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For the 2017-18 influenza season, A/Saitama/103/2014 (CEXP-002) (Saitama strain) was antigenically more similar to prior circulating strains than A/Hong Kong/4801/2014 (X-263) (Hong Kong strain) in a ferret model and was selected as the A(H3N2) vaccine virus strain in Japan. However, the Saitama strain grew poorly, and the Japanese government switched to the Hong Kong strain, raising public concerns of poor effectiveness. To enhance understanding of the correlation between antigenicity in experimental models and immunogenicity, as a surrogate measure of vaccine effectiveness, in the human population, we compared the immunogenicity of specially-prepared single dose monovalent influenza A(H3N2) vaccines containing the Saitama or the Hong Kong strain.A randomized controlled trial of 100 healthy adults aged 20-64 years (n = 50/group) was conducted. Virus neutralization assay was performed on sera from days 0 (pre-vaccination) and 21 (post-vaccination). Geometric mean titer (GMT), mean fold rise (MFR), seroconversion proportion (SCP), and seroprotection proportion (SPP) were calculated for vaccine strains and a representative circulating A(H3N2) virus strain (A/Osaka/188/2017).For the Hong Kong strain, post-vaccination GMT was significantly higher in the Hong Kong vaccine recipients (1:546 vs 1:260, p 0.01), but MFR, SCP, and SPP were similar for both vaccine groups. For the Saitama strain, post-vaccination GMT (1:116 vs 1:61, p = 0.01) and SPP (86% vs 68%, p = 0.03) were significantly higher in the Hong Kong vaccine recipients, but MFR and SCP were similar for both vaccine groups. Against A/Osaka/188/2017, post-vaccination GMT and MFR were similar in both vaccine groups, but SCP (32% vs 4%, p 0.01) and SPP (28% vs. 6%, p 0.01) were significantly higher in the Hong Kong vaccine recipients.The Hong Kong vaccine induced better or equivalent immunogenicity in comparison to the Saitama vaccine. Our trial showed that antigenic similarity in experimental models does not necessarily correlate with immunogenicity in the human population.UMIN000029293.

Little is known about the differences in coronavirus disease (COVID-19) vaccine acceptance and hesitancy between the general population and healthcare workers in Japan. To compare these differences, a nationwide web-based cross-sectional survey was conducted on 19 January 2021, shortly before the initiation of COVID-19 vaccinations in Japan. A total of 6180 men and women aged 20–69 years and 1030 healthcare workers aged 20–69 years were enrolled. Data on COVID-19 vaccine acceptance, basic characteristics, including socioeconomic factors, and confidence in immunization in general were collected. COVID-19 vaccine acceptance was also evaluated under hypothetical vaccine effectiveness and adverse event frequencies. Factors associated with vaccine hesitancy were examined using multinomial logistic regression analysis. The COVID-19 vaccine acceptance rate was 48.6% among the general population and was lower among nurses (45.5%) and medical clerks (40.7%). Women and young adults had significantly higher COVID-19 vaccine hesitancy odds ratios, and current smokers had significantly lower odds ratios. The frequency of adverse events was a COVID-19 vaccine hesitancy factor. Even if these factors were adjusted, COVID-19 vaccine hesitancy among nurses was 1.4 times higher than that among the general population. Thus, interventions to improve health literacy and vaccine hesitancy among the general population and healthcare workers, especially nurses, are needed.

Background Norovirus infection and Clostridioides difficile infection (CDI) are major causes of acute infectious diarrhea at medical facilities. “Geriatric intermediate care facilities” are a type of medical facility that tend to the daily life needs of elderly Japanese people. However, there is no research about norovirus- or CDI-related diarrhea at Japanese geriatric intermediate care facilities. Methods This prospective cohort study included 1445 residents at 10 geriatric intermediate care facilities in Osaka between November 2018 and October 2019. The study subjects were followed regarding the occurrence of acute infectious diarrhea and the results of rapid diagnostic tests for norovirus and CDI. We calculated incidence rates and hazard ratios (HR) with 95% confidential intervals (CI) to identify the risk factors of infectious diarrhea. Results Thirty-seven residents developed diarrhea during the observation period, although none of them was positive for norovirus or CDI. The total incidence rate was 1.21/10,000 person-days (95%CI: 0.82-1.60). Compared with residents aged 87-91 years, those aged ≤ 80 years had a significantly higher risk of diarrhea (HR = 3.85, 95%CI: 1.27-11.66). Moreover, residents with thyroid diseases had a significantly higher risk of diarrhea than those without thyroid disease (HR = 5.33, 95%CI: 2.32-12.25). Conclusions The incidence of acute infectious diarrhea is relatively low. However, residents who are < 80 years old and those with thyroid diseases are more likely to develop diarrhea. Key messages We describe the situation of acute infectious diarrhea at Japanese geriatric intermediate care facilities

5G NR (New Radio) employs OFDMA (Orthogonal Frequency Division Multiple Access) for both uplink and downlink where sub-carrier spacing can be modified. To enable flexible uplink access for IoT (Internet of Things) in beyond 5G, it is required to accommodate various types of mobile terminals from low to high-speed transmission. When sub-channel spacing is different and/or transmission timing is asynchronous in adjacent channels, OFDMA signals will not be orthogonal with each other and channel filtering is required to reduce ACI (Adjacent channel interference). Supposing joint use of OW-DFTs-OFDM (Overlap-Windowed Discrete Fourier Transform spreading OFDM) signals for low PAPR (Peak to Average Power Ratio) and FFT (Fast Fourier Transform) based filter-bank for flexible channel filtering, this paper discusses FFT-based frequency domain filter design for receiving multi-channel OW-DFTs-OFDM signals to avoid performance degradation due to ACI and ISI (Inter-Symbol Interference).

Background In Japan, freeze-dried live attenuated varicella-zoster vaccine is available for adults aged ≥50 years to prevent herpes zoster. However, limited evidence has been accumulated regarding vaccine safety for patients with underlying illnesses, who have been considered as the high-risk group for herpes zoster. Methods A prospective cohort study of 1200 healthy adults and 300 patients with underlying illnesses such as malignancy, diabetes mellitus, autoimmune diseases, and renal diseases was conducted. All subjects were vaccinated and then their adverse events (AEs) were followed for 28 days after vaccination. Key safety measures included any AEs, severe AEs (SAEs), and vaccine-related AEs such as injection-site AEs and systemic AEs. The frequencies and 95% confidence intervals of AEs were calculated. Results During the follow-up period, 2 SAEs (bone fracture and acute cholecystitis) among healthy adults and 1 SAE (disseminated mycobacteriosis) among patients with underlying illnesses were reported, although none of them was diagnosed as vaccine-related. Vaccine-related AEs were reported in 42% of healthy adults and patients with underlying illnesses, and the proportions were similar between the groups. The most frequent AEs were injection-site AEs in both groups (i.e., 41 and 39%), and systemic AEs were observed in 4% of both groups. Only among healthy adults, those with a history of herpes zoster were more likely to report injection-site AEs than those without a history of herpes zoster (53% vs 39%). Conclusions The present study confirmed the safety of freeze-dried, live attenuated varicella-zoster vaccine even in patients with underlying illnesses. A history of herpes zoster might be related to development of injection-site AEs in healthy adults. Trial registration The study was prospectively registered on Japic-Clinical Trials Information as JapicCTI-163415 on October 31, 2016.

Supplemental Digital Content is available in the text, In young children, infrequent antigen exposure, which is partly characterized by fewer vaccinations, may be a factor impairing the immunogenicity of inactivated influenza vaccine. We assessed the effects of prior vaccinations on age-specific immune responses in Japanese children aged 6 months to 3 years, using data from a cohort study with 266 children who had received 2 doses (0.25 mL/dose for < 3 years old, 0.5 mL/dose for 3 years old) in the 2006/2007 season. Serological measures, primarily seroprotection rates, between previously vaccinated and vaccine-naïve children were compared within 1-year age strata. The seroprotection rate was defined in 2 ways as the proportion of subjects who achieved an antibody titer of 1:40 or 1:160. Multivariate logistic regression was also performed to estimate the independent effect of prior vaccination on seroprotection rate. After the first dose, seroprotection rates with the threshold of 1:40 in vaccine-naïve 1-year-olds remained low (28% for AH1, 26% for AH3, 2% for B), similar to those of 0-year-olds. In contrast, seroprotection rates in previously vaccinated 1-year-olds (77% for AH1, 86% for AH3, 18% for B) were significantly higher than those in vaccine-naïve 1-year-olds. These seroprotection rates for AH1 and AH3 were comparable with those in previously vaccinated 2- and 3-year-olds. Although seroprotection rates for B remained low in every age stratum even after the second dose, seroprotection rate in previously vaccinated 1-year-olds (50%) was similar to that in 3-year-olds. After adjustment for age, baseline antibody titer and experience of acute febrile respiratory illness in the preceding season, odds ratios showed a significant independent positive effect of prior vaccination on seroprotection rate for every strain. After the seroprotection threshold was changed from 1:40 to 1:160, the results of the effects of prior vaccinations on immunogenicity were similar or became more evident, which demonstrate the robustness of our findings. Our study found that prior vaccinations improved poor immunogenicity among young children, especially in 1-year-olds.

In Japan, the routine immunization program with oral polio vaccine (OPV) has been suspended since September 2012, when a program with 4 doses of inactivated monovalent polio vaccine (IPV) or quadrivalent vaccine against diphtheria, pertussis, and tetanus with IPV (DTaP-IPV) was introduced. The aim of this study was to examine the interchangeability among these 3 types of polio vaccines.We conducted a prospective cohort study at 5 pediatric clinics in Japan. A total of 153 infants were assigned to 1 of the 4 groups by considering the vaccination history of OPV and trivalent vaccine against DTaP. Eleven infants with a history of OPV received 3 doses of DTaP-IPV; 49 infants with a history of OPV and DTaP received 3 doses of IPV; 50 polio vaccine-naive infants received 2 doses of IPV followed by 2 doses of DTaP-IPV; and 43 polio vaccine-naive infants received 2 doses of DTaP-IPV followed by IPV. The immunogenicity after polio vaccination was evaluated among these 4 groups.After 2 doses of polio vaccination, more than 80% of the infants exhibited a neutralization antibody titer ≥1:8 for all Sabin strains and wild strains in all groups. After the third dose, the seroprotection proportion (i.e., a neutralization antibody titer ≥1:8) reached about 100%. After the fourth dose, a neutralization antibody titer exceeded the required protective levels (i.e., a neutralization antibody titer ≥1:8) considerably in all groups.Four doses of polio vaccines induced a sufficient level of immunity in Japanese infants, irrespective of vaccine combinations or order.

In this study, we assessed the effects of the prevaccination titer and age on the immunogenicity of a low dose of influenza vaccine in children less than 4 years of age. A total of 259 children received two vaccine doses (0.1 ml for 0-year-olds and 0.2 ml for children 1 year of age or older) 4 weeks apart during the 2005/2006 season. The hemagglutination inhibition antibody titers were measured before vaccination and 4 weeks after the first and second doses. The geometric mean titer, mean fold rise, seroresponse proportion (≥4-fold rise in titer), and seroprotection proportion (titer ≥1:40) were calculated for the prevaccination titer and age categories. A multivariate logistic regression analysis was performed using the seroresponse and seroprotection proportions as dependent variables and the prevaccination titer and age as explanatory variables. As for the seroresponse against the H1 antigen after the first dose, the adjusted odds ratios of the prevaccination titers (versus Ptrend< 0.001). Similar results were also obtained for the H3 and B strains. Significantly elevated odds ratios for seroprotection were observed with greater prevaccination titers and older ages for all strains. The prevaccination titer and age were independently associated with the antibody response in young children. The immune response was weaker in the younger children and those without preexisting immunity.

Gene therapy has been proposed as a strategy for the treatment of intractable human diseases since the early 1990s. For the expression of a specific transgene in desired cells or tissues with the proper timing, many vectors carrying transgenes have been developed (Matrai et al., 2010; Nayak & Herzog, 2010; Sliva & Schnierle, 2010). Retroviral, lentiviral, adenoviral, and adeno-associated viral vectors are used in various ways to achieve these goals. However, the introduced transgenes frequently become silenced in the host cells (Harbers et al., 1981; Jahner et al., 1982; Palmer et al., 1991). We searched for bioactive substances from Actinomycetes that enhance transgene expression, and found that trichostatin A (TSA), a histone deacetylase inhibitor (HDACi), enhanced several promoter activities remarkably (Y. Ma et al., 2009). HDACis have been used as anti-cancer drugs, because they have various effects on tumor cells to arrest cell growth, induce apoptosis, inhibit metastasis, and enhance anti-tumor immunity, by regulating the expression of the relevant genes (Bolden et al., 2006; Haberland et al. 2009; X. Ma et al., 2009; Mai et al., 2005). Here, we developed effective TSA-inducible killer constructs to enhance the anti-cancer effects of TSA, by identifying the TSA-responsive element of the herpes simplex virus thymidine kinase (hsvTK) promoter, and TSA-dependently activating some cell-death-inducing genes. We determined the most relevant regions responsive to TSA, and constructed chimeric promoters with higher fold-increases and greater induced strengths with TSA, by replacing the weak TSA-responsible region (TSA2) of the CMV promoter with two or three copies of the TSA-responsible sites (TSA1) of the hsvTK promoter. In addition, the synthetic intron sequence (0.2kb) from the pRL-TK vector and the long 3’-untranslated region (1.0kb) from the pSV2-neo vector, including the SV40 late polyA site, were important for the basal expression of the transgene and the TSA-induction, respectively. To create the TSA-inducible killer constructs, we placed the hsvTK gene for combination therapy with the prodrug Ganciclovir, and some strong death-inducing molecules (Bax, caspase8, and TRIF) under the control of the TSA-responsible chimeric promoters. They effectively killed the cells in which they were introduced, in a TSA-dependent manner. To evaluate the utility of the killer constructs for cancer gene therapy, the TSA-dependent death-inducing constructs were transferred to retroviral and adenoviral vectors.

We studied the immunogenicity of trivalent-inactivated influenza vaccine. Subjects were 259 children under 4 years old who visited six pediatric clinics to undergo influenza vaccination. Age distribution was 64 aged1.0, 65 aged 1.0-1.9, 64 aged 2.0-2.9, and 66 aged 3.0-3.9 years, including subjects who had been previously vaccinated within the last three years, 0% (0/64) aged1.0, 26% (17/65) aged 1.0-1.9, 72% (46/64) aged 2.0-2.9, and 77% (51/66) aged 3.0-3.9 years old. Two doses of vaccine were given subcutaneously four weeks apart. Dosage was 0.l mL for children under 1 year old, while for children aged one year or older, dosage was 0.2mL, based on standard Japanese recommendations. To measure hemagglutination inhibition (HI) antibody titer, triplet sera were obtained before vaccination (S0), 4 weeks after the first vaccination (S1), and 4 weeks after the second vaccination (S2). The geometric mean of HI antibody titer, the response proportion (titer riseor =4-fold), and the achievement proportion (postvaccination titeror =1 : 40) were calculated by age group. Analysis of variance was used to estimate the independent effect of age and prevaccination titer on antibody increase. The geometric means of HI antibody titer were lower among the two younger age groups than among the two older age groups, regardless of vaccine strain or when blood samples were collected. The achievement proportion after 2 doses of vaccine in the1.0, 1.0-1.9, 2.0-2.9, 3.0-3.9 year age groups were 38%, 58%, 89%, and 85% against A (HI) ; 52%, 54%, 81%, and 73% against A (H3) ; and 23%, 49%, 67%, and 71% against B. Regarding the analysis of variance, prevaccination titer consistently indicated strong effects on antibody increase, regardless of vaccine strain or combination of paired sera. After two doses of vaccine (S2/S0), significant effects of age on antibody induction were shown against A (H1) and B (p = 0.000 and 0.002). Thus, the immunogenicity of trivalent-inactivated influenza vaccine was strongly influenced by prevaccination titer and age. Even two doses of vaccine did not induce a protective antibody level in about 50 to 80% of subjects among infants aged1.0 year, and 40 to 50% among children 1.0-1.9 year old.