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• The Japanese immunization law was revised in October 2020. • Rotavirus vaccines are now included in the Japanese National Immunization Program. • Rules on vaccine intervals have been withdrawn. • The Japan Pediatric Society Vaccine Information Statement was published in 2018. • Concerns remain regarding the Japanese immunization program. The Japanese immunization program has made considerable progress since 2009: several new vaccines have been introduced and most are included in the National Immunization Program (NIP). In October 2020, the Japanese law on immunization was revised, which resulted in a few laudable achievements. First, rotavirus vaccines were added to the NIP, 10 years after their introduction, and noteworthy studies of vaccine effectiveness and the incidence of intussusception in Japanese children were published. Second, rules on vaccine intervals—which had been a longstanding concern—were withdrawn. In addition to this revision of the law, the Japanese version of the Vaccine Information Statement (VIS) was released by the Japan Pediatric Society in 2018. The VIS provides useful caregiver information on general immunization concepts and individual vaccines. Further challenges for the Japanese immunization program include (1) administering a booster dose of pertussis-containing vaccine to preschool children or teenagers, (2) reestablishing the active recommendation for human papilloma virus vaccines, (3) adding the mumps and influenza vaccines to the NIP, and (4) ensuring optimal dosing of seasonal influenza vaccines. During the current coronavirus disease 2019 (COVID-19) pandemic, vaccination rates among children have been decreasing in many countries. In Japan, vaccination rates have been stable in infants, but declining among toddlers and school-aged children, despite public awareness of the need for timely administration of vaccines during the pandemic. Clearly, further action is needed if we are to adequately protect children living in Japan from vaccine-preventable diseases. [ABSTRACT FROM AUTHOR]

Because of the overabundance of vaccination information on the internet, in the media, and on social media, providing clear and correct information on immunization is critical for parental decision-making. In 2018, the Japan Pediatric Society created and distributed a Vaccine Information Statement (VIS) to provide appropriate immunization information to caregivers. The objectives of the present study were to evaluate the effect of the VIS on immunization rates, adherence to schedule, and parental understanding of immunization in Japan. This cross-sectional study was conducted at 18 centers in 2 prefectures in Japan. Caregivers were assigned to an intervention group, which received the VIS and a questionnaire when their child reached the age of 1 month, and a control group, which received only the questionnaire. Using the self-reported questionnaires, we evaluated vaccination rates and schedule adherence at age 2 months, and parental knowledge, attitudes, and beliefs regarding immunization. Three months later, the questionnaires were returned, and the findings were compared between the 2 groups. We contacted 422 and 428 persons in the intervention and control groups, respectively, and 111/422 (26.3%) and 119/428 (27.8%) returned the surveys. Vaccination rates and adherence rates for the first dose of 4 recommended vaccines did not differ significantly (P > 0.25); however, there were some positive effects on items related to vaccine knowledge (P = 0.03), perceived benefits (P = 0.02), perceived barriers (P < 0.001), and perceived behavioral control (P = 0.01). The VIS improved parent comprehension of infant immunization. Future studies should examine if the effects of such an intervention persist and affect vaccine uptake throughout childhood. [ABSTRACT FROM AUTHOR]

Intradermal (ID) injection is an alternate route that enhances vaccine immunogenicity and decreases vaccine dose. Regular immunization usually starts at age 2 months, and the limited immune capacity of neonates and young infants makes them vulnerable to infection. Successful ID vaccine delivery in this population requires knowledge of skin thickness. Although skin thickness has been evaluated in infants aged 2 months or older, no comparable data are available for neonates, including preterm neonates. This prospective observational study used ultrasonography to assess skin thickness in 70 neonates (35 full-term and 35 preterm neonates) at deltoid, suprascapular, and thigh sites. The measurements were compared in relation to anatomical site, between full-term and preterm infants, and with skin thickness values for children aged 2 months or older, which were collected in our previous study using the same measurement technique. In full-term neonates, skin was significantly thicker at the suprascapular site than at the deltoid and thigh sites (P < 0.05); in preterm neonates, skin was significantly thicker at the suprascapular site than at the thigh site (P < 0.05). Skin thickness values at all three sites were significantly lower in preterm neonates than in full-term neonates (P < 0.05). As compared with skin thickness values for infants aged 2 months, values for full-term neonates were significantly lower for the deltoid and suprascapular sites (P < 0.001). Skin thickness values for neonates were affected by prematurity and were significantly lower than those for infants aged 2 months. These findings are important in the design of ID injection devices for neonates and young infants. [ABSTRACT FROM AUTHOR]

The Japanese immunization program has made considerable recent progress. The introduction of several new vaccines, especially foreign-produced vaccines, and the inclusion of important new vaccines in the National Immunization Program (NIP) are closing the “vaccine gap”, i.e., the delay in the Japanese immunization program relative to programs in other developed countries. Major progress in the Japanese immunization program since 2014 includes (1) elimination of measles in March 2015, (2) introduction of a varicella vaccine as a routine immunization in the NIP in October 2015, and (3) introduction of hepatitis B virus vaccines as routine immunizations in the NIP in October 2016. Despite these promising developments, important issues remain. First, the government withdrew the active recommendation for human papilloma virus vaccines temporarily in 2013. The withdrawal has continued and unresolved despite new scientific evidence confirming the safety of these vaccines. Second, a few important voluntary vaccines, including vaccines for mumps and rotavirus, have not been included in the NIP since their introduction to Japan. Finally, there are concerns related to a shortage of mandatory domestic vaccines, which was caused by a natural disaster in the area where a vaccine-producing factory was located. Additionally, the manufacturer included unauthorized additives in some vaccine products with falsifying the production-process records. To avoid problems related to vaccine shortages, essential vaccines need to be stockpiled, and the future vaccine needs for children should to be discussed. New initiatives must continue to close the vaccine gap, as this will protect children living in Japan from vaccine-preventable diseases. [ABSTRACT FROM AUTHOR]

Background Perinatal immunization education is important for improving the immunization outcomes of infants; however, the content of educational materials used at each perinatal period has not been carefully evaluated. We hypothesized that stepwise education offered at different perinatal periods would improve infant immunization status and enhance maternal immunization knowledge. Methods In this cluster-randomized controlled trial, pregnant women were recruited from nine obstetric sites in Niigata, Japan. The intervention group received a stepwise, interactive education intervention (prenatally, postnatally, and 1 month after birth). The control group received a leaflet containing general information on immunization. Infant immunization status was evaluated at 6 months of age, and maternal immunization knowledge was evaluated by a written survey after each intervention. Results Among 188 study participants, 151 (80.3%) replied to the final post-intervention survey. At 6 months of age, the percentage of children who completed three doses of inactivated polio, diphtheria, tetanus toxoid, and acellular pertussis (DTaP-IPV) vaccine was higher in the intervention group than in the control ( p = 0.04); however, no differences between groups were observed for the Haemophilus influenzae type b (Hib) ( p = 0.67) or 13-valent pneumococcal conjugate (PCV13) vaccines ( p = 0.20). The duration to the completion of the third dose of the DTaP-IPV, Hib, and PCV13 vaccines was shorter in the intervention group than in the control ( p = 0.03, p < 0.01, and p < 0.01, respectively). Furthermore, maternal knowledge scores exhibited significantly greater improvement in the intervention group over time compared with those of the control group ( p = 0.02). Conclusions Stepwise perinatal immunization education improved immunization schedule adherence for required vaccines and improved maternal immunization knowledge. [ABSTRACT FROM AUTHOR]

Background Accurate, standardized information on childhood immunization is not available in Japan. We investigated current practices in perinatal childhood immunization education in the community and the needs and interest for such education among Japanese mothers. Methods This cross-sectional, descriptive study evaluated pregnant and postnatal women at four institutions in Niigata, Japan from May through July 2014. Data were collected using questionnaires inquiring about demographics, immunization education received, intent to receive childhood vaccines, and needs regarding information on childhood immunization. Results Questionnaires were distributed to 300 women, and 116 (38.6%) were returned; 70 (59.6%) of the respondents were pregnant women and 46 (40.3%) were postnatal women. Fourteen (20%) of the 70 pregnant women reported receiving some form of immunization education; in contrast, 34 (73.9%) of 46 postnatal women had received such education within 1 month of delivery. The rates of respondents who felt that the information was insufficient were high: 78.6% among pregnant women and 52.9% among postnatal women. Pregnant women reported that the most important information was general concepts of immunization; in contrast, postnatal women desired more-detailed information, e.g., on immunization scheduling. Conclusions Japanese women do not receive sufficient perinatal immunization education. The information needed during the prenatal and postnatal periods differs. Thus, educational approaches may need to provide carefully targeted information. [ABSTRACT FROM AUTHOR]

As compared with standard intramuscular and subcutaneous vaccines, intradermal (ID) vaccines elicit a more potent immune response in both adults and children, with equivalent dosage or antigen dose sparing. Recently, various devices for ID injection have been developed; the length of needles ranges in 0.6–1.5 mm. However, skin thickness must be measured to determine optimal needle length for ID vaccines. Use of ID vaccines in infants and children is appealing because children require more vaccines than do adults; however, information on skin thickness in infants and children is limited. We used ultrasound echography to measure skin thickness in Japanese infants aged 2 months ( n = 78) and adolescents aged 13–15 years ( n = 82). Mean (range) deltoid and suprascapular skin thickness was 1.67 mm (1.16–2.39 mm) and 1.83 mm (1.24–2.60 mm), respectively, in infants and 1.81 mm (1.25–3.00 mm) and 2.43 mm (1.51–3.95 mm), respectively, in adolescents. Among infants who underwent re-measurement of skin thickness at age 6 months ( n = 11), mean deltoid skin thickness (1.84 mm) was significantly greater than at age 2 months (1.60 mm) ( P < 0.001). In contrast, no significant difference was observed in suprascapular skin thickness (1.79 mm vs. 1.67 mm, respectively; P = 0.17). Gender was not associated with skin thickness in either age group. Skin thickness was positively correlated with body weight in adolescents ( r = 0.43, P < 0.001 in deltoid region; r = 0.30, P = 0.01 in suprascapular region). In conclusion, this is the first study to evaluate skin thickness in different age groups of children, including at age 2 months. Skin thickness gradually increased from age 2 months to age 13–15 years, but no consistent trend was noted in analysis stratified by measurement site, gender, or age. These findings suggest that an appropriate length of ID device needle for infants and children is likely to be less than 1.2 mm and a special device with shorter length of needle is warranted for infants and children. [ABSTRACT FROM AUTHOR]

Abstract: The “vaccine gap” is a term which has been used in Japan to indicate that the current immunization program is behind compared to the programs in other developed countries. The current national immunization program (NIP) which was established under the Japanese Immunization Law includes only six vaccines (eight targeted diseases), and the rest of available vaccines have been categorized as voluntary vaccines, which require out-of-pocket expense in order for the patients to receive them. This has led the vaccination rates for the voluntary vaccines remaining low, and the incidence of the target diseases remaining high. In addition, there are a few domestic rules that exist for immunizations including (1) subcutaneous injection is the standard method of vaccination, (2) the thigh is not considered to be the common site of vaccination in infants, and (3) the intervals of administration of inactivated and live vaccines are strictly determined by law. Along with the “vaccine gap” and the domestic rules, some movements to improve our current NIP are underway; including increased calls to change the NIP from civilians and professionals, the establishment of a group by the representatives from 13 medical professional societies asking the government to consider the immunization policy a “national policy” and seeking the establishment of a new and reorganized national immunization technical advisory group (NITAG). In addition, the Vaccination Subcommittee of Health Sciences Council was formed in the government to reform the current Immunization Law and NIP, which established a new national program for three voluntary vaccines funded by a temporary budget. We hope these new movements will fill the “vaccine gap” and that the NITAG will help ensure that vaccine policy becomes a national policy, and will provide necessary vaccinations without out-of-pocket expense to protect children in Japan from vaccine preventable diseases. [Copyright &y& Elsevier]

• Mumps is still endemic in Japan because mumps vaccination is voluntary. • We clarified several parental factors associated with mumps vaccination. • Our study also highlights the importance of clear explanations of mumps vaccine. Mumps is still endemic in Japan because mumps vaccination is voluntary. In this study, we investigated associations of parental socioeconomic status, family structure, and knowledge/belief about mumps and mumps vaccine with parental decision to vaccinate their children. We also evaluated effectiveness of a campaign based on survey results. We conducted a cross-sectional survey of parents with children aged 1–6 years attending preschools or kindergartens in Tokamachi City, Japan. We assessed the association of parental factors with their decision to vaccinate their children using multivariable logistic regression analyses. We designed a campaign based on the survey results, and compared the number of annual vaccinations at Tokamachi Hospital per the child population aged 1–6 years in Tokamachi City before and after the campaign using a trend test. In total, 1391 of 1617 (86%) eligible parents completed the survey. Among these parents, 229 (16%) vaccinated their children. In multivariable analyses, higher parental education [odds ratio (OR) = 2.21; 95% CI, 1.59–3.08; P < 0.001], greater knowledge about mumps and the mumps vaccine (OR = 1.88; 95% CI, 1.60–2.21; P < 0.001), and living without grandparents (OR = 1.44; 95% CI, 1.05–1.99; P = 0.024) were significantly associated with parental decision to vaccinate their children. The number of annual vaccinations per the child population significantly increased following the campaign (P < 0.001). Our study showed several sociodemographic factors significantly associated with mumps vaccination. Further research is needed to examine the relevance of our findings to the uptake of other voluntary vaccines among children. [ABSTRACT FROM AUTHOR]

Vaccine-preventable diseases are a significant cause of morbidity and mortality in solid organ transplant recipients who undergo immunosuppression after transplantation. The primary strategy for immunizing transplant recipients is to deliver all potential vaccines prior to transplantation. However, time constraints limit the number of vaccines that may be delivered. In such cases, the administration of live attenuated vaccines that are contraindicated after transplantation should be prioritized. Simultaneous vaccination is also encouraged to maximize the number of vaccines delivered. Immunity induced by both inactivated and live vaccines wane after transplantation. The limited but available evidence suggests that immunization using inactivated vaccines in transplant recipients is both effective and safe. An increasing number of studies also suggest that once patients are under minimal immunosuppression, live attenuated vaccines may be given effectively and safely. The need for serologic monitoring and booster immunizations remain issues for future research. [ABSTRACT FROM AUTHOR]

The coronavirus disease 2019 (COVID-19) pandemic has greatly affected daily life. COVID-19 often causes asymptomatic or mild disease in children; however, delayed routine childhood immunization is a concern, as it could increase the risk of vaccine-preventable disease. No study has evaluated the status of childhood vaccinations in Japan during the COVID-19 pandemic. This retrospective observational study evaluated the number of vaccine doses administered to children in 4 Japanese cities (2 cities in the Tokyo metropolitan area and 2 cities far from Tokyo) during the period from 2016 to 2020. Vaccine doses administered between January and September 2020 during the COVID-19 pandemic were compared, by month, with those given during 2016–2019. Age-stratified demographic data were collected to determine whether factors other than change in the child population over time affected vaccination trends. In all cities the decrease in vaccine doses administered was most apparent in March and April 2020, i.e., just before or coincident with the declaration of a nationwide COVID-19 emergency on April 7, 2020. The decrease started as early as February in the Tokyo metropolitan area. As child age increased, the decrease became more apparent. Before the lift of national emergency on May 25, catch-up of the vaccination was observed in all age groups in all cities. Vaccine doses persistently increased in older age groups but not in infants. The overall vaccination trends did not differ significantly among the 4 cities. The COVID-19 pandemic significantly affected routine childhood immunization in Japan. Thus, a nationwide electronic surveillance system and announcements for guardians to encourage timely routine immunization are warranted. [ABSTRACT FROM AUTHOR]

Recently, efforts have been made to fill a so-called "vaccine gap" between Japan and other countries; however, more work remains. Concerns about adverse events following immunization (AEFI) resulted in an historically passive approach to policy making in the National Immunization Program (NIP). For example, reports of AEFI following human papillomavirus vaccine (HPVV) in 2013 led the Japanese government to withdraw its proactive recommendations, resulting in a sharp drop in HPVV coverage rate to less than 1.0%. In this report, we review key historical incidents that led to the current immunization system in Japan, compare it to that in the United States, and discuss strategies for improving the Japanese immunization system. By strengthening existing policies and programs, such as National Immunization Technical Advisory Groups and AEFI reporting, compensation laws, and immunization education, the remaining vaccine gap in Japan could be filled. [ABSTRACT FROM AUTHOR]

Highlights • EF-Tu is a common factor expressed on the surface of various pneumococcal strains. • Immunization with EF-Tu induces serotype-independent protection against pneumococci. • EF-Tu could be an antigen candidate for vaccine against pneumococcal infection. Abstract Vaccination is an effective strategy to prevent pneumococcal diseases. Currently, licensed vaccines include the pneumococcal polysaccharide vaccine (PPSV) and the pneumococcal conjugate vaccine (PCV), which target some of the most common of the 94 serotypes of S. pneumoniae based on their capsular composition. However, it has been reported that PPSV is not effective in children aged less than 2 years old and PCV induces serotype replacement, which means that the pneumococcal population has changed following widespread introduction of these vaccines, and the non-vaccine serotypes have increased in being the cause of invasive pneumococcal disease. Therefore, it is important that there is development of novel pneumococcal vaccines to either replace or complement current polysaccharide-based vaccines. Our previous study suggested that S. pneumoniae releases elongation factor Tu (EF-Tu) through autolysis followed by the induction of proinflammatory cytokines in macrophages via toll-like receptor 4, that may contribute to the development of pneumococcal diseases. In this study, we investigated the expression of EF-Tu in various S. pneumoniae strains and whether EF-Tu could be an antigen candidate for serotype-independent vaccine against pneumococcal infection. Western blotting and flow cytometry analysis revealed that EF-Tu is a common factor expressed on the surface of all pneumococcal strains tested, as well as intracellularly. In addition, we demonstrate that immunization with recombinant (r) EF-Tu induced the production of inflammatory cytokines and the IgG1 and IgG2a antibodies in mice, and increased the CD4+ T-cells proportion in splenocytes. We also reveal that anti-EF-Tu serum increased the phagocytic activity of mouse peritoneal macrophages against S. pneumoniae infection, independent of their serotypes. Finally, our results indicate that mice immunized with rEF-Tu were significantly and non-specifically protected against lethal challenges with S. pneumoniae serotypes (2 and 15A). Therefore, pneumococcal EF-Tu could be an antigen candidate for the serotype-independent vaccine against pneumococcal infection. [ABSTRACT FROM AUTHOR]

Highlights • An active surveillance through a phased introduction of the Hib vaccine in Japan was studied. • Hib disease incidence decreased significantly after vaccine introduction. • Hif and non-typeable H. influenzae were isolated from a few cases. • Serotype replacement was not observed after the introduction of the Hib vaccine. • Continuous capsular typing and strain identification surveillance is important. Abstract Background Haemophilus influenzae type b (Hib) vaccine was introduced as a voluntary vaccine in December 2008 and was included in the national routine immunization program in April 2013 in Japan. Currently, no nationwide data are available to evaluate the effectiveness of Hib vaccine in Japan. Methods To evaluate the effectiveness of Hib vaccine in Japan, nationwide active population-based surveillance of culture-proven invasive infections caused by H. influenzae in children was performed in 2008–2017 in 10 prefectures in Japan (covering approximately 23% of the total Japanese population). Clinical data were recorded on a standardized case report form. Capsular type and antimicrobial susceptibility of the H. influenzae isolates were examined. The incidence rate ratio (IRR) and its confidence interval (CI) were calculated to compare data from 5 years before and that from after the introduction of the national routine Hib vaccine immunization program. Results During the 10-year study period, 566 invasive H. influenzae disease cases including 336 meningitis cases were identified. The average number of invasive H. influenzae disease cases among children <5 years of age during 2013–2017 decreased by 93% (IRR: 0.07, 95%CI 0.05–0.10, p < 0.001) compared with those occurring during 2008–2012. Hib strains have not been isolated from invasive H. influenzae disease cases since 2014; however, non-typeable H. influenzae and H. influenzae type f isolates have been noted as causes of invasive H. influenzae diseases among children <5 years in the post-Hib vaccine era. Conclusions After the governmental subsidization of the Hib vaccine, invasive Hib disease cases decreased dramatically in the study population, as per our surveillance. Continuous surveillance is necessary to monitor the effectiveness of Hib vaccine and for detecting any emerging invasive capsular types. [ABSTRACT FROM AUTHOR]

Background In Japan, the seven-valent pneumococcal conjugate vaccine (PCV7) was introduced in 2010. PCV13 has replaced PCV7 since November 2013. Methods The effectiveness of PCV7 in protecting against invasive pneumococcal disease (IPD) in children aged <5 years was evaluated in a nationwide active population-based surveillance of IPD in 2008–2013 in 10 prefectures in Japan. Results 1181 cases were identified; 711 pneumococcal strains were analyzed for serotyping and antimicrobial resistance. Compared with the baseline IPD incidence (25.0 per 100,000), a 98% decline in IPD caused by PCV7 serotypes was found after the introduction of PCV7. This was partially offset by an increased incidence of IPD caused by PCV13 minus PCV7 and non-PCV13 serotypes, resulting in a 57% decline in overall IPD incidence. Absolute increases in the incidence rates of IPD caused by PCV13 minus PCV7 and non-PCV13 serotypes were 2.1 and 2.8 per 100,000 during the study period, respectively. The proportion of meropenem-nonsusceptible strains, especially with serotypes 19A and 15A, increased significantly after PCV7 introduction. Conclusions Our data confirmed a 98% decline in IPD incidence caused by PCV7 serotypes in children aged <5 years and serotype replacement after PCV7 introduction. This shows the importance of continuing surveillance of serotypes responsible for IPD and their antimicrobial resistance in Japan. [ABSTRACT FROM AUTHOR]