ABSTRACT
Human papillomavirus (HPV) vaccination is central to preventing cervical and other HPV-associated cancers. Although clinical trials have established favorable safety profiles, long-term, brand-specific real-world data remain limited. We evaluated adverse events (AEs) reported to the U.S. Vaccine Adverse Event Reporting System (VAERS) for Cervarix® (bivalent), Gardasil® (quadrivalent), and Gardasil-9® (9-valent) between January 2006 and December 2024. Domestic VAERS reports listing ≥1 HPV vaccine were extracted, deduplicated, and classified by brand. Disproportionality analyses were performed using reporting odds ratios (RORs) and 95% confidence intervals (CIs), adjusting for multiplicity with a 5% Benjamini – Hochberg false discovery rate (FDR). Time-to-onset was assessed with Kaplan–Meier analysis. This analysis of 76,575 HPV vaccine adverse event reports shows improving safety profiles across vaccine generations. Serious adverse events decreased significantly from Cervarix® (33.4%) to Gardasil® (16.2%) to Gardasil-9® (7.8%). The most common signals were presyncope for Cervarix® (ROR 11.5) and administration errors for Gardasil® and Gardasil-9®, including inappropriate scheduling (ROR 19.5) and incorrect storage (ROR 12.1). Most adverse events (82.9%) occurred within 7 d post-vaccination, with 62.5% occurring on the same day. Gardasil-9® exhibited the narrowest IQR for time to onset (0–1 d), compared to other HPV vaccines. HPV vaccines demonstrate a consistent, favorable safety profile in U.S. real-world practice. Most reported AEs were acute vasovagal reactions, and strongest signals reflected preventable errors. Strengthening provider education in cold-chain management and schedule adherence may further enhance vaccine safety. Continued active surveillance is recommended.
KEYWORDS: Human papillomavirus vaccines, vaccine safety, pharmacovigilance, VAERS, real-world evidence
Introduction
Infection with high-risk human papillomavirus (HPV) types is a necessary cause of nearly all cervical cancers and contributes substantially to the burden of anogenital and oropharyngeal malignancies.1 In 2020, an estimated 604,000 new cases of cervical cancer and 342,000 related deaths occurred globally, with over 90% cases arising in low- and middle-income countries.2 In response, the World Health Organization (WHO) has set a 2030 goal of achieving 90% HPV vaccination coverage among girls to accelerate elimination efforts.3
In the United States, three prophylactic HPV vaccines have been licensed: quadrivalent Gardasil® (2006), bivalent Cervarix® (2009), and 9-valent Gardasil-9® (2014). Each demonstrated greater than 90% efficacy against vaccine-type high-grade cervical lesions in phase 3 clinical trials.4–6 Since 2006, more than 135 million doses have been distributed nationwide.7 Vaccination recommendations have expanded to include males8 and, more recently, adults up to 45 y of age through shared clinical decision-making.9 The widespread use of these vaccines underscores the need for ongoing, robust post-marketing pharmacovigilance.
The Vaccine Adverse Event Reporting System (VAERS), jointly managed by the Centers for Disease Control and Prevention (CDC) and the Food and Drug Administration (FDA), serves as a passive surveillance system to generate early safety signals. Initial VAERS analyses identified syncope as the predominant acute adverse event following HPV vaccination and found no unexpected serious risks.10 However, earlier evaluations were constrained by shorter follow-up periods and did not fully capture Gardasil-9‘s safety profile across its entire marketing duration. Furthermore, the temporal distribution of symptom onset – a critical factor for biological plausibility – remains insufficiently characterized.
In this study, using 18 y of VAERS data, we aimed to (i) describe longitudinal reporting trends; (ii) compare demographic and seriousness profiles across vaccine brands; (iii) detect disproportionality signals with false discovery rate (FDR) adjustment; and (iv) evaluate time-to-onset distributions.
Methods
Data source
Publicly available data from the Vaccine Adverse Event Reporting System (VAERS; 2025 Q1 release) were downloaded for analysis. U.S. reports listing at least one HPV vaccine code were retained. VAERS accepts reports of adverse events following vaccination, including administration errors such as storage failures or scheduling deviations, as these represent preventable events that may affect vaccine safety or effectiveness.11
Duplicate case IDs were resolved by preserving the most complete record based on field completeness and clinical relevance. Reports flagged as foreign were excluded.
Case definitions
Vaccines were categorized as Cervarix® (bivalent, code HPV2), Gardasil® (quadrivalent, code HPV4), or Gardasil-9® (9-valent, code HPV9). Serious adverse events were defined according to the U.S. Food and Drug Administration (FDA) MedWatch criteria, including death, life-threatening illness, initial or prolonged hospitalization, permanent disability, or congenital anomaly.12 All percentages in descriptive analyses were calculated relative to the total number of reports for each specific vaccine brand to enable meaningful cross-brand comparisons.
Statistical analysis
Descriptive statistics were used to summarize annual reporting counts, sex distribution, age groups (0–8, 9–26, 27–45, and ≥46 y), and seriousness classification. Disproportionality analyses were performed using 2 × 2 contingency tables comparing each HPV vaccine brand against all other vaccines in the VAERS database. Complete methodological details are provided in Supplementary Table S1. Reporting odds ratios (RORs) and 95% confidence intervals (CIs) were calculated using the Woolf method. A signal was defined as requiring at least three reports and a lower limit of the 95% CI greater than 1.13,14 The false discovery rate (FDR) was controlled at 5% using the Benjamini–Hochberg procedure. Kaplan–Meier curves were generated to illustrate time-to-symptom-onset distributions, with differences assessed using the chi-square (χ2) test for trend. Percentages for demographic and severity outcomes were calculated using vaccine-specific denominators to account for the varying number of reports across brands.
Software
All analyses were performed using R software (version 4.4.2; Copyright (C) 2024 The R Foundation for Statistical Computing), utilizing the tidyverse, epitools, survival, and ggplot2 packages.
Results
Descriptive overview
From January 1, 2006, to December 31, 2024, a total of 76,575 HPV vaccine adverse event (AE) reports met the inclusion criteria: Cervarix® accounted for 5,004 reports (6.5%), Gardasil® for 47,539 reports (62.1%), and Gardasil-9® for 24,032 (31.4%). The annual number of reports peaked in 2008 for Gardasil, 2010 for Cervarix, and 2021 for Gardasil-9, as illustrated in Figure 1. Overall, 68% of reports involved females, reflecting historic programmatic targeting. Among vaccines with known sex, Gardasil-9® exhibited the highest proportion of male reports (35.3%), compared to 11.1% for Gardasil® and 3.0% for Cervarix®. The 9–26 y age group comprised the majority of reports across all vaccines: 64.9% for Cervarix®, 68.8% for Gardasil®, and 57.1% for Gardasil-9®. The proportion of serious reports declined markedly across vaccine generations with 33.4% of Cervarix®, 16.2% of Gardasil®, and 7.8% of Gardasil-9® reports classified as serious events. Deaths were rare across all vaccines, totaling 504 cases (0.6% of all reports): 45 deaths (0.9%) for Cervarix®, 401 (0.8%) for Gardasil®, and 58 (0.2%) for Gardasil-9®. Table 1 presents the complete breakdown of reports by vaccine brand, age group, sex, and severity outcomes, with both absolute numbers and percentages to facilitate comparison. Importantly, disproportionality analysis revealed that death did not meet signal detection criteria for any HPV vaccine. The reporting odds ratios were all below 1.0: Cervarix® (ROR 0.43, 95% CI: 0.31–0.60), Gardasil® (ROR 0.70, 95% CI: 0.63–0.77), and Gardasil-9® (ROR 0.23, 95% CI: 0.17–0.31), indicating significantly lower proportional reporting of deaths following HPV vaccination compared to other vaccines in the database.
Figure 1.
Annual number of VAERS reports associated with Cervarix®, Gardasil®, and Gardasil-9® vaccination in the United States, 2006–2024.
Bars represent the annual number of adverse event reports for each HPV vaccine brand submitted to the Vaccine Adverse Event Reporting System (VAERS). Colors denote vaccine brands: purple for Gardasil®, green for Cervarix®, and orange for Gardasil-9®.
Table 1.
Severity outcomes stratified by age group and sex following Cervarix®, Gardasil®, and Gardasil-9® vaccination in the United States, 2006–2024.
| Vaccine (n, % of HPV) |
Age Group | Sex | Events Reported (n, % of brand) | Serious (n, % of brand) | Deaths (n, % of brand) |
|---|---|---|---|---|---|
| Cervarix® (5004; 6.5%) | – | – | 5004 (100.0%) | 1668 (33.3%) | 45 (0.9%) |
| ≥46 y | F | 20 (0.4%) | 4 (0.1%) | 0 (0.0%) | |
| M | 1 (0.0%) | 1 (0.0%) | 0 (0.0%) | ||
| 27–45 y | F | 200 (4.0%) | 81 (1.6%) | 6 (0.1%) | |
| M | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | ||
| U | 10 (0.2%) | 2 (0.0%) | 0 (0.0%) | ||
| 9–26 y | F | 3139 (62.7%) | 977 (19.5%) | 14 (0.3%) | |
| M | 82 (1.6%) | 14 (0.3%) | 0 (0.0%) | ||
| U | 34 (0.7%) | 17 (0.3%) | 0 (0.0%) | ||
| 0–8 y | F | 6 (0.1%) | 3 (0.1%) | 0 (0.0%) | |
| M | 2 (0.0%) | 2 (0.0%) | 0 (0.0%) | ||
| U | 1 (0.0%) | 0 (0.0%) | 0 (0.0%) | ||
| Unknown | F | 1347 (26.9%) | 516 (10.3%) | 18 (0.4%) | |
| M | 60 (1.2%) | 24 (0.5%) | 3 (0.1%) | ||
| U | 102 (2.0%) | 27 (0.5%) | 4 (0.1%) | ||
| Gardasil® (47539; 62.1%) |
– | – | 47539 (100.0%) | 7709 (16.2%) | 401 (0.8%) |
| ≥46 y | F | 93 (0.2%) | 15 (0.03%) | 0 (0.0%) | |
| M | 40 (0.1%) | 3 (0.01%) | 0 (0.0%) | ||
| U | 7 (0.01%) | 1 (0.0%) | 0 (0.0%) | ||
| 27–45 y | F | 1239 (2.6%) | 411 (0.9%) | 2 (0.0%) | |
| M | 85 (0.2%) | 22 (0.05%) | 0 (0.0%) | ||
| U | 35 (0.1%) | 7 (0.01%) | 0 (0.0%) | ||
| 9–26 y | F | 28053 (59.0%) | 5439 (11.4%) | 131 (0.3%) | |
| M | 3761 (7.9%) | 324 (0.7%) | 18 (0.04%) | ||
| U | 885 (1.9%) | 52 (0.1%) | 7 (0.01%) | ||
| 0–8 y | F | 124 (0.3%) | 10 (0.02%) | 2 (0.0%) | |
| M | 81 (0.2%) | 4 (0.01%) | 0 (0.0%) | ||
| U | 80 (0.2%) | 2 (0.0%) | 2 (0.0%) | ||
| Unknown | F | 6716 (14.1%) | 1187 (2.5%) | 160 (0.3%) | |
| M | 572 (1.2%) | 70 (0.1%) | 11 (0.02%) | ||
| U | 5768 (12.1%) | 162 (0.3%) | 68 (0.1%) | ||
| Gardasil9® (24032; 31.4%) | – | – | 24032 (100.0%) | 1878 (7.8%) | 58 (0.2%) |
| ≥46 y | F | 136 (0.6%) | 12 (0.05%) | 0 (0.0%) | |
| M | 78 (0.3%) | 2 (0.01%) | 0 (0.0%) | ||
| U | 22 (0.1%) | 0 (0.0%) | 0 (0.0%) | ||
| 27–45 y | F | 998 (4.2%) | 144 (0.6%) | 0 (0.0%) | |
| M | 230 (1.0%) | 17 (0.07%) | 2 (0.01%) | ||
| U | 56 (0.2%) | 2 (0.01%) | 0 (0.0%) | ||
| 9–26 y | F | 7656 (31.9%) | 898 (3.7%) | 16 (0.07%) | |
| M | 4906 (20.4%) | 304 (1.3%) | 6 (0.02%) | ||
| U | 1150 (4.8%) | 14 (0.06%) | 0 (0.0%) | ||
| 0–8 y | F | 188 (0.8%) | 4 (0.02%) | 0 (0.0%) | |
| M | 163 (0.7%) | 0 (0.0%) | 0 (0.0%) | ||
| U | 175 (0.7%) | 0 (0.0%) | 0 (0.0%) | ||
| Unknown | F | 2359 (9.8%) | 370 (1.5%) | 21 (0.09%) | |
| M | 816 (3.4%) | 84 (0.35%) | 4 (0.02%) | ||
| U | 5099 (21.2%) | 27 (0.11%) | 9 (0.04%) | ||
| Total | – | – | 76575 (100.0%) | 11255 (14.7%) | 504 (0.6%) |
Abbreviations: F, female; M, male; U, unknown; AE, adverse event.
Note: Data represent reported adverse events following HPV vaccination stratified by vaccine brand, age group, and sex. Serious events were defined according to U.S. Food and Drug Administration criteria, including death, life-threatening illness, hospitalization, permanent disability, or congenital anomaly.
Disproportionality signals
After false discovery rate (FDR) adjustment, a total of 218 preferred terms (PTs) from the Medical Dictionary for Regulatory Activities (MedDRA) met the predefined signal detection criteria. For Cervarix®, vasovagal-related events predominated, with presyncope emerging as the top signal (reporting odds ratio [ROR]: 11.5; 95% confidence interval [CI]: 10.5–12.7).
In contrast, Gardasil® and Gardasil-9® were primarily associated with administration-related errors. The strongest signals included inappropriate schedule adherence (ROR: 19.5; 95% CI: 18.6–20.4) and improper storage (ROR: 12.1; 95% CI: 11.6–12.6), as illustrated by the top 20 disproportionality signals for each vaccine brand (Figures 2–4). These administration errors are reportable to VAERS as preventable events that may compromise vaccine effectiveness or patient safety – for example, improper storage can reduce immunogenicity, while inappropriate scheduling may result in suboptimal protection or unnecessary revaccination. Notably, no neurological or autoimmune PTs – including Guillain–Barré syndrome15,16 and demyelinating diseases,17,18 which have been identified as potential concerns in previous research – surpassed the signal detection threshold in this analysis. These findings reinforce the favorable long-term safety profile of HPV vaccines under real-world conditions. Similarly, mortality analysis demonstrated no safety signal, with death reports occurring less frequently for HPV vaccines than for other vaccines in VAERS (combined ROR 0.70, 95% CI: 0.65–0.76).
Figure 2.
Top 20 disproportionality signals for Cervarix® identified in the vaccine adverse event reporting System (VAERS), United States, 2006–2024.
Forest plot showing the reporting odds ratio (ROR) and 95% confidence intervals (CIs) for the top 20 preferred terms (PTs) associated with Cervarix® adverse event reports submitted to VAERS. The vertical dashed line indicates the null value (ROR = 1). Data points to the right of the line represent higher reporting frequency compared to other vaccines. The number of reports (N) for each PT is indicated in the second column.
Figure 3.
Top 20 disproportionality signals for Gardasil® identified in the vaccine adverse event reporting System (VAERS), United States, 2006–2024.
Forest plot showing the reporting odds ratio (ROR) and 95% confidence intervals (CIs) for the top 20 preferred terms (PTs) associated with Gardasil® adverse event reports submitted to VAERS. The vertical dashed line indicates the null value (ROR = 1). Data points to the right of the line represent a higher reporting frequency compared to other vaccines. The number of reports (N) for each PT is shown in the second column.
Figure 4.
Top 20 disproportionality signals for Gardasil-9® identified in the vaccine adverse event reporting System (VAERS), United States, 2006–2024.
Forest plot showing the reporting odds ratio (ROR) and 95% confidence intervals (CIs) for the top 20 preferred terms (PTs) associated with Gardasil-9® adverse event reports submitted to VAERS. The vertical dashed line represents the null value (ROR = 1). Points to the right of the line indicate a higher reporting frequency compared to other vaccines. The number of reports (N) for each PT is shown in the second column.
The overall landscape of disproportionality signals is illustrated in the volcano plot (Figure 5), which displays the strength and significance of associations across the top 100 preferred terms (PTs) identified in VAERS reports.
Figure 5.
Volcano plot of top 100 disproportionality signals for HPV vaccines reported to VAERS, United States, 2006–2024.
Each point represents a preferred term (PT) from the Medical Dictionary for Regulatory Activities (MedDRA). The x-axis shows the log2-transformed reporting odds ratio (ROR), and the y-axis displays the -log10(FDR-adjusted p-value). The color gradient indicates the number of reports associated with each PT.
Time-to-onset analysis
Among 51,436 reports with valid onset dates, the median time to symptom onset was 0 d for all vaccine brands (overall IQR 0–2; see Figure 6(a)), reflecting the acute nature of most reported events. The interquartile range (IQR) further underscores this pattern, with Cervarix® exhibiting an IQR of 0–7 d, Gardasil® 0–3 d, and Gardasil-9® 0–1 d, indicating progressively narrower time distributions with successive vaccine generations. Cumulative incidence curves depicting these time-to-onset distributions are presented in Figure 6(a) (overall), and separately in Figures 6(b) (Cervarix®), Figure 6(c) (Gardasil®), and Figure 6(d) (Gardasil-9®). Stratified analysis by event seriousness revealed important temporal differences, with serious events showing a delayed onset pattern (median 5 d, IQR 0–44) compared to all events (median 0 d, IQR 0–2), as illustrated in Figure 6(e).
Figure 6a.
Time-to-onset distribution of adverse events following HPV vaccination in the United States, 2006–2024.
Kaplan–Meier curve illustrating the cumulative incidence of adverse events following HPV vaccination, based on reports submitted to the Vaccine Adverse Event Reporting System (VAERS).
The x-axis shows time to symptom onset in days, and the y-axis shows the cumulative incidence percentage.
The median time to onset was 0 d (interquartile range [IQR]: 0–2 d). The table below the plot indicates the number of individuals at risk at each time interval.
Figure 6b.
Time-to-onset distribution of adverse events following Cervarix® vaccination in the United States, 2006–2024.
Kaplan–Meier curve illustrating the cumulative incidence of adverse events following Cervarix® vaccination, based on reports submitted to the Vaccine Adverse Event Reporting System (VAERS).
The x-axis shows time to symptom onset in days, and the y-axis shows the cumulative incidence percentage.
The median time to onset was 0 d (interquartile range [IQR]: 0–7 d). The table below the plot indicates the number of individuals at risk at each time interval.
Figure 6c.
Time-to-onset distribution of adverse events following Gardasil® vaccination in the United States, 2006–2024.
Kaplan–Meier curve illustrating the cumulative incidence of adverse events following Gardasil® vaccination, based on reports submitted to the Vaccine Adverse Event Reporting System (VAERS). The x-axis represents time to symptom onset (days), and the y-axis represents cumulative incidence (%). The median time to onset was 0 d (interquartile range [IQR]: 0–3 d). The table below the plot displays the number of individuals remaining at risk at specified time points.
Figure 6d.
Time-to-onset distribution of adverse events following Gardasil-9® vaccination in the United States, 2006–2024.
Kaplan–Meier curve depicting the cumulative incidence of adverse events following Gardasil-9® vaccination, based on data from the Vaccine Adverse Event Reporting System (VAERS). The x-axis shows time to symptom onset (days), and the y-axis shows cumulative incidence (%). The median time to onset was 0 d (interquartile range [IQR]: 0–1 d). The table beneath the plot displays the number of individuals remaining at risk over specified time intervals.
Figure 6e.
Time-to-onset distribution of serious adverse events following HPV vaccination in the United States, 2006–2024.
Kaplan–Meier curve depicting the cumulative incidence of serious adverse events following HPV vaccination, based on data from the Vaccine Adverse Event Reporting System (VAERS). The x-axis shows time to symptom onset (days), and the y-axis shows cumulative incidence (%). The median time to onset was 5 d (interquartile range [IQR]: 0–44 d). The table beneath the plot displays the number of individuals remaining at risk over specified time intervals.
A detailed breakdown of symptom onset times across 10 predefined intervals is presented in Figure 7. The analysis revealed that 62.5% (n = 32,692) of events occurred on the vaccination day, 20.4% (n = 10,703) within 1–7 d, and 6.3% (n = 3,287) within 8–30 d. Overall, 82.9% of all adverse events occurred within the first week, and 89.2% within the first 30 d following vaccination. Events beyond 180 d post-vaccination represented only 4.2% (n = 2,212) of all reports, emphasizing the predominantly acute nature of reported adverse events.
Figure 7.
Time distribution of adverse event reporting following HPV vaccination in the United States, 2006–2024.
Time-to-onset distribution showing percentage (left) and absolute numbers (right) across 10 intervals: 0 d (vaccination day), 1–7 d, 8–30 d, 31–60 d, 61–90 d, 91–120 d, 121–150 d, 151–180 d, 181–360 d, and >360 d. This stratification, based on established immunological response timelines and pharmacovigilance best practices, allows differentiation between immediate hypersensitivity reactions, early immune responses, and delayed phenomena. Results show 82.9% events occurred within the first week, with 62.5% on vaccination day, demonstrating the predominantly acute nature of HPV vaccine adverse events.
Discussion
Principal findings
This 18-y national analysis reaffirms the favorable and consistent safety profile of HPV vaccines under real-world conditions in the United States. Most reported adverse events were non-serious and consisted predominantly of immediate vasovagal reactions. Serious outcomes became progressively rarer across successive vaccine generations. The progressive improvement in safety profiles across vaccine generations – from 33.3% serious reports for Cervarix® to 7.8% for Gardasil-9® – likely reflects both enhanced vaccine formulation and improved provider familiarity with vaccine administration and adverse event management. The refined temporal analysis revealed that the vast majority of adverse events (82.9%) occurred within the first week post-vaccination, with immediate same-day reactions comprising 62.5% of all reports. This temporal distribution strongly supports the biological plausibility of acute vaccine-related adverse events and reinforces the importance of immediate post-vaccination observation periods.
These findings align with phase 3 clinical trial data, underscoring the durability of the vaccines’ safety profile beyond controlled trial settings and across diverse, real-world populations. The most disproportionate preferred terms (PTs) for Gardasil® and Gardasil-9® were related to vaccination-process errors, suggesting that targeted provider training focused on schedule adherence and cold-chain management could substantially reduce preventable incident reports.
Consistency with the literature
Our findings are consistent with early post-licensure evaluations10,19,20 and align with extensive evidence from large-scale active surveillance systems. The landmark Denmark-Sweden registry study by Arnheim-Dahlström et al.21 followed 997,585 girls aged 10–17 y, including 296,826 who received 696,420 doses of quadrivalent HPV vaccine between 2006–2010. Using nationwide health registries and applying stringent signal-strengthening criteria, the investigators found no consistent evidence of causal associations with autoimmune, neurological, or venous thromboembolic adverse events.
Similarly, multiple analyses from the US Vaccine Safety Datalink (VSD) have corroborated our passive surveillance findings. Gee et al.16 conducted a self-controlled case series examining Guillain–Barré syndrome risk following 1.4 million HPV vaccine doses administered between 2006–2015, demonstrating no increased risk (rate ratio 0.94, 95% CI 0.28–3.19). Klein et al.22 employed rapid cycle analysis to monitor 189,629 HPV vaccine doses for multiple prespecified outcomes, identifying no safety signals after rigorous sequential testing. Most recently, Donahue et al.19 evaluated 838,991 doses of 9-valent HPV vaccine using near real-time sequential monitoring, finding no new safety concerns and reinforcing the vaccine’s favorable safety profile.
The convergence between our VAERS disproportionality analysis – which found no neurological or autoimmune signals – and these large registry-based cohort studies is particularly reassuring. Scheller et al.17 analyzed a combined Danish-Swedish cohort of nearly 4 million females, finding no association between quadrivalent HPV vaccination and demyelinating diseases of the central nervous system. A recent WHO VigiBase® global pharmacovigilance analysis23 similarly identified syncope and vasovagal reactions as the most frequently reported events, without detecting new serious risks.
Furthermore, by extending surveillance through 2024 and incorporating Gardasil-9® into the analysis, this study provides new insights covering the complete post-approval lifecycle of all licensed HPV vaccines. These findings complement extended VSD cohort studies, including Sundaram et al.‘s evaluation of over 600,000 doses of 9-valent HPV vaccine, which reported similar safety outcomes without signal detection for serious events.24 Together, these passive and active surveillance approaches provide the most comprehensive safety evidence base for HPV vaccines to date.
Public health implications
Given the predominance of preventable administration errors and acute vasovagal reactions among reported adverse events, maintaining a 15-minute observation period following HPV vaccination and reinforcing provider training on cold-chain management and schedule adherence remain critical. Administration errors are captured in VAERS because they represent preventable events that can impact vaccine effectiveness (e.g., vaccines exposed to improper temperatures may have reduced immunogenicity) or lead to patient harm (e.g., incorrect dosing intervals may compromise immune response), even when immediate adverse health events are not observed. These interventions could significantly reduce preventable harms, lower the incidence of vaccine-related reports, and sustain public confidence in immunization programs.
Moreover, the integration of real-time active surveillance systems, enhanced interoperability between immunization registries and electronic health records, and continued global pharmacovigilance initiatives are essential to ensure early detection of rare safety signals while preserving high vaccine uptake. Sustaining public trust is crucial to achieving and maintaining WHO’s global cervical cancer elimination goals.
Strengths and limitations
Strengths of this study include the analysis of the largest HPV vaccine adverse event dataset to date, brand-specific comparisons within a consistent national surveillance system, and rigorous signal detection with false discovery rate (FDR) control. These methodological strengths enhance the reliability and comprehensiveness of the findings.
However, limitations inherent to passive reporting systems must be acknowledged. These include underreporting, stimulated reporting, absence of reliable denominator data, and variable completeness of clinical information. The ROR quantifies reporting disproportionality but does not establish causality; findings should therefore be interpreted with caution. The comparison against all vaccines in VAERS, without age stratification, may introduce confounding from vaccines with different age indications (e.g., zoster vaccines for older adults vs. pediatric vaccines). However, this approach follows standard pharmacovigilance methodology and maximizes statistical power for signal detection. Active surveillance studies are necessary to estimate true incidence rates and to validate or refute potential rare safety signals. These limitations must be carefully considered when interpreting results and formulating public health recommendations.
Conclusions
Eighteen years of national surveillance reaffirm the favorable and consistent safety profile of Cervarix®, Gardasil®, and Gardasil-9® under routine clinical practice in the United States. Most reported adverse events were mild and acute vasovagal reactions, with no new serious safety concerns identified.
Strengthening provider education on vaccine storage protocols and schedule adherence could further enhance vaccination program safety and efficiency. Continued pharmacovigilance efforts remain critical to maintaining public trust and supporting high HPV vaccination coverage.
Supplementary Material
Acknowledgments
The authors sincerely thank the U.S. Vaccine Adverse Event Reporting System (VAERS) team, the Centers for Disease Control and Prevention (CDC), and the Food and Drug Administration (FDA) for providing access to the publicly available surveillance data used in this study.
We are also grateful to our colleagues at the Fujian Institute for Food and Drug Quality Control and Xiamen Haicang Hospital for their valuable support and encouragement throughout the project.
Special thanks to the editorial assistance team for their guidance in manuscript preparation.
Biography
Honghong Fu holds a Master’s degree in Medicinal Chemistry from Capital Medical University. She has over 10 y of experience at the Fujian Institute for Food and Drug Quality Control, affiliated with the Fujian Medical Products Administration. Her work focuses on the lot release and quality control of biological products, with particular emphasis on human papillomavirus (HPV) vaccines. She was seconded to the National Institutes for Food and Drug Control (NIFDC) in Beijing, where she contributed to national COVID-19 vaccine quality testing and participated in the evaluation of HPV vaccines, including imported quadrivalent Gardasil®, bivalent Cervarix®, and 9-valent Gardasil-9®. Additionally, she was appointed by the Fujian Medical Products Administration to serve for 1 y as an on-site inspector at Xiamen Innovax Biotech Co., Ltd., where she oversaw vaccine manufacturing processes and regulatory compliance. Ms. Fu’s expertise spans laboratory quality control, regulatory inspection, and post-marketing surveillance of biologics. Her work supports national vaccine safety assurance and evidence-based regulatory decision-making in China.
Funding Statement
The author(s) reported there is no funding associated with the work featured in this article.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Ethical approval statement
This study utilized de-identified, publicly available data and did not require institutional review board approval.
Supplementary Information
Supplemental data for this article can be accessed online at https://doi.org/10.1080/21645515.2025.2539590
References
- 1.Moody CA, Laimins LA.. Human papillomavirus oncoproteins: pathways to transformation. Nat Rev Cancer. 2010;10(8):550–14. doi: 10.1038/nrc2886. [DOI] [PubMed] [Google Scholar]
- 2.Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–249. doi: 10.3322/caac.21660. [DOI] [PubMed] [Google Scholar]
- 3.World Health Organization . Global strategy to accelerate the elimination of cervical cancer as a public health problem [Internet]. Geneva: World Health Organization; 2020. [accessed 2025 Apr 22]. https://www.who.int/publications/i/item/9789240014107. [Google Scholar]
- 4.Luna J, Plata M, Gonzalez M, Correa A, Maldonado I, Nossa C, Radley D, Vuocolo S, Haupt RM, Saah A, et al. Long-term follow-up observation of the safety, immunogenicity, and effectiveness of Gardasil™ in adult women. PLOS ONE. 2013;8(12):e83431. doi: 10.1371/journal.pone.0083431. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Paavonen J, Jenkins D, Bosch FX, Naud P, Salmerón J, Wheeler CM, Chow S-N, Apter DL, Kitchener HC, Castellsague X, et al. Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial. Lancet. 2007;369(9580):2161–2170. doi: 10.1016/S0140-6736(07)60946-5. [DOI] [PubMed] [Google Scholar]
- 6.Huh WK, Joura EA, Giuliano AR, Iversen OE, de Andrade RP, Ault KA, Bartholomew D, Cestero RM, Fedrizzi EN, Hirschberg AL, et al. Final efficacy, immunogenicity, and safety analyses of a nine-valent human papillomavirus vaccine in women aged 16–26 y: a randomised, double-blind trial. Lancet. 2017;390(10108):1653–1663. doi: 10.1016/S0140-6736(17)31821-4. [DOI] [PubMed] [Google Scholar]
- 7.Centers for Disease Control and Prevention . HPV vaccination: what everyone should know [Internet]. Atlanta: Centers for Disease Control and Prevention; 2022. [accessed 2025 Apr 22]. https://www.cdc.gov/vaccines/vpd/hpv/public/index.html. [Google Scholar]
- 8.Centers for Disease Control and Prevention (CDC) . Recommendations on the use of quadrivalent human papillomavirus vaccine in males: advisory committee on immunization practices (ACIP), 2011. MMWR Morb Mortal Wkly Rep. 2011;60(50):1705–1708. [PubMed] [Google Scholar]
- 9.Meites E, Szilagyi PG, Chesson HW, Unger ER, Romero JR, Markowitz LE. Human papillomavirus vaccination for adults: updated recommendations of the advisory committee on immunization practices. MMWR Morb Mortal Wkly Rep. 2019;68(32):698–702. doi: 10.15585/mmwr.mm6832a3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Slade BA, Leidel L, Vellozzi C, Woo EJ, Hua W, Sutherland A, et al. Postlicensure safety surveillance for quadrivalent human papillomavirus recombinant vaccine. JAMA. 2009;302(7):750–757. doi: 10.1001/jama.2009.1201. [DOI] [PubMed] [Google Scholar]
- 11.Hibbs BF, Moro PL, Lewis P, Miller ER, Shimabukuro TT. Vaccination errors reported to the vaccine adverse event reporting system (VAERS), United States, 2000–2013. Vaccine. 2015;33(28):3171–3178. doi: 10.1016/j.vaccine.2015.05.006. [DOI] [PubMed] [Google Scholar]
- 12.Piazza-Hepp TD, Kennedy DL. Reporting of adverse events to MedWatch. Am J Health Syst Pharm. 1995;52(13):1436–1439. doi: 10.1093/ajhp/52.13.1436. [DOI] [PubMed] [Google Scholar]
- 13.van Puijenbroek EP, Bate A, Leufkens HG, Lindquist M, Orre R, Egberts AC. A comparison of measures of disproportionality for signal detection in spontaneous reporting systems for adverse drug reactions. Pharmacoepidemiol Drug Saf. 2002;11(1):3–10. doi: 10.1002/pds.668. [DOI] [PubMed] [Google Scholar]
- 14.Ahmed I, Thiessard F, Miremont-Salamé G, Bégaud B, Tubert-Bitter P. Pharmacovigilance data mining with methods based on false discovery rates: a comparative simulation study. Clin Pharmacol Ther. 2010;88(4):492–499. doi: 10.1038/clpt.2010.111. [DOI] [PubMed] [Google Scholar]
- 15.Andrews N, Stowe J, Miller E. No increased risk of Guillain–Barré syndrome after human papilloma virus vaccine: a self-controlled case-series study in England. Vaccine. 2017;35(13):1729–1732. doi: 10.1016/j.vaccine.2017.02.045. [DOI] [PubMed] [Google Scholar]
- 16.Gee J, Weinbaum C, Sukumaran L, Markowitz L. Risk of Guillain–Barré syndrome following quadrivalent human papillomavirus vaccine in the vaccine safety datalink. Vaccine. 2017;35(43):5756–5758. doi: 10.1016/j.vaccine.2017.08.077. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Scheller NM, Svanström H, Pasternak B, Arnheim-Dahlström L, Sundström K, Fink K, Hviid A. Quadrivalent HPV vaccination and risk of multiple sclerosis and other demyelinating diseases of the central nervous system. JAMA. 2015;313(1):54–61. doi: 10.1001/jama.2014.16946. [DOI] [PubMed] [Google Scholar]
- 18.Mouchet J, Salvo F, Raschi E, Poluzzi E, Antonazzo IC, De Ponti F, Bégaud B. Human papillomavirus vaccine and demyelinating diseases: a systematic review and meta-analysis. Pharmacol Res. 2018;132:108–118. doi: 10.1016/j.phrs.2018.04.002. [DOI] [PubMed] [Google Scholar]
- 19.Donahue JG, Kieke BA, King JP, Mascola MA, Shimabukuro TT, Gee J, Vickers ER, Gee J, Daley MF, DeStefano F, et al. Safety of the 9-valent human papillomavirus vaccine. Pediatrics. 2019;144(6):e20191791. doi: 10.1542/peds.2019-1791. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Moro PL, Arana J, Cano M, Lewis P, Harrington T, Yue X, Stewart B, Markowitz LE, Shimabukuro TT. Safety of bivalent human papillomavirus vaccine in the U.S. Vaccine adverse event reporting system (VAERS), 2009–2017. Vaccine. 2018;36(52):8035–8040. doi: 10.1016/j.vaccine.2018.11.033. [DOI] [Google Scholar]
- 21.Arnheim-Dahlström L, Pasternak B, Svanström H, Sparén P, Hviid A. Autoimmune, neurological, and venous thromboembolic adverse events after immunisation of adolescent girls with quadrivalent human papillomavirus vaccine in Denmark and Sweden: cohort study. BMJ. 2013;347:f5906. doi: 10.1136/bmj.f5906. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Klein NP, Hansen J, Chao C, Velicer C, Sy LS, Slezak J, Lewis N, Deosaransingh K, Sy L, Ackerson B, et al. Safety of the quadrivalent human papillomavirus vaccine administered routinely to females. Arch Pediatr Adolesc Med. 2012;166(12):1140–1148. doi: 10.1001/archpediatrics.2012.1451. [DOI] [PubMed] [Google Scholar]
- 23.Chandler RE, Juhlin K, Fransson J, Caster O, Edwards IR, Norén GN. Current safety concerns with human papillomavirus vaccine: a cluster analysis of reports in VigiBase®. Drug Saf. 2017;40(11):1049–1060. doi: 10.1007/s40264-016-0456-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Sundaram ME, Kieke BA, Hanson KE, Belongia EA, Weintraub ES, Daley MF, Hechter RC, Klein NP, Lewis EM, Naleway AL, et al. Extended surveillance to assess safety of 9-valent human papillomavirus vaccine. Hum Vaccin Immunother. 2022;18(7):2159215. doi: 10.1080/21645515.2022.2159215. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.