of type IV collagen staining in the early diagnosis of AS.

Pleiotropic effect of erythropoiesis-stimulating agents on circulating endothelial progenitor cells in dialysis patients.

BACKGROUND: Recent studies have suggested that erythropoiesis-stimulating agents (ESAs) may accelerate not only angiogenesis but also vasculogenesis, beyond erythropoiesis. METHODS: We conducted a 12-week prospective study in 51 dialysis patients; 13 were treated with recombinant human erythropoietin (EPO, 5290.4 ± 586.9 IU/week), 16 with darbepoetin (DA, 42.9 ± 4.3 µg/week), 12 with epoetin ß pegol (CERA, 40.5 ± 4.1 µg/week) and 10 with no ESAs. Vascular mediators comprising endothelial progenitor cells (EPCs), vascular endothelial growth factor (VEGF), matrix metalloproteinase-2 (MMP-2), and high-sensitivity C-reactive protein (hs-CRP) were measured at 0 and 12 weeks. EPCs were measured by flow cytometry as CD45lowCD34+CD133+ cells. RESULTS: The EPC count increased significantly to a greater extent in the EPO group than in the other three group, and increased significantly from 0 to 12 weeks in a EPO dose-dependent manner. In both the DA and CERA groups, the EPC count did not change at 12 weeks. Serum levels of VEGF, MMP-2 and hs-CRP were not affected by ESA treatment in all groups. In the CERA group, serum ferritin decreased significantly compared to the no-ESA group and correlated with CERA dose, although use of iron was permitted if required during the prospective study period of 12 weeks. CONCLUSIONS: When patients on dialysis were treated with clinical doses of various ESAs, only EPO induced a significant increase of circulating EPCs from bone marrow, whereas, DA and CERA had no effect.

Modulation of circulating endothelial progenitor cells by erythropoiesis-stimulating agents in patients with chronic kidney disease stage G5 and 5D
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AIMS: Circulating endothelial progenitor cells (EPCs) play a pivotal role in vasculogenesis and promote angiogenesis by secreting growth factors. Recent studies have suggested that erythropoietin (EPO) may accelerate not only angiogenesis but also vasculogenesis, beyond erythropoiesis. The aim of this study was to investigate whether two erythropoiesis-stimulating agents (ESAs) modulate vascular-related factors and EPC mobilization in patients with chronic kidney disease stage G5 and dialysis (CKD G5 and 5D). MATERIALS AND METHODS: We conducted a 12-week prospective study in 63 patients; 21 patients received recombinant human erythropoietin (rhEPO) (EPO group, 4,565.5 ± 1,994.4 IU/week), 21 patients received darbepoetin (DA) (DA group, 40.1 ± 13.8 µg/week), and 21 patients received no ESAs (no-ESA group). Vascular mediators, including EPCs, vascular endothelial growth factor, matrix metalloproteinase-2 (MMP-2), high-sensitivity C-reactive protein, and asymmetric dimethyl arginine, were measured at 0 and 12 weeks. EPCs were measured by flow cytometry as CD45lowCD34+CD133+ cells. We also performed a subanalysis of dialysis (5D) patients (n = 32) in the three groups. RESULTS: In the EPO group, EPC count increased significantly from 0 to 12 weeks in a dose-dependent manner (r = 0.62, p = 0.005), and the increase was more conspicuous in the subgroup of dialysis 5D patients. In the DA group, the EPC number did not change at 12 weeks. Neither rhEPO nor DA affected the serum levels of the aforementioned biomarkers other than EPC. ;Conclusion: We speculate that the pleiotropic effects of rhEPO and DA beyond their hematopoietic effects may differ between CKD G5 and 5D patients.
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