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.

Reactogenicity and immunogenicity of BNT162b2 or mRNA-1273 COVID-19 booster vaccinations after two doses of BNT162b2 among healthcare workers in Japan: a prospective observational study.

BACKGROUND: This study evaluates the immunogenicity and reactogenicity of BNT162b2 and mRNA-1273 booster doses after the primary two-dose BNT162b2 series in Japan and is the first report from Western Pacific region. RESEARCH DESIGN AND METHODS: Healthcare workers receiving the two-dose BNT162b2 series and eligible for booster vaccination were enrolled. Self-reported adverse reactions were recorded for 8 days. Antibody titer was measured at baseline and on day 28. RESULTS: A total of 2,931 and 890 subjects received BNT162b2 (homologous) and mRNA-1273 (heterologous) booster vaccinations, respectively. The anti-SARS-CoV-2 spike protein IgG titer increased by 50.9- and 64.3-fold in the homologous and heterologous groups, respectively. Immunogenicity was greater with increasing age, regardless of sex. Adverse reactions were mild to moderate and decreased with age. The most common adverse reactions were injection-site pain (92.2%), fatigue (71.8%), headache (58.3%), and fever ≥37.5°C (46.5%). Two cases of non-severe myocarditis occurred in the heterologous group and resolved without clinical sequelae. CONCLUSION: Homologous booster schedules had fewer reported adverse reactions; heterologous boosters elicited greater immunogenicity. Among different age groups, subjects aged 60 or over had the lowest immunogenicity before the booster, and both homologous and heterologous boosters restored vaccine immunogenicity level comparable to those of younger age groups.

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.