Infectious Diseases In Japan Research Articles

Shibasaburo Kitasato (1853-1931): Pioneer of Japanese Medicine and Global Immunology Innovator.

Shibasaburo Kitasato (1853-1931), a pivotal figure in modern Japanese medicine, made groundbreaking contributions to bacteriology and immunology. His achievements include pure cultivation of the tetanus bacillus and the development of serum therapy, which continue to influence modern immunology and vaccination strategies. Kitasato established the Institute for Infectious Diseases in Japan, the Kitasato Institute, played a crucial role in establishing the Keio University School of Medicine, and served as the first president of the Japan Medical Association. His international collaboration with Robert Koch and Emil von Behring elevated Japan's status in global medical research. Kitasato's research philosophy emphasizes clinical applicability and passionate pursuit of effective topics, inspiring the generation of prominent Japanese medical researchers. This study highlights Kitasato's life, work, and enduring impact on medical research, education, and healthcare administration. Kitasato's legacy, commemorated on the new 1000-yen banknote in 2024, continues to serve as an inspiration for contemporary medical professionals worldwide.

Impact of Diabetes Mellitus On In-Hospital Mortality of COVID-19 Patients in Japan Since COVID-19 Became a Common Infectious Disease.

The number of severe cases of coronavirus disease 2019 (COVID-19) has been decreasing since the emergence of the Omicron variant at the end of 2021. COVID-19 has become a common infectious disease in Japan and was downgraded to a category five infectious disease on May 8, 2023. This study aimed to compare the impact of diabetes mellitus on in-hospital mortality in COVID-19 patients since COVID-19 became a common infectious disease. We conducted a retrospective observational study using data from an advanced critical care center in Osaka, Japan. The study included 1,381 patients of COVID-19 admitted to the center between March 1, 2020, and May 7, 2023, before COVID-19 became a category five infectious disease in Japan. Individuals younger than 18 years and pregnant women were excluded. We divided the patients into two groups: pre- and post-Omicron epidemic groups. The primary endpoint of the study was the in-hospital mortality, and the prognostic impact of diabetes mellitus was compared between the groups. The Kaplan-Meier curve showed a significantly lower rate of in-hospital mortality in the post-Omicron epidemic group than in the pre-Omicron epidemic group. The hazard ratio (HR) was 1.83 (95% CI, 1.36-2.50; p < 0.0001). Patients with diabetes mellitus had higher in-hospital mortality in both the pre- and post-Omicron epidemic groups; their HRs were 1.39 (95% CI, 1.21-1.59; p < 0.0001) and 1.45 (95% CI, 1.15-1.83; p = 0.0012), respectively. Diabetes mellitus had no significant interaction effect on the association between the post-Omicron epidemic and in-hospital mortality (p for interaction = 0.2154). Diabetes mellitus may continue contributing to COVID-19 in-hospital mortality in the future, as the Omicron sub-strain may still be prevalent.

Launch of Board Certification in Pediatric Infectious Diseases in Japan.

To cultivate specialists in pediatric infectious diseases (ID) in Japan, the Japanese Society for Pediatric Infectious Diseases initiated board certification for pediatric ID in 2017. Previously, in 2014, we had formed a committee for board certification in pediatric ID and discussed the fundamentals of the board certification system, including the goals, requirements for designated training institutions, provisional certification of pediatric ID specialists and eligibility for and content of the board certification examination. After approval from 31 programs, the pediatric ID programs started in 2017 with 8 fellows in 7 programs. The first 6 graduates received board certification in 2020. To date, 61 pediatricians have been board certified as pediatric ID specialists. In parallel, we introduced board certification for pediatricians who work mainly in primary care settings and have a special interest in pediatric ID. This system has certified 338 pediatricians. During and after the development of the programs, we achieved substantial progress in highlighting the pivotal role of pediatric ID specialists, including the establishment and maintenance of antimicrobial stewardship programs, pediatric ID consultations and introduction of viral diagnosis by polymerase chain reaction at institutions. However, several issues need to be addressed, including the establishment of independent pediatric ID departments in institutions, payment of consultation fees, program site visits, maintenance of certification and cultivation of physician-scientists. These challenges will be the focus of future efforts.

Disease burden of main bacterial infections in Japan, 2015–2020: A population-level study

IntroductionComprehensive evidence about the burden of infectious diseases in the Western Pacific Region is scarce. We thus examined the disease burden of infectious diseases in Japan in terms of disability-adjusted life years (DALYs). MethodsWe extracted national claims data from Japan's universal health insurance system to estimate the burden of disease for selected infections between 2015 and 2020 using DALYs. The mortality rate, disability duration and severity weight of each disease were estimated based on national data and literature reviews. ResultsDisease burden per 100,000 population was 1307.0 in 2015 and 972.1 in 2020 for bloodstream infections (BSI), 796.5 DALYs in 2015 and 498.9 DALYs in 2020 for pneumonia, 171.5 in 2015 and 149.4 in 2020 for meningitis and 11.6 in 2015 and 11.4 in 2020 for urinary tract infections (UTI). Only surgical site infections (SSI) showed a slightly increasing trend over the 5-year period, from 2.2 in 2015 to 2.8 in 2020. ConclusionsOur results showed that the disease burden of the five major infectious diseases was higher in Japan than in other countries. However, while the burden of SSI increased, the burden of pneumonia, meningitis, BSI and UTI gradually decreased year on year. The possible causes of the decreased morbidity should be examined in future work.

Effects of Serum Antibody Test Reagent Discontinuation on Diagnosis of Amebiasis in Japan: Interrupted Time-Series Analysis.

Amebiasis is a notifiable infectious disease in Japan, and the number of reported cases had been on the rise, but since the discontinuation of insurance-covered serum antibody testing reagent in 2017, concerns have arisen regarding the decrease in reported cases. This study aimed to investigate changes occurring after discontinuation of the serum antibody test reagent production. We retrospectively analyzed amebiasis cases from January 2014 to December 2019 using the National Center for Epidemiology of Infectious Diseases system. Interrupted time-series regression analysis was used to evaluate trends in weekly amebiasis cases before and after the discontinuation period. The study period was divided into prediscontinuation (2014-2017) and discontinuation (2018-2019) periods. A total of 6,179 amebiasis cases were reported. The average numbers of weekly cases were 21.5 during 2014-2017 and 16.3 during 2018-2019. The frequency of diagnoses decreased in the discontinuation period (prevalence rate ratio = 0.78; 95% CI, 0.67-0.89; P < 0.01). Subgroup analysis showed lower diagnostic rates, particularly for extraintestinal amebiasis (prevalence rate ratio = 0.37; 95% CI, 0.22-0.55; P < 0.01). We observed a significant decrease in the number of reported amebiasis cases per week after discontinuation of the serum antibody test reagent in Japan. Our findings hold significance for both public health policy and practice in Japan, underscoring the requirement for enhanced amebiasis diagnostic tools and strategies. To ensure accurate diagnosis, availability of antibody reagents for serum testing, covered by insurance, should be encouraged.

Willingness to pay for nationwide wastewater surveillance system for infectious diseases in Japan

A nationally-representative survey indicated that the population's valuation would economically justify the nationwide wastewater surveillance system in Japan.

Resurgence of human metapneumovirus infection and influenza after three seasons of inactivity in the post-COVID-19 era in Hokkaido, Japan, 2022-2023.

Following the coronavirus disease 2019 (COVID-19) outbreak in February 2020, incidences of various infectious diseases decreased notably in Hokkaido Prefecture, Japan. However, Japan began gradually easing COVID-19 infection control measures in 2022. Here, we conducted a survey of children hospitalized with human metapneumovirus (hMPV), influenza A and B, and respiratory syncytial virus infections in 18 hospitals across Hokkaido Prefecture, Japan, spanning from July 2019 to June 2023. From March 2020 to June 2022 (28 months), only 13 patients were hospitalized with hMPV, and twopatients had influenza A. However, in October to November 2022, there was a re-emergence of hMPV infections, with a maximum of 27 hospitalizations per week. From July 2022 to June 2023 (12 months), the number of hMPV-related hospitalizations dramatically increased to 317 patients, with the majority aged 3-6 years (38.2%, [121/317]). Influenza A also showed an increase from December 2022, with a peak of 13 hospitalizations per week in March 2023, considerably fewer than the pre-COVID-19 outbreak in December 2019, when rates reached 45 hospitalizations per week. These findings suggest the possibility of observing more resurgences in infectious diseases in Japan after 2023 if infection control measures continue to be relaxed. Caution is needed in managing potential outbreaks.

Changing Patterns of Infectious Diseases Among Hospitalized Children in Hokkaido, Japan, in the Post-COVID-19 Era, July 2019 to June 2022.

Many reports have reported a reduction in respiratory infectious diseases and infectious gastroenteritis immediately after the coronavirus disease 2019 (COVID-19) pandemic, but data continuing into 2022 are very limited. We sought to understand the current situation of various infectious diseases among children in Japan as of July 2022 to improve public health in the post-COVID-19 era. We collected data on children hospitalized with infectious diseases in 18 hospitals in Japan from July 2019 to June 2022. In total, 3417 patients were hospitalized during the study period. Respiratory syncytial virus decreased drastically after COVID-19 spread in early 2020, and few patients were hospitalized for it from April 2020 to March 2021. However, an unexpected out-of-season re-emergence of respiratory syncytial virus was observed in August 2021 (50 patients per week), particularly prominent among older children 3-6 years old. A large epidemic of delayed norovirus gastroenteritis was observed in April 2021, suggesting that the nonpharmaceutical interventions for COVID-19 are less effective against norovirus. However, influenza, human metapneumovirus, Mycoplasma pneumoniae , and rotavirus gastroenteritis were rarely seen for more than 2 years. The incidence patterns of various infectious diseases in Japan have changed markedly since the beginning of the COVID-19 pandemic to the present. The epidemic pattern in the post-COVID-19 era is unpredictable and will require continued careful surveillance.

Clinical trial experience in Japan and future issues in developing drugs to treat COVID-19.

The National Center for Global Health and Medicine plays a central role in the treatment and research of infectious diseases in Japan. It has conducted various research and development activities on drugs to treat coronavirus disease 2019 (COVID-19) with clinical questions as starting points. Clinical trials are essential in developing new treatment modalities, but we have noticed some characteristic difficulties in clinical trials on emerging and re-emerging infectious diseases. For example, since there is no standard of care when an emerging infectious disease starts to spread, establishing an appropriate control group is complicated, and many things are hurried at the start of trials. This means there is little time to arrange a placebo, and conducting blinded, randomized, controlled trials has been difficult. Another issue characteristic of infectious disease has been that progress in enrolling subjects is affected by the spread of the disease. It was also a struggle to select institutions that provide medical care on the front lines of infectious disease and conduct clinical trials regularly. To start multicenter clinical trials expeditiously, a regulated and structured network is thus considered necessary. From the perspective of implementation, it is preferable to conduct decentralized clinical trials (DCTs) that do not depend on people coming to the medical institution, while from the perspective of preventing infections during the spread of COVID-19, wide adoption of eConsent is desirable. Based on the experience of COVID-19, new measures must be taken to prepare for emerging and re-emerging infectious diseases in the future.

SG-APSIC1155: Drug susceptibility patterns of fulminant group G Streptococcus (GGS) infection as a re-emerging infectious disease in Japan

Objectives: Severe streptococcal infections are invasive, re-emerging infections that rapidly worsen and lead to death. Not only group A Streptococcus (GAS) but also group g Streptococcus (GGS) are the causative agents of this infection. Moreover, GGS produces hemolytic toxins, proteolytic toxins, and other toxins like GAS. Furthermore, drug-resistant Streptococcus spp, like other pathogenic bacteria, are on the rise worldwide. However, drug resistance has not been studied extensively in invasive GGS. Therefore, we investigated the drug susceptibility of GGS clinical isolates that are closely related to fulminant streptococcal infections. Methods: We used GGS strains isolated from sterile sites of invasive infections at a hospital in Nagoya City, Japan, from 2017 to 2021. Bacterial identification and drug-susceptibility testing were performed using a VITEK-2 system. Results: Overall, 53 strains were included in the study. The GGS strains examined in this study were resistant to 3 different antibiotics (erythromycin, clindamycin, and minocycline). Also, 18 strains (34%) were resistant to erythromycin, 9 (17%) were resistant to clindamycin, and 18 (34%) were resistant to minocycline. Moreover, there were 5 strains (9.4%) of 2-drug–resistant bacteria and 8 strains (15.1%) of 3-drug–resistant bacteria. Conclusions: Acquired resistance not only to individual antibiotics but also to multiple antibiotics suggests that GGS tends to become multidrug resistant. Continued surveillance of the drug susceptibility of GGS as a potential cause of fulminant streptococcal infections will be necessary in the future.

Genomic characterization of Japanese meningococcal strains isolated over a 17-year period between 2003 and 2020 in Japan.

While invasive meningococcal disease (IMD) is a major public concern worldwide, IMD is categorized as a rare infectious disease in Japan and, thus, its causative agents and epidemiology have not yet been characterized in detail. In the present study, we used molecular methods to epidemiologically characterize 291 meningococcal strains isolated in Japan over a 17-year period between 2003 and 2020 by whole genome sequencing (WGS). Serogroup Y meningococci (MenY) were the most abundant, followed by B (MenB) and then C and W among meningococci from IMD patients, while non-groupable as well as MenY and MenB were the most abundant among isolates from healthy carriers. Sequence type (ST) defined by multilocus sequence typing (MLST) showed that ST-1655 and ST-23 belonging to clonal complex (cc) 23 were dominant among Japanese IMD isolates, while ST-11026 (cc32) unique to Japan as well as ST-23 were dominant among Japanese non-IMD isolates. Phylogenetic analyses of ST by MLST revealed that Japanese isolates were classified with 12 ccs, including recently reported cc2057. Phylogenic analyses by WGS showed that isolates of ST-11026 and of ST-1655 were genetically close, whereas ST-23 isolates appeared to be diverse. Moreover, comparisons with other cc11 isolates isolated worldwide indicated that some Japanese cc11 isolates were genetically close to those isolated in Europe and China. An in silico analysis suggested that 14.3 and 44.2% of Japanese MenB were cross-reactive with 4CMenB and rLP2086 MenB vaccines, respectively. The results in the present study revealed that some epidemiological features were unique to Japan.

Infection control of COVID-19 in operating theaters in a designated hospital for specified infectious diseases in Japan.

At the beginning of the COVID-19 pandemic in 2020, many hospitals around the world recommended stopping elective surgery as a precaution to stop the spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The number of elective surgeries was reduced in Japan due to several waves of the pandemic. This work describes the management of COVID-19 and actual polymerase chain reaction (PCR) screening in operating theaters at the National Center for Global Health and Medicine (NCGM), a designated hospital for specified infectious diseases in Japan. The following three steps for COVID-19 infection control were taken to maintain the operating theater: i) Do not bring COVID-19 into the operating theater, ii) Infection control for all medical staff, and iii) Surgical management of surgical patients with COVID-19. We introduced checklists for surgical patients, simulations of surgery on infected patients, screening PCR tests for all surgical patients, and use of a negative pressure room for infective or suspected cases. We determined the flow and timing of surgery for patients with COVID-19. However, many aspects of COVID-19 infection control measures in the operating theater are still unclear. Therefore, infection control measures require further advances in the future to manage new infections.

Gastrointestinal endoscopy trends in a designated hospital for specified infectious diseases in Japan during the dawn of the "living with COVID-19" era.

January 2020 marked the very early period of SARS-CoV-2's arrival in Japan. At the time, we immediately and strictly adopted the use of enhanced PPE, including a N95, gown, gloves, eye protection, and an apron, during every endoscopic procedure for every patient, with or without COVID-19. One reason why we use enhanced PPE for every patient is because all endoscopic procedures should be considered aerosol-generating procedures, and another reason is that asymptomatic patients with COVID-19 cannot be identified during a pandemic. The volume of endoscopic screening/surveillance endoscopies decreased markedly, but therapeutic endoscopies did not decrease. In contrast, urgent endoscopic hemostasis has increased more than ever. The most common reason for the increase might be that the lack of protective equipment and the need for medical staff to deal with an unknown virus, creating a pandemic panic in emergency medicine.

The development of SARS-CoV-2 PCR testing methods at a designated medical institution for specific infectious diseases in Japan

Due to the coronavirus disease 2019 (COVID-19) pandemic, we have been conducting polymerase chain reaction (PCR) testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at this facility since March 2020. In the early days, the PCR testing system had limited capabilities, so testing had to be conducted manually and only a few tests were conducted. Moreover, we lacked sufficient experience to conduct PCR testing manually, so we struggled with the manual work, which required intense concentration, and we felt pressured not to make mistakes such as allowing contamination. Since we introduced upgraded equipment, new methods, and additional staff for testing and we cooperated with the clinical technologist on the night shift in the Emergency Department, we are currently able to conduct urgent PCR testing on more than 2,000 specimens per month 24 hours a day. We will continue to meet new needs for COVID-19 treatment with the cooperation of other departments.

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.

The impact of the COVID-19 pandemic on other infections differs by their route of transmission: A retrospective, observational study in Japan

IntroductionThe Coronavirus disease 2019 (COVID-19) pandemic and people's subsequent behavioral changes have decreased the cases of respiratory infection worldwide. However, research on infectious diseases with other transmission modes is insufficient. The aim was to assess the impact of the COVID-19 pandemic on non-respiratory infectious diseases: infectious enterocolitis, sexually transmitted diseases such as human immunodeficiency virus (HIV) infection and syphilis, and tick-borne diseases. MethodsThis retrospective, cohort study used comprehensive surveillance data from the National Institute of Infectious Diseases in Japan from January 1, 2018, to December 31, 2021. The number of cases of infectious diseases before the COVID-19 pandemic (2018–2019) was compared with that during the COVID-19 pandemic (2020–2021). Reduction rates were calculated as the number of disease cases during the COVID-19 pandemic in 2020 and 2021, respectively, divided by the mean number of disease cases in 2018 and 2019. ResultsThe total numbers of cases of infectious enterocolitis, sexually transmitted diseases, and tick-borne diseases during the study period were 2,507,304 cases, 24,972 cases, and 3012 cases, respectively. The number of cases decreased for infectious enterocolitis and sexually transmitted diseases during the COVID-19 pandemic compared with before the COVID-19 pandemic, with an approximately 40–50% decrease in enterocolitis and 30–55% decreases in sexually transmitted diseases. However, cases of tick-borne diseases changed little, with a 0.2% increase in 2020 and a 6% increase in 2021. ConclusionThe COVID-19 pandemic had a different impact on the number of cases of infectious diseases depending on their mode of transmission.

One Example of Research Collaboration between Zoo, Aquarium and University: Toward Elucidation of the Transmission Cycle of Vector-borne Infectious Diseases in Japan

国内の動物園・水族館（園館）の飼育下ペンギン類で見られる感染症のうち，鳥マラリアは致死例もあるため予防や治療に対する関心が高いが，原因となる鳥マラリア原虫の種類，媒介するベクター昆虫種，さらにそれらの分布状況は不明であった。宿主動物や昆虫を捕獲して病原体の分布状況や伝播経路を把握・解明する際は，天候・時季・人員などの制約もあり，必ずしも十分な情報が得られない。一方，様々な野生動物を飼育展示している園館では，年齢，性別，健康状態などの個体情報が明らかな上，飼育環境も把握・管理され，定期的な採材も可能であり，理想的な疫学調査フィールドと言える。2004年以降，我々は主にペンギン類を対象に，国内の多くの園館から多数の検体提供を受け，鳥マラリア感染状況や，園館内に生息するアカイエカ（Culex pipiens）がペンギン類を始めとする園館内の各種鳥類を吸血してベクターとなることを明らかにしてきた。そして，国内の飼育下ペンギン類に見られた各種原虫は，園館内外に飛来・生息する様々な野鳥が感染源であることも示し，鳥マラリア感染制御のために必要な基盤となる知見を提供することができた。他にも犬糸状虫（Dirofilaria immitis）の伝播経路に関しても同様に解明した。以上の結果は，園館の特性を活かし，関係者の全面的な協力を受けた成果であり，今後も年間を通した感染経緯，感染時の病原性や治療の検討など，希少種の域外保全へ向けた共同研究が期待される。

Imported Infectious Diseases, Tropical Diseases and Local Endemic Infectious Diseases in Japan.

We aimed to describe the historical perspectives and the current epidemiology of tropical, imported and local endemic infectious diseases in Japan in this review. Public health legislation for infectious diseases and immigration statistics were overviewed to provide the background of the infectious disease situation in Japan. Many tropical diseases were successfully controlled and eliminated in the latter half of the 20th century and the majority of those diseases are imported today. The trend of the main 15 imported infectious diseases before the advent of COVID-19 was summarized as well as local endemic infectious diseases in Japan. Transmission risks of traditional cuisines, lifestyles and nature exposures in Japan are introduced to guide clinicians for travel advice to prevent those local infectious diseases.

The Change of after lifting the State of Emergency by COVID-19 on the Physical Activity of the Elderly Japanese People

In April 2020, the spread of COVID-19 infectious disease in Japan issued a state of emergency, making it impossible for people to go out except for unnecessary and urgent matters. It has been reported that the declaration of self-restraint will significantly reduce the volume of physical activity (PA). However, since the volume of change in the volume of PA after 6 months or more after the declaration of self-control was lifted is unknown, the volume of PA was compared. The participants were 13 elderly people living in Hiroshima City. In October 2020, an activity meter with a 3-axis accelerometer was attached to the participant's waist, and PA and physical function were measured for one week and compared with the PA measured in October 2019. Six months after the declaration was issued, there was changes volume of moderate intensity walking PA, were no changes in the number of steps, activity time, volume of light intensity PA, and volume of total PA (p ≥ 0.07%). Six months have passed since the self-restraint of activities due to the state of emergency, and now that the number of infected people has decreased, it is possible that the volume of PA in the elderly has improved due to the improvement in the sense of security and happiness. This suggests that it is important to continue daily activities, hobbies, and exercises as much as possible while taking measures against infection in order to reduce the risk of cardiovascular events.

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.