Safety monitoring of bivalent, quadrivalent, and 9-valent human papillomavirus vaccination in Japan: The vaccine effectiveness, networking, and universal safety (VENUS) study
Assessment of the risk of adverse events of special interest following HPV vaccination among females aged 12–26 using medical claims data linked to routine or catch-up vaccination records provided by municipalities found no statistically significant increased risk.
Abstract
ABSTRACT Safety data on human papillomavirus (HPV) vaccination in the Japanese population remain limited owing to the lack of healthcare databases available for vaccine safety assessment. In this study, we assessed the risk of adverse events of special interest (AESIs) following HPV vaccination among females aged 12–26 y using medical claims data linked to routine or catch-up vaccination records provided by municipalities. We conducted a population-based cohort study and self-controlled case series (SCCS) from April 2015 to March 2023 for bivalent/quadrivalent vaccines and from April 2023 to March 2024 for the 9-valent vaccine. All females eligible for the vaccination program were included in the cohort study, whereas only those who experienced AESIs were included in the SCCS. The observation period was classified according to vaccination status as unvaccinated and post-vaccination risk periods following the first, second, and third doses. Adjusted rate ratios with 95% confidence intervals were estimated for the cohort and SCCS. In the bivalent/quadrivalent vaccines analysis cohort (25131 females), 1763, 1492, and 975 received the first, second, and third doses, respectively. In the 9-valent vaccine analysis cohort (38970 females), 3931, 2389, and 934 received the first, second, and third doses, respectively. Rates of 54 AESIs were calculated during unvaccinated periods. AESIs with feasible quantitative analyses for either the bivalent/quadrivalent or 9-valent vaccines included migraine, hypotension, asthma, polycystic ovary syndrome, postural orthostatic tachycardia syndrome, hypothyroidism, hyperthyroidism, and epilepsy. No statistically significant increased risk following HPV vaccination was observed for these AESIs. Larger datasets are needed to assess rarer AESIs.
OBJECTIVE
Papilloguard® is developed by Nivad Pharmed Salamat as a quadrivalent human papillomavirus (HPV) vaccine, uniquely combined with the adjuvant system 04 (AS04). The objective of this study was to evaluate the immunogenicity and safety of the quadrivalent Papilloguard® in comparison with Gardasil® (Merck).
METHODS
This study enrolled 670 healthy participants aged 15-25 years. Vaccines were administered at Months 0, 2, and 6. Immunogenicity was assessed by geometric mean concentrations of HPV-specific antibodies at days 60, 180, and 210. Safety data were collected through direct monitoring, phone follow-ups, and diary cards.
RESULTS
Papilloguard® demonstrated non-inferior immunogenicity compared to Gardasil® across all four HPV types at day 210. Moreover, Papilloguard® demonstrated consistently higher geometric mean antibody concentrations across all four HPV types compared with Gardasil®. Seroconversion rates were also higher for HPV types 6, 11, and 18 at day 210 in the Papilloguard® group. However, superiority analyses were not prespecified and these findings should be interpreted cautiously. This enhanced immunogenicity may be associated with the AS04 in the quadrivalent formulation. Most reported adverse events were grade 1 or 2. Vaccination site pain was observed in both groups as the most commonly reported local solicited adverse event. Headache and fatigue were the most frequently reported systemic solicited adverse events. Two serious adverse events were reported in each group, none of which were considered related to the vaccines. While associated with increased local reactogenicity, the overall safety profile of Papilloguard® was acceptable and comparable to other HPV vaccines.
CONCLUSION
Papilloguard®, the first quadrivalent HPV vaccine combined with AS04, demonstrated non-inferior immunogenicity compared to Gardasil® for HPV types 6, 11, 16, and 18. Despite a higher incidence of local reactogenicity, likely associated with AS04, Papilloguard® showed enhanced immunogenicity while maintaining an acceptable overall safety profile, positioning it as a promising HPV vaccine.
M. Mardani, I. Darazam, Ashraf Moini et al.· Vaccine· 0 citations
This post-marketing, real-world study compared the risk of ADs between females who received bivalent human papillomavirus (HPV) vaccine (Cecolin) and unvaccinated females, providing real-world evidence further confirming that Cecolin vaccination does not increase the risk of ADs.
BACKGROUND
Efficacy of the nine-valent human papillomavirus (9vHPV; HPV6, 11, 16, 18, 31, 33, 45, 52, and 58) vaccine was shown in females and inferred for males through immunobridging. We evaluated the efficacy of the 9vHPV vaccine in males aged 16-26 years.
METHODS
This randomised, double-blind, placebo-controlled, efficacy, immunogenicity, and safety phase 3 trial was conducted at 22 clinical research, hospital, medical, or treatment sites in Japan, with masking of investigators, sponsor personnel, and participants. Healthy males aged 16-26 years with no history of human papillomavirus (HPV)-related lesions and no previous HPV vaccination were randomly assigned (1:1) centrally, using permutated blocks (block sizes of four), to receive three intramuscular injections of the 9vHPV vaccine or placebo (saline) at day 1, month 2, and month 6. The primary and secondary efficacy endpoints were the combined incidences of 6-month anogenital persistent infection related to HPV6, 11, 16, and 18 and HPV31, 33, 45, 52, and 58. Anogenital swabs and external genital tissue samples were tested for the presence of HPV DNA. Tissue samples were adjudicated for histopathology diagnosis. The primary and secondary efficacy evaluations were tested for superiority with a margin of 0% in the per-protocol population. Another secondary endpoint was antibody responses to each vaccine-targeted HPV type at month 7; immunogenicity analyses were conducted in the per-protocol immunogenicity population. Safety was assessed in participants who received at least one dose of vaccine or placebo. This study is registered with ClinicalTrials.gov (NCT04635423) and is completed.
FINDINGS
Between Nov 30, 2020, and Dec 25, 2021, 1059 participants were enrolled and randomly assigned to receive the 9vHPV vaccine (n=529) or placebo (n=530). Vaccine efficacy for the primary and secondary endpoints was 89·3% (95% CI 55·4-98·2; p=0·0002) and 63·5% (2·7-86·0; p=0·023), respectively, in the initial efficacy analysis based on a visit cutoff date of Dec 29, 2023, and 91·6% (67·7-98·6) and 72·9% (38·7-89·3) in the end-of-study efficacy analysis based on a visit cutoff date of July 16, 2024. Seroconversion rates were greater than 98% for each vaccine-targeted HPV type. Injection-site adverse events were reported in 370 (70%) of 529 9vHPV vaccine recipients and 162 (31%) of 530 placebo recipients, and vaccine-related systemic adverse events in 58 (11%) vaccine recipients and 52 (10%) placebo recipients; most cases were mild or moderate. No deaths, vaccine-related serious adverse events, or discontinuations due to adverse events were reported.
INTERPRETATION
The 9vHPV vaccine prevents anogenital persistent infection related to vaccine-targeted HPV types in males and has an acceptable safety profile. These findings support the use of the 9vHPV vaccine in males to prevent HPV-related anogenital diseases.
FUNDING
Merck Sharp & Dohme.
TRANSLATIONS
For the Japanese translation of the abstract see Supplementary Material section.
Koji Hisamoto, Masaki Yamanaka, Masayasu Nomura et al.· Lancet. Infectious Diseases...· 0 citations
BACKGROUND
Real-world data studies suggest that the vaccine effectiveness (VE) of a fourth mRNA vaccine dose against SARS-CoV2 infection related hospitalisation wanes after a few months, potentially warranting consideration of additional booster doses.
METHODS
A multi-database cohort study was conducted through the Data Analysis and Real World Interrogation Network (DARWIN EU®) using routinely collected electronic health records from the UK (CPRD GOLD), the Netherlands (IPCI), and Spain (SIDIAP) from January 2021 to June 2023. The study included individuals aged 12 and above, vaccinated with at least three doses. We matched fourth-dose to third-dose vaccinated individuals using a weekly sequential approach, defining the date of the last dose received by the exposed individual as index date. Primary outcomes were SARS-CoV2 infection related death and hospitalisation. Hazard ratios (HR) were estimated using Cox proportional hazard models, with VE defined as the percentage of 1 minus HR. Waning of VE was assessed at monthly intervals.
FINDINGS
A total number of 975,496 matched pairs were identified from the three databases, with a median age of 63-78. The pooled VE of a fourth vaccine dose against SARS-CoV2 infection related death compared to three vaccine doses was 30% (95%CI 9 to 46, I2=0). VE against SARS-CoV2 infection related hospitalisation was 26% (19% to 33%) and 46% (15% to 66%), in Spain (SIDIAP, median follow-up 8 weeks) and Netherlands (IPCI, median follow-up 21 weeks) respectively. VE of a fourth dose started waning at 4-8 weeks after vaccination.
INTERPRETATION
A fourth dose of a mRNA COVID-19 vaccination was effective against SARS-CoV2 infection related death and hospitalisation. However, effectiveness waned over time. Periodic revaccination should be considered, with recommendations regarding booster timing taking into account circulating variants, patterns of viral transmission, and population uptake.
FUNDING
European Medicines Agency.
Xintong Li, N. Mercadé-Besora, Amy Shuk Man Lam et al.· Journal of Infection· 0 citations
Background To enhance global vaccine coverage and reduce costs, Human papillomavirus (HPV) immunization schedules are shifting from the standard three–dose (3D) regimen toward reduced–dose (1D or 2D) schedules. We aimed to evaluate the comparative immunogenicity, efficacy, and safety of diverse dose schedules and vaccine types using a Bayesian network meta–analysis. Methods Two reviewers independently searched PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), CNKI, and Wanfang Data from inception to February 15, 2026, for randomized controlled trials (RCTs) evaluating different dose schedules of HPV vaccines in females aged 9–26 years. Primary outcomes were HPV–16/18 Seroconversion rates (SCR) and 6–month Persistent infection (PI). A Bayesian random–effects model was constructed using the multinma package in R, and treatments were ranked using the Surface Under the Cumulative Ranking (SUCRA) values. Results For immunogenicity, the 9v–3D regimen demonstrated the highest SCR compared with placebo (OR 62.45, 95% CrI 15.20–158.30; SUCRA 0.96). However, these large effect estimates are largely driven by near–zero events in placebo arms. Regarding protective efficacy against PI, while 3–dose regimens ranked highest (9v–3D SUCRA 0.95; 2v–3D SUCRA 0.89), single–dose schedules (1D) maintained clinically significant protection (e.g., 2v–1D vs. placebo: OR 0.32, 95% CrI 0.07–0.96; SUCRA 0.61). Safety rankings identified 1D schedules as having the lowest risk of injection–site pain (SUCRA: 2v–1D 88.0%, 9v–1D 82.0%). Subgroup analysis suggested comparable efficacy of 2–dose regimens in adolescents aged 9–14 years compared to the standard 3D regimen (P–interaction = 0.04). Conclusions Although reduced–dose schedules induce lower antibody titers than the standard 3–dose regimen, they provide robust protective efficacy against persistent HPV infection with a superior safety profile. Our findings support the widespread adoption of 2–dose schedules in adolescents and suggest that a single–dose strategy is a viable alternative in resource–constrained settings to accelerate the elimination of cervical cancer. However, given the surrogate nature of the study endpoints and the limitations of network meta-analysis for establishing non-inferiority, cautious interpretation of these results is warranted, and further long-term clinical endpoint data are needed.
Jing Ye, Zhen-qiong Zhu, Fang Wang et al.· Frontiers in Immunology· 0 citations
Yisheng Jun’an® rabies vaccine exhibits a favorable safety profile with mild-to-moderate reactions, support its use in post-exposure prophylaxis, supporting its use in post-exposure prophylaxis.
Zhijie Cui, Lianfu Wang, Zhiyuan Ran et al.· Frontiers in Public Health· 0 citations
