Aim The quadrivalent human papillomavirus (4vHPV) vaccine has demonstrated efficacy and immunogenicity and was generally well tolerated in clinical trials conducted in Japan. We report a detailed safety analysis of injection-site reactions in female Japanese 4vHPV clinical trial participants. Methods This post-hoc analysis included data from 2 double-blind, placebo-controlled phase II clinical trials of a 3-dose (Day 1, Month 2, Month 6) regimen of 4vHPV vaccine in Japanese young women aged 18–26 years (N = 1021; NCT00378560) and girls aged 9–17 years (N = 107; NCT00411749). Injection-site and systemic adverse events (AEs) were monitored using vaccination report cards for 15 days after each vaccine dose; serious AEs were reported throughout the trials. Post-hoc analyses of data from these trials were performed to examine details of injection-site AEs, including day of onset, time from onset to resolution, and maximum intensity. Results Injection-site AEs were reported by 85.6% of 4vHPV vaccine recipients and 72.4% of placebo recipients, most commonly erythema, pain, pruritus, and swelling (each >5% of 4vHPV vaccine recipients). The majority of injection-site AEs had an onset within 3 days of vaccination and were mild to moderate in intensity; few 4vHPV vaccine recipients reported severe injection-site AEs (2.0% overall). All injection-site AEs resolved, and most (4vHPV: 87.5%; placebo: 92.7%) resolved within 5 days of onset. Conclusions Most injection-site reactions are mild or moderate in intensity and of short duration. The 3-dose regimen of 4vHPV vaccine is well tolerated in Japanese female clinical trial participants based on this post-hoc analysis. These results will further support safety communication between healthcare providers and vaccine recipients regarding the HPV vaccine. Trial registration Clinicaltrials. gov: NCT00378560 and NCT00411749.

Vaccine confidence reflects social, individual, and political factors indicating confidence in vaccines and associated health systems. In Japan, the government ceased proactive recommendation of the human papillomavirus (HPV) vaccine in June 2013, only several months after the recommendation had begun. Seven years later, as of October 2020, the suspension persists and vaccine coverage has precipitously declined, resulting in many young women being continually exposed to the risk of preventable HPVrelated diseases. Accordingly, understanding stakeholder opinions on HPV vaccination issues is critical for informing strategies to improve HPV vaccine confidence and acceptance. In October 2019, we performed a nationwide, web-based survey of 1646 mothers of HPV-vaccination-eligible girls, 562 female adolescents aged 15-19 years, and 919 healthcare professionals (HCPs) in Japan. This survey captured key elements of vaccine confidence (i.e., importance, effectiveness, and safety of the HPV vaccine), awareness, and the willingness to receive (in HPV-vaccination-eligible girls) or recommend (in HCPs) the HPV vaccine, and the factors responsible for these decisions. HPV vaccine confidence was generally higher among HCPs than among mothers or female adolescents. Nearly half of all stakeholders were neutral regarding their willingness to receive/recommend the HPV vaccine. The seriousness of cervical cancer and the HPV vaccine's effectiveness or safety were important deciding factors for receiving/recommending the HPV vaccine. Besides these factors, sufficient information and free vaccination were crucial. Our results suggest several factors that could help shape public policy and communication strategies to improve HPV vaccine confidence and acceptance in Japan.