Using Regular High-Quality Serosurveys to Identify and Close National Immunity Gaps-Measles and Rubella Elimination in Japan.

In Japan, periodic measles outbreaks occurred mainly among young children under the routine immunization program with one dose of the measles-containing vaccine (MCV). A second dose of MCV was introduced in 2006. During a nationwide measles resurgence in 2007-2008, the most affected age group was teenagers. The national serological surveillance for vaccine-preventable diseases made it clear that there was a measles immunity gap among teenagers who had not received a second dose of MCV. To fill this immunity gap, nationwide non-selective supplementary immunization activities (SIAs) were carried out as a five-year program from April 2008 to March 2013 by providing an opportunity to be vaccinated with the measles and rubella vaccine during the first year of junior high school (12-13 years old) and the last year of high school (17-18 years old). The SIA was conducted with the strong involvement of local governments in charge of vaccination delivery and collaboration between the health and education sectors. Japan was verified as achieving measles elimination in 2015 and this has been sustained to date. The challenge of rubella elimination following a similar strategy of a serological diagnosis of an immunity gap and targeted vaccination is also discussed.

Addressing practical issues in the smooth implementation of revised guidelines for non-clinical studies of vaccines for infectious disease prevention.

Herein, we investigated possible practical issues for the smooth implementation of the revised Japanese Guidelines for Non-clinical Studies of Vaccines for the Prevention of Infectious Diseases, which were raised in response to public comments on the proposed guideline revision and a gap analysis of the World Health Organization and European Medicines Agency guidelines. We identified main issues such as the non-clinical safety studies of adjuvants and evaluation of local cumulative tolerance in toxicity studies. The revised Japanese Pharmaceuticals and Medical Devices Agency (PMDA)/Ministry of Health, Labour and Welfare (MHLW) guidelines require non-clinical safety studies for vaccines containing new adjuvants, but additional safety pharmacology studies or safety studies in two animal species may be required if non-clinical safety studies raise any concerns (i.e., systemic distribution). Adjuvant biodistribution studies may aid in understanding vaccine characteristics. The evaluation of local cumulative tolerance in non-clinical studies, which was the focus of the Japanese review, can be omitted by including a warning in the package insert to avoid injection to the same site. The study's findings will be reflected in a Q&A to be released by the Japanese MHLW. We hope that this study will contribute to the global and harmonized development of vaccines.

Acute and Postacute Clinical Characteristics of Coronavirus Disease 2019 in Children in Japan.

BACKGROUND: The clinical features of coronavirus disease 2019 (COVID-19) in children have been changing because of the emergence and rapid spread of variants of concern (VOC). The increase in cases infected with VOC has brought concern with persistent symptoms after COVID-19 in children. This survey aimed to analyze the clinical manifestations and persistent symptoms of pediatric COVID-19 cases in Japan. METHODS: We analyzed the clinical manifestations of pediatric COVID-19 cases reported between February 2020 and April 2022 in Japan, using a dedicated database updated voluntarily by the members of the Japan Pediatric Society. Using the same database, we also analyzed persistent symptoms after COVID-19 in children who were diagnosed between February 2020 and November 2021. RESULTS: A total of 5411 and 1697 pediatric COVID-19 cases were included for analyzing clinical manifestations and persistent symptoms, respectively. During the Omicron variant predominant period, the percentage of patients with seizures increased to 13.4% and 7.4% in patient groups 1-4 and 5-11 years of age, respectively, compared with the pre-Delta (1.3%, 0.4%) or Delta period (3.1%, 0.0%). Persistent and present symptoms after 28 days of COVID-19 onset were reported in 55 (3.2%). CONCLUSIONS: Our survey showed that the rate of symptomatic pediatric COVID-19 cases increased gradually, especially during the Omicron variant predominant period, and a certain percentage of pediatric cases had persistent symptoms. Certain percentages of pediatric COVID-19 patients had severe complications or prolonged symptoms. Further studies are needed to follow such patients.

Proposal for the revision of guidelines for clinical trials of vaccines to prevent infectious diseases in Japan.

The development of vaccines against infectious diseases requires a different approach from that of therapeutics, because vaccines are inoculated into healthy individuals and have a preventive effect by activating the immunity of the inoculated human. In Japan, "The Guideline for Clinical Trials of Vaccines for the Prevention of Infectious Diseases" was published in 2010 before changes occurred in the vaccine development environment in Japan, such as the introductions of foreign vaccines and simultaneous global development. This study aimed to identify current challenges in vaccine development through a questionnaire-based survey of pharmaceutical companies in Japan and by comparing the domestic and international guidelines and surveying review reports of 35 vaccines approved in Japan between April 2010 and December 2020. Identified challenges included the requirement for protective efficacy trials, efficacy evaluation of combination vaccines, development of multiregional and foreign clinical trials, and immunization of older adults and immunocompromised patients. We propose that new vaccines against infectious diseases should be evaluated for the protective efficacy, preferably through multiregional clinical trials. Additionally, differences in the incidence of infectious diseases or in epidemic virus strains between regions may affect the trials, when multiregional clinical trials are conducted, but immunogenicity-based studies can be conducted if a correlation between protective efficacy and immunogenicity has been established. We suggest that licensed combination vaccines can be used as comparators when an antigen is added to a licensed combination vaccine. We also proposed that the efficacy of a vaccine in non-major subjects, such as older adults or immunocompromised patients could be evaluated by comparing immunogenicity in major subjects with the confirmed protective effects of the vaccine. It is expected that these revisions will lead to the rapid advancement of vaccine development, which should contribute to the improvement of public health.

Two hidden taxa in the Japanese encephalitis vector mosquito, Culex tritaeniorhynchus, and the potential for long-distance migration from overseas to Japan.

The Culex vishnui subgroups, particularly Culex tritaeniorhynchus, are considered the primary vectors of the Japanese encephalitis virus (JEV) in Asia. Recent molecular phylogenetic analyses of JEV isolates from Asian countries have shown that JEVs with diverse genetic variants are present in Asia. Furthermore, some JEV strains have been found to have crossed the East China Sea and been introduced into Japan. In this study, the possibility of overseas migration of the JE vector mosquito, Cx. tritaeniorhynchus was examined from the genetic, physical, and meteorological perspectives. Molecular phylogenetic analysis was performed based on both whole coding sequences and on the barcoding region of the mitochondrial cytochrome c oxidase subunit I (COI) gene of Cx. vishnui subgroups collected from Asian countries. Culex tritaeniorhymchus was classified into two genetically independent taxa by COI sequences: the Japanese type (Ct-J), which inhabits Japan except for the Amami Islands of southern Japan, and the continental type (Ct-C), which inhabits the Asian region except for Japan. It was confirmed that approximately 10% of Cx. tritaeniorhynchus trapped during the summer in western Kyushu were Ct-C, and that they could fly for up to 38 h continuously. The meteorological analysis also confirmed that the atmospheric flow occurring over the continent coincided with the date of Ct-C capture. This is the first report showing the existence of two taxa in Cx. tritaeniorhynchus. Their physical and physiological characteristics suggest the possibility of long-distance migration from overseas regions to Japan across the East China Sea. Future efforts are expected to provide evidence to support the occurrence of long-distance migration of Cx. tritaeniorhynchus with JEV.

Proposal for the revision of the guidelines for Non-clinical studies of vaccines for the prevention of infectious diseases in Japan.

The efficacy and safety of vaccines for the prevention of infectious diseases are mostly evaluated based on the induction of an immune response against antigens, and do not necessarily depend on the dose administered. Therefore, there are some specific aspects that need to be considered in the development of vaccines and have been described in "The Guidelines for the non-clinical studies of vaccines for the prevention of infectious disease" in Japan. Recent changes in the vaccine development field, such as the introduction of vaccines developed overseas in Japan and vaccine development on a global scale have increased the need for revision of these guidelines. In this study, we identified the current challenges in the development of vaccines through comparison of Japanese and international guidelines. We conducted a questionnaire-based survey of pharmaceutical industries in Japan, and found issues related to non-clinical studies, such as the necessity of safety pharmacology studies and repeated-dose toxicity studies for each route of administration. We examined international guidelines on these issues as well as review reports by regulatory authorities, and determined that the results of repeated-dose toxicity studies can be used to decide whether safety pharmacology studies are required, and that studies to evaluate toxicity due to systemic effects may not be necessary for both intramuscular and subcutaneous administration. We propose revision of the guidelines for the non-clinical studies of vaccines in Japan taking international harmonizaion into account. We expected that the revised guidelines will promote smooth and rational vaccine development.

Detection of Rotavirus Strains in Freshwater Clams in Japan.

Bivalve molluscan shellfish like clams and oysters, etc., are capable to bioaccumulate surrounding contaminants from waters into their digestive systems and posing serious threats of food poisoning. Detection of rotaviruses (RVs) in shellfish is of particular importance because RVs are prone to genome reassortment resulting in the emergence of new RV variants that may compromise vaccine safety. Herein, we have detected the wild-type RVs and Rotarix/RotaTeq vaccine strains in freshwater clams collected on the riverside, Kawasaki city, from July 2019 to January 2020 and correlated the detected genotypes with that of gastroenteritis cases of nearby clinics to understand the transmission of RVs in the environment. The wild-type RVs were detected in 62 (64.6%) out of 96 freshwater clams in every study month: July, September, November, and January that are considered as off-season for RV infections. The most frequent genotypes were G2 (42.9%), G8 (28.6%), G3 (14.3%), G1 (7.1%), and G10 (7.1%), which remained comparable with genotypic distribution found in the clinical samples over the last few years indicating that these RVs may accumulate in clams since a long time. However, G10 genotype was detected in clam but not in clinical samples suggesting the presence of asymptomatic infection or RVs could be carried out from a long distance. Importantly, vaccine strains, RotaTeq (1%) but not Rotarix (0%), were also detected in a clam. Attention must be paid to monitoring the potential transmission of wild-type and vaccine RV strains in the environment to prevent the emergence of new variants generated from genome reassortment with vaccine strains.

The clinical characteristics of pediatric coronavirus disease 2019 in 2020 in Japan.

BACKGROUND: The COVID-19 pandemic has affected the lives of people of all ages. Most reports on pediatric cases suggest that children experience fewer and milder symptoms than do adults. This is the first nationwide study in Japan focusing on pediatric cases reported by pediatricians, including cases with no or mild symptoms. METHODS: We analyzed the epidemiological and clinical characteristics and transmission patterns of 840 pediatric (<16 years old) COVID-19 cases reported between February and December 2020 in Japan, using a dedicated database which was maintained voluntarily by members of the Japan Pediatric Society. RESULTS: Almost half of the patients (47.7%) were asymptomatic, while most of the others presented mild symptoms. At the time of admission or first outpatient clinic visit, 84.0% of the cases were afebrile (<37.5°C). In total, 609 cases (72.5%) were exposed to COVID-19-positive household members. We analyzed the influence of nationwide school closures that were introduced in March 2020 on COVID-19 transmission routes among children in Japan. Transmission within households occurred most frequently, with no significant difference between the periods before and after declaring nationwide school closures (70.9% and 74.5%, respectively). CONCLUSIONS: COVID-19 symptoms in children are less severe than those in adults. School closure appeared to have a limited effect on transmission. Controlling household transmission from adult family members is the most important measure for prevention of COVID-19 among children.

Association of bleeding symptoms during influenza infection and administered drugs.

On March 1, 2019, the Ministry of Health, Labour and Welfare added bleeding symptoms to adverse reaction package inserts as a possible adverse event for a new anti-influenza drug, baloxavir marboxil, because 13 patients with bleeding symptoms were identified among influenza patients taking the drug. Nevertheless, aspects of the epidemiology of bleeding symptoms among influenza patients remain unclear. This study elucidated bleeding symptoms among influenza patients and hospitalized patients as severe cases. A survey was administered to all physicians in Japan during the 2019-2020 season for reporting of bleeding symptoms in influenza patients. The survey elicited information about outcomes, assuming associated underlying diseases and drugs in addition to administered drugs including acetaminophen and anti-influenza (antiviral) drugs. We received reports of 63 cases with bleeding symptoms, including 5 cases of hospitalized patients. Among all patients, 54% had been administered oseltamivir; 10% had been administered baloxavir marboxil. Among hospitalized patients, all had been administered acetaminophen; 40% of them had been administered oseltamivir, and one patient had been administered baloxavir marboxil. Accumulation of bleeding symptom cases is expected to be necessary to evaluate the association.

Proactive Engagement of the Expert Meeting in Managing the Early Phase of the COVID-19 Epidemic, Japan, February-June 2020.

To deal with the risk of emerging diseases with many unknowns, close and timely collaboration and communication between science experts and policymakers are crucial to developing and implementing an effective science-based intervention strategy. The Expert Meeting, an ad hoc medical advisory body, was established in February 2020 to advise Japan's COVID-19 Response Headquarters. The group played an important role in the policymaking process, promoting timely situation awareness and developing science-based proposals on interventions that were promptly reflected in government actions. However, this expert group may have been overly proactive in taking on the government's role in crisis management. For the next stage of managing the coronavirus disease pandemic and future pandemics, the respective roles of the government and its advisory bodies need to be clearly defined. Leadership and strategic risk communication by the government are key.

Changes and remaining challenges for the Japanese immunization program: Closing the vaccine gap.

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.

Highly specific monoclonal antibodies and epitope identification against SARS-CoV-2 nucleocapsid protein for antigen detection tests.

The ongoing coronavirus disease 2019 (COVID-19) pandemic is a major global public health concern. Although rapid point-of-care testing for detecting viral antigen is important for management of the outbreak, the current antigen tests are less sensitive than nucleic acid testing. In our current study, we produce monoclonal antibodies (mAbs) that exclusively react with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and exhibit no cross-reactivity with other human coronaviruses, including SARS-CoV. Molecular modeling suggests that the mAbs bind to epitopes present on the exterior surface of the nucleocapsid, making them suitable for detecting SARS-CoV-2 in clinical samples. We further select the optimal pair of anti-SARS-CoV-2 nucleocapsid protein (NP) mAbs using ELISA and then use this mAb pair to develop immunochromatographic assay augmented with silver amplification technology. Our mAbs recognize the variants of concern (501Y.V1-V3) that are currently in circulation. Because of their high performance, the mAbs of this study can serve as good candidates for developing antigen detection kits for COVID-19.

Serogroup B invasive meningococcal disease (IMD) outbreak at a Japanese high school dormitory: An outbreak investigation report from the first IMD outbreak in decades.

PURPOSE: The first outbreak of invasive meningococcal disease (IMD) in decades occurred in a high school dormitory in 2011. This report aims to describe the results of the IMD outbreak investigation and to discuss current issues of IMD in Japan. METHODS: We conducted an epidemiological and microbiological investigation against the IMD outbreak of serogroup B among students and staff in a high school dormitory. Information on patients was collected to analyze risk factors for IMD. Control measures and public health actions were summarized. RESULTS: Three cases of meningitis and two cases of bacteremia were identified. Freshmen (15-16 years old) living in the dormitory with preceding cough were high-risk populations in this outbreak. Pulsed-field gel electrophoresis, multilocus sequence typing, and porA gene sequencing results revealed that all isolates were closely related to each other and had deep similarities to the domestic circulating meningococcal strain. The outbreak was terminated after promptly implementing control measures. Based on the results of our investigation, from April 2013, national infectious disease surveillance started to target meningococcal bacteremia as part of IMD, in addition to meningococcal meningitis, which was newly designated as a category II school infectious disease under the School Health and Safety Act. CONCLUSIONS: This outbreak has enhanced public health measures against IMD in Japan. The development of national guidelines for appropriate public health interventions on the IMD outbreak response including chemoprophylaxis is still needed.

Zika virus protease induces caspase-independent pyroptotic cell death by directly cleaving gasdermin D.

The association of Zika virus (ZIKV) infection with a congenital malformation in fetuses, neurological, and other systemic complications in adults have brought significant global health emergency. ZIKV targets nerve cells in the brain and causes cell death, such as pyroptosis, leading to neuroinflammation. Here we described a novel mechanism of pyroptosis caused by ZIKV protease. We found that ZIKV protease directly cleaved the GSDMD into N-terminal fragment (1-249) leading to pyroptosis in a caspase-independent manner, suggesting a direct mechanism of ZIKV-induced cell death and subsequent inflammation. Our findings might shed new light to explore the pathogenesis of ZIKV infections where ZIKV protease might be a suitable target for the development of antiviral agents.

Prolonged viral shedding of SARS-CoV-2 in an immunocompromised patient.

The duration of viral shedding of SARS-CoV-2 is usually less than 10 days. We experienced a COVID-19 case with prolonged viral shedding for 2 months. His cell mediated immunity has been depressed (CD4+T cell <100/µl) due to advanced malignant lymphoma and chemotherapy which had been completed 4 months prior to the onset of symptoms of COVID-19. We administered several treatments against COVID-19, however the results of Polymerase Chain Reaction (PCR) from nasopharyngeal specimens remained positive to SARS-CoV-2 for 2 months. Moreover, virus isolation assays performed on Day 59 also remained positive. He was finally discharged on Day 69 with two consecutive negative PCR results for SARS-CoV-2. Immunocompromised status may prolong viral shedding and it is therefore important for the clinician to take into account this when assessing such patients.

Effect of a vaccine information statement (VIS) on immunization status and parental knowledge, attitudes, and beliefs regarding infant immunization in Japan.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Comparing catch-up vaccination programs based on analysis of 2012-13 rubella outbreak in Kawasaki City, Japan.

During the 2012-13 rubella outbreak in Japan, local governments implemented subsidy programs for catch-up vaccination to mitigate the rubella outbreak and prevent congenital rubella syndrome (CRS). In most local governments, to prevent CRS, eligible persons of the subsidy program were women who were planning to have a child and men who were partners of pregnant women. On the other hand, in Kawasaki City, unimmunized men aged 23-39 years were additionally included in the eligible persons, because they were included in an unimmunized men group resulting from the historical transition of the national routine vaccination in Japan. The number of rubella cases in the city decreased earlier than that in the whole Japan. First, in order to estimate the effect of the catch-up vaccination campaign in Kawasaki City on the epidemic outcome, we performed numerical simulations with a Susceptible-Vaccinated-Exposed-Infectious-Recovered (SVEIR) model incorporating real data. The result indicated that the catch-up vaccination campaign showed a beneficial impact on the early decay of the rubella cases. Second, we numerically compared several different implementation strategies of catch-up vaccinations under a fixed amount of total vaccinations. As a result, we found that early and intensive vaccinations are vital for significant reduction in the number of rubella cases and CRS occurrences. Our study suggests that mathematical models with epidemiological and social data can contribute to identifying the most effective vaccination strategy.

Association Between Seasonal Influenza and Absolute Humidity: Time-Series Analysis with Daily Surveillance Data in Japan.

Seasonal influenza epidemics are associated with various meteorological factors. Recently absolute humidity (AH) has garnered attention, and some epidemiological studies show an association between AH and human influenza infection. However, they mainly analyzed weekly surveillance data, and daily data remains largely unexplored despite its potential benefits. In this study, we analyze daily influenza surveillance data using a distributed lag non-linear model to examine the association of AH with the number of influenza cases and the magnitude of the association. Additionally, we investigate how adjustment for seasonality and autocorrelation in the model affect results. All models used in the study showed a significant increase in the number of influenza cases as AH decreased, although the magnitude of the association differed substantially by model. Furthermore, we found that relative risk reached a peak at lag 10-14 with extremely low AH. To verify these findings, further analysis should be conducted using data from other locations.

Global landscape analysis of no-fault compensation programmes for vaccine injuries: A review and survey of implementing countries.

To update the landscape analysis of vaccine injuries no-fault compensation programmes, we conducted a scoping review and a survey of World Health Organization Member States. We describe the characteristics of existing no-fault compensation systems during 2018 based on six common programme elements. No-fault compensation systems for vaccine injuries have been developed in a few high-income countries for more than 50 years. Twenty-five jurisdictions were identified with no-fault compensation programmes, of which two were recently implemented in a low- and a lower-middle-income country. The no-fault compensation programmes in most jurisdictions are implemented at the central or federal government level and are government funded. Eligibility criteria for vaccine injury compensation vary considerably across the evaluated programmes. Notably, most programmes cover injuries arising from vaccines that are registered in the country and are recommended by authorities for routine use in children, pregnant women, adults (e.g. influenza vaccines) and for special indications. A claim process is initiated once the injured party or their legal representative files for compensation with a special administrative body in most programmes. All no-fault compensation programmes reviewed require standard of proof showing a causal association between vaccination and injury. Once a final decision has been reached, claimants are compensated with either: lump-sums; amounts calculated based on medical care costs and expenses, loss of earnings or earning capacity; or monetary compensation calculated based on pain and suffering, emotional distress, permanent impairment or loss of function; or combination of those. In most jurisdictions, vaccine injury claimants have the right to seek damages either through civil litigation or from a compensation scheme but not both simultaneously. Data from this report provide an empirical basis on which global guidance for implementing such schemes could be developed.