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.

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.

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.

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.

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.

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.

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.

Infection and transmission of COVID-19 among students and teachers in schools in Japan after the reopening in June 2020.

We aimed to investigate the confirmed COVID-19 cases among students and teachers in elementary schools (ages 6-12 years) and junior high schools (ages 13-15 years) in Japan between 1 June and 31 July 2020. We requested all schools to provide reports when students or teachers tested positive for COVID-19. A total of 207 cases were reported among students. Household transmission was identified as the dominant transmission route, confirmed in 71.4% of elementary schools and 60.3% of junior high schools. A total of 39 cases were reported among teachers, of which transmission route was unknown in 72.4% of elementary schools and 90.0% of junior high schools.

[Clinical Course of 11 Cases of SARS-CoV-2 Infection Occurred in A Large Cruise Ship�E�Factors Associated with Severity and Prolonged Hospitalization]

The number of the patients with coronavirus disease 2019 (COVID-19) is increasing, and shortage of hospital beds for these patients is a cause for serious concern. Here, we report the clinical course of 11 patients who were admitted to our hospital with COVID-19 that developed during their quarantine period in a large cruise ship, and discuss the factors associated with the disease severity and length of hospitalization. The median age of the 11 patients was 62 years, and 36% were men. The disease severity was mild in 7 patients, moderate in 4 patients, and severe in none of the patients. The median time from symptom onset to disease remission was 13 days for patients with moderately severe disease, and 7 days for patients with mild disease. The median interval from symptom onset to confirmation of the first negative result of PCR was 16 days for patients with moderately severe disease, and 14 days for patients with mild disease. The median time from symptom onset to discharge was 22.5 days for patients with moderately severe disease cases, and 16 days for patients with mild disease. Some patients needed prolonged hospitalization because of persistently positive results of PCR even after remission of symptoms. Comparison between the patient groups with moderately severe disease and mild disease showed that the patients with moderately severe disease were older and had higher serum ferritin and serum amyloid protein (SAA) levels than the patients with mild disease. Even in patients with mild to moderate COVID-19, two to three weeks were required from symptom onset to confirmation of the first negative result of PCR, and this was one of the major factors for prolonged hospitalization. The serum ferritin levels and SAA levels might be predictors of the disease severity.