Real-world safety data of human papillomavirus vaccines after marketing in Shandong, China, August 2017–October 2025

ABSTRACT

After the Human papillomavirus (HPV) vaccine was listed for use in China in 2017, it has proven to be a safe and cost-effective method for preventing HPV infection. With the increase in vaccination volume, its safety is becoming increasingly important. The safety data from post-marketing can enhance public confidence in vaccines. We collected adverse events following immunization (AEFI) through the Chinese National AEFI Information Management System (CNAEFIs) between August 2017 and October 2025. Vaccination data from the same period were obtained via the Shandong Provincial Immunization Program Information Systems (SDIPIs). A Univariate Poisson regression model was used to explore risk factors associated with HPV vaccine AEFI. Disproportionality analysis was performed to detect abnormal signals related to the HPV vaccine. From August 2017 to October 2025 in Shandong, CNAEFIs received 1056 AEFI cases, with an overall reporting AEFI rate of 7.99 per 100,000 doses. 1008 cases (95.46%) were mild vaccine-related reactions, and 15 cases (1.42%) were rare adverse reactions. Myalgia, induration with a diameter greater than 5 cm, immune thrombocytopenia, and mild reactions such as fatigue, drowsiness, dizziness, and headache were detected as abnormal signals. The reporting AEFI rate of the HPV vaccine in Shandong was low, and the majority of AEFIs were mild cases. The safety profile in post-marketing was good.

Introduction

The Human papillomavirus (HPV) is one of the most widespread sexually transmitted infections globally and is a major cause of several cancers.¹ More than 200 genotypes of HPV,² categorized as low-risk and high-risk genotypes, have been described. Most HPV infections are asymptomatic and clear spontaneously, but persistent HPV infection may lead to the development of diseases,³ among which is persistent infection with high-risk types (including HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, etc.) causes almost all cervical cancers and a substantial proportion of anal, vulvar, penile, and oropharyngeal cancers.⁴ Low-risk types primarily include HPV6 and 11, which can cause skin warts, genital condyloma acuminatum, anal warts, and similar conditions. HPV infection leading to cervical cancer is a common malignant tumor in women, which remains a major public health problem, ranking as the fourth most common cause of cancer incidence and mortality in women worldwide.⁵ HPV vaccination is a proven, safe, and cost-effective method for preventing infection and related diseases in both sexes.⁶ A meta-regression analysis of HPV health economics across 195 countries showed that, globally in 2017, the incremental cost-effectiveness ratio (ICER) for HPV vaccination was 4,217$ per disability-adjusted life year (DALY).⁷ A modeling study in China showed that two-dose routine HPV vaccination of 14-y-olds would be the optimal, cost-saving strategy for a national program (net cost saving: $15 164 million–$22 034 million, return on investment: 7–14, depending on vaccine type).⁸

Since introducing two-valent HPV vaccine (adsorbed) in 2016, China has gradually rolled out four-valent HPV vaccines (S. cerevisiae) and nine-valent HPV vaccine (S. cerevisiae). Among domestically developed HPV vaccines, the E. coli-expressed two-valent HPV vaccine received marketing approval in 2019, the Pichia pastoris-expressed two-valent HPV vaccine in 2022, and the E. coli-expressed nine-valent HPV vaccine in 2025. Since August 2017, residents in Shandong Province have been able to receive HPV vaccination on a self-pay basis. In 2021, some cities began to offer free vaccination of the domestically produced two-valent HPV vaccine to new female junior high school students as a public welfare project. By 2024, this program was expanded to cover all newly enrolled junior high school girls across the entire province. On 10th November, 2025, China included domestic 2vHPV in its national immunization plan. With the increasing variety of vaccines and the gradual increase in vaccination volume, their safety has received attention. Although clinical trials consistently demonstrate a favorable safety profile. A survey in Norway released that children and adolescents had lower confidence on vaccine safety than effectiveness.⁹ Analyzing this large-scale provincial data in Shandong, China, offers a critical opportunity to reassure public confidence. This study sought to answer the following research questions: (1) To characterize the epidemiological distribution and clinical manifestations of adverse events following immunization (AEFI) reported with HPV vaccines; (2) To compare the AEFI reporting rates between different vaccine types, different systems, and different dose numbers; (3) To detect abnormal signals related to the HPV vaccine. The study aimed to characterize the real-world safety profile of HPV vaccines after marketing based on provincial passive immunization adverse event surveillance data to provide safety evidence for ensuring the smooth implementation of HPV vaccination after its inclusion in the national immunization program.

Methods

Study design and setting

This retrospective study was conducted using AEFI data from Shandong, China, August 2017 to October 2025. Shandong Province was purposively selected as the study setting for three primary reasons. First, AEFI surveillance in China follows a jurisdiction-based management framework, and provincial researchers are only authorized to access AEFI individual records within their own administrative region. Second, Shandong has one of the highest numbers of HPV vaccine doses administered in China, with over 13 million doses administered during the study period, providing a sufficiently large sample size for detecting rare adverse events. Third, the province has maintained a well-established, digitized AEFI surveillance system with consistently high reporting sensitivity (>90% completeness and timeliness) since 2015, thereby minimizing under-reporting bias.

Data sources

The Chinese National AEFI Information Systems (CNAEFIs) is a passive system collecting AEFI cases nationwide, and each region can only manage individual cases within its jurisdiction. The data from CNAEFIs include variables such as vaccine name, age, date of vaccination, manufacturer, symptom, and so on. This system is equipped with a multi-layered quality control framework, such as daily data review by the CDC, monthly data analysis, and key variables set as mandatory fields in the platform’s data entry system to ensure complete ascertainment of the matching variables. Data on AEFI cases (August 2017 to October 2025) associated with the HPV vaccine in Shandong were collected through CNAEFIs. HPV vaccination data during the same period were collected through the Shandong Provincial Immunization Program Information Systems (SDIPIs).

Vaccines and immunization schedule

HPV vaccines are divided into three types according to valency. 2vHPV (adsorbed, E. coli, and P. pastoris), 4vHPV (S. cerevisiae), and 9vHPV (S. cerevisiae and E. coli). The starting age for all vaccines is 9 y old, except that the upper age limit for vaccination with 2vHPV (P. pastoris) is 30 y old, the upper age limit for the others is 45 y old. The 4vHPV and 9vHPV (S. cerevisiae) were approved for male vaccination in 2025. For females aged 9–14 y, a two-dose schedule is adopted; for older females and males, a three-dose schedule is adopted.

AEFI classification and definitions

AEFI surveillance, reporting, and diagnosis followed the Chinese National AEFI Surveillance Guidelines.¹⁰ AEFI refers to suspected reactions or events related to vaccination that occur after vaccination. AEFI cases were categorized into five types: adverse reactions (including mild and rare reaction), psychogenic reactions, coincidental events, vaccine quality incidents, and vaccination accidents. Mild reaction refers to a reaction that occurs after vaccination, caused by the inherent characteristics of the vaccine itself, and only causes transient physiological dysfunction to the body. Mainly, they include symptoms such as fever and local redness, possibly accompanied by systemic discomfort, fatigue, loss of appetite, and other comprehensive symptoms. Rare reactions refer to reactions caused by a qualified vaccine during or after a standard vaccination process, which leads to damage to the body’s tissues, organs, and functions, with no fault from any party involved. Psychogenic reactions are those triggered by psychological or mental factors in the recipient after vaccination, unrelated to the vaccine ingredients. Coincidental event was defined as the recipient being in the latent or prodromal phase of a certain disease at the time of vaccination, and coincidentally develops symptoms after vaccination. Severe AEFI were defined as individuals who died, were in a life-threatening condition, required hospitalization or prolonged hospitalization, had significant disability or incapacity, had congenital anomaly or congenital disability, or the above situation occurs without intervention or treatment. An AEFI investigation expert group evaluated the causal relationship between incidents and vaccine.

Data analysis

Excel 2019 was used to establish a database, and R software (Version 4.5.3) was utilized for statistical analysis. The AEFI reporting rate was calculated as: AEFI rate (/100,000) = number of AEFI cases associated with HPV vaccine/number of HPV vaccination doses × 100,000. Between-group differences in AEFI reporting rates (by time period and region) and in the distribution of post-vaccination onset time intervals were evaluated using Fisher’s exact test, with statistical significance set at P < .05. A Univariate Poisson regression model was used to explore the risk factors for HPV vaccine AEFI.

Proportional reporting ratio (PRR), reporting odds ratio (ROR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayes Gamma-Poisson Shrinker (GPS) were used to detect the abnormal signals of the HPV vaccine. Signal detection was based on the following criteria 10: (1) PRR lower limit of the 95% confidence interval (95% CI) > 1; (2) ROR lower limit of the 95% CI > 1; (3) Information Component (IC) lower limit of the 95% CI > 1; (4) Empirical Bayes Geometric Mean (EB₀₅) lower limit of the one-sided 95% CI > 2; and (5) at least three cases of the disease were reported.

Ethical approval

Ethical approval was sought from the Medical Ethics Committee of Shandong Province Center for Disease Control and Prevention (Approval notice: SDJK(K)2026–016-01). The study involved only retrospective aggregate statistical analysis of de‑identified surveillance records, and no individual‑level interventions were conducted; therefore, individual informed consent was waived.

Results

Basic characteristics of AEFI

The reporting AEFI rate (/100,000 doses) in the 9–17-y-old group is 14.35, higher than the other age groups (P < .01). The reporting AEFI rate was significantly higher after the first dose than the second and third doses (P < .05). The reporting rate of HPV (adsorbed) was 15.38, statistically higher than the other expression systems (P < .05). Due to the sparse number of male events (n = 2), formal comparison of sex-specific rates was not performed (Table 1).

Table 1.

Characteristics of HPV AEFI in Shandong, August 2017–October 2025.

Variables	No.	Number of vaccination	Ratea	RR (95% CI)	P
Age (years)
9–17	172	1199016	14.35
18–26	346	7240336	4.78	0.33 (0.28–0.40)	<.01
27–45	538	4779507	11.26	0.78 (0.66–0.93)	<.01
Vaccination doses
1	462	4842791	9.54
2	286	4540800	6.30	0.66 (0.57–0.76)	<.01
3	308	3835268	8.03	0.84 (0.73–0.97)	.02
Expression systems
Adsorbed	55	357600	15.38
E. coli	190	3892285	4.88	0.32 (0.24–0.43)	<.01
P. pastoris	73	679931	10.74	0.70 (0.49–0.99)	.04
S. cerevisiae	738	8289043	8.90	0.58 (0.44–0.77)	<.01
Gender
Male	2	11841	16.89
Female	1054	13207018	7.98	-*	*
Total	1056	13218859	7.99

^aper 100,000 doses.

*Formal statistical comparisons between sexes were not conducted due to the sparse number of male events (n = 2).

AEFI reports classification

The reporting AEFI rate of 9vHPV was significantly higher than 2vHPV (10.83 vs. 6.45/100,000 doses) (P < .01); The reporting rate of mild vaccine reactions, non-severe reactions, and severe reactions of 9vHPV was significantly higher than those of 2vHPV (P < .05). There was no statistically significant difference in the reporting rate of psychogenic reaction, coincidental event, and rare reaction among HPV vaccines (Table 2).

Table 2.

Classification of HPV vaccine AEFI in Shandong, August 2017–October 2025.

Variables	2vHPV		4vHPV				9vHPV				Total
	No.	Ratea	No.	Rate	RR (95% CI)*	P*	No.	Rate	RR (95% CI)**	P**	No.	Rate
Vaccine-related reaction	310	6.29	193	5.77	0.92 (0.76–1.09)	.34	520	10.52	1.67 (1.45–1.93)	<.01	1023	7.74
Mild	306	6.21	187	5.59	0.90 (0.75–1.08)	.26	515	10.42	1.68 (1.46–1.94)	<.01	1008	7.62
rare	4	0.08	6	0.18	2.21 (0.63–8.64)	.22	5	0.10	1.25 (0.33–5.04)	.74	15	0.11
Psychogenic reaction	2	0.04	1	0.03	0.74 (0.03–7.69)	.80	4	0.08	1.99 (0.39–14.39)	.43	7	0.05
Coincidental event	6	0.12	9	0.27	2.21 (0.80–6.59)	.13	11	0.22	1.83 (0.70–5.31)	.24	26	0.20
Severe
Yes	2	0.04	3	0.09	2.21 (0.37–16.77)	.39	10	0.20	4.99 (1.31–32.45)	.04	15	0.11
No	316	6.41	200	5.97	0.93 (0.78–1.11)	.44	525	10.62	1.66 (1.44–1.91)	<.01	1041	7.88
Total	318	6.45	203	6.06	0.94 (0.79–1.12)	.49	535	10.83	1.68 (1.46–1.93)	<.01	1056	7.99

^aPer 100,000 doses.

*Comparison of 4vHPV and 2vHPV; **Comparison of 9vHPV and 2vHPV.

Regional distribution of AEFI reports

The reporting AEFI rate was the highest in Taian city (16.33/100,000 doses), and the lowest in Dongying city (1.56/100,000 doses), and the differences between different cities were significant (P < .01) (Figure 1).

Figure 1.

Regional distribution of AEFI in Shandong Province, August 2017–October 2025.

Temporal distribution of AEFI reports

Figure 2 shows that the reporting AEFI rate of HPV vaccine in 2017 was the highest (22.98/100,000 doses), and the lowest reporting rate was 4.17/100,000 doses in 2022. The differences between different years were significant (P < .01).

Figure 2.

Temporal distribution of AEFI in Shandong Province, August 2017–October 2025.

Clinical diagnosis distribution and disproportionality analysis method for detecting HPV vaccine abnormal signals

The most (448) HPV vaccine-related clinical symptoms were other mild reactions, including fatigue, drowsiness, dizziness, headache, nausea, diarrhea, abdominal pain, joint pain, mild rash, etc., accounting for 42.42%; followed by fever (399, 37.78%); the most rare reaction cases were allergic rash (5, 0.47%). According to PRR, ROR, and BCPNN, induration with a diameter greater than 5 cm, myalgia, and other mild reactions were detected for abnormal signal. According to GPS, other mild reactions, myalgia, and immune thrombocytopenia (ITP) were detected for abnormal signal (Tables 3 and 4).

Table 3.

Clinical diagnosis distribution of mild reaction, and detection of abnormal signals of HPV vaccine AEFI in Shandong, August 2017–October 2025.

Clinical diagnoses	2vHPV		4vHPV		9vHPV		Total		PRR	ROR	BCPNN	GPS
	No.	Ratea	No.	Rate	No.	Rate	No.	Rate	PRRL0.05	RORL0.05	ICL0.05	EB05
Fever (°C)	117	2.37	69	2.06	213	4.31	399	3.02
37.1–37.5	15	0.30	16	0.48	27	0.55	58	0.44	0.82	0.81	0.73	0.98
37.6–38.5	40	0.81	24	0.72	67	1.36	131	0.99	0.44	0.40	0.31	0.46
≥38.6	62	1.26	29	0.87	119	2.41	210	1.59	0.34	0.25	0.21	0.34
Swelling (Diameter, cm)	126	2.56	86	2.57	175	3.54	387	2.93
≤2.5	36	0.73	25	0.75	50	1.01	111	0.84	0.85	0.84	0.77	0.98
2.6–5.0	54	1.10	31	0.93	80	1.62	165	1.25	0.69	0.66	0.57	0.74
>5.0	36	0.73	30	0.90	45	0.91	111	0.84	0.72	0.70	0.61	0.98
Induration (Diameter, cm)	95	1.93	46	1.37	114	2.31	255	1.93
≤2.5	38	0.77	16	0.48	50	1.01	104	0.78	0.94	0.94	0.90	0.98
2.6–5.0	29	0.59	14	0.42	40	0.81	83	0.63	0.64	0.63	0.52	0.81
>5.0	28	0.57	16	0.48	24	0.49	68	0.51	1.04*	1.04*	1.03*	0.98
Myalgia	27	0.55	28	0.84	63	1.28	118	0.89	2.51*	2.61*	3.53*	2.53*
Other mild reaction**	143	2.90	81	2.42	224	4.53	448	3.39	17.81*	23.34*	46.99*	15.36*

^aPer 100,000 doses.

*Abnormal signal.

**Including fatigue, drowsiness, dizziness, headache, nausea, diarrhea, abdominal pain, joint pain, and mild rash, etc.

Table 4.

Clinical diagnosis distribution of rare adverse reaction and coincidental event, and detection of abnormal signals of HPV vaccine AEFI in Shandong, August 2017–October 2025.

Clinical diagnoses	2vHPV		4vHPV		9vHPV		Total		PRR	ROR	BCPNN	GPS
	Rare adverse event (No.)	Coincidental event (No.).	Rare adverse event (No.)	Coincidental event (No.).	Rare adverse event (No.)	Coincidental event (No.).	No.	Ratea	PRRL0.05	RORL0.05	ICL0.05	EB05
Allergic reactions	2	1	4		2	4	13	0.10
Allergic rash	1		2		2	1	6	0.05	0.14	0.14	0.06	1.20
Urticaria	1	1					2	0.02	/	/	/	/
Erythema multiforme						1	1	0.01	/	/	/	/
Allergic shock			1				1	0.01	/	/	/	/
Henoch–Schönlein purpura						1	1	0.01	/	/	/	/
Other allergic reactions			1			1	2	0.02	/	/	/
Neurologic diseases		2	2	1	1	2	8	0.06
Acute disseminated encephalomyelitis					1		1	0.01	/	/	/	/
Acute myelitis			1				1	0.01	/	/	/	/
Optic neuritis			1				1	0.01	/	/	/	/
Retrobulbar neuritis						1	1	0.01	/	/	/	/
Facial neuritis		1					1	0.01	/	/	/	/
Multiple neuritis						1	1	0.01	/	/	/	/
Brachial plexus neuritis		1					1	0.01	/	/	/	/
Neuromyelitis optica spectrum disorders				1			1	0.01	/	/	/	/
Hematologic diseases		1			1	2	4	0.03
Immune thrombocytopenia					1	2	3	0.02	0.38	0.38	0.22	2.66*
Acute myeloid leukemia		1					1	0.01	/	/	/	/
Skin diseases		1		1		1	3	0.02
Eczema						1	1	0.01	/	/	/	/
Vitiligo		1		1			2	0.02	/	/	/	/
Others	2	1		7	1	2	13	0.10
Sterile abscess	1						1	0.01	/	/	/	/
Localized purulent infection – lymphangitis and lymphadenitis	1						1	0.01	/	/	/	/
Abnormal uterine bleeding					1	1	2	0.02	/	/	/	/
Joint effusion						1	1	0.01	/	/	/	/
Acute gastroenteritis		1					1	0.01	/	/	/	/
Hypoglycemic reaction				1			1	0.01	/	/	/	/
Self perceived limited mobility and muscle pain				1			1	0.01	/	/	/	/
Staphylococcus aureus infection				1			1	0.01	/	/	/	/
Thyroid adenoma				1			1	0.01	/	/	/	/
Depressive state, cardiac abnormalities, fetal structural abnormalities				1			1	0.01	/	/	/	/
Reactive arthritis				1			1	0.01	/	/	/	/
Vestibular dysfunction				1			1	0.01	/	/	/	/

^aPer 100,000 doses.

*Abnormal signal.

Time interval of AEFI reports

1056 cases of AEFI, of which 708 cases (67.05%) occurred within 1 d after vaccination, followed by 1–5 d (293, 27.75%), 23 cases (2.18%) occurred 6–10 d, 32 cases (3.03%) occurred after 11 d or later after vaccination. The difference was significant (P < .01) (Table 5).

Table 5.

Time interval between AEFI onset and immunization (days) in Shandong, August 2017–October 2025.

Time interval	No.	Proportion(%)	P
<1	708	67.05	<.01
1–5	293	27.75
6–10	23	2.18
>11	32	3.03

Discussion

The cost-effectiveness evaluation of HPV vaccination among Chinese women indicates that administering various types of HPV vaccines to women aged 12–25 is cost-effective benefit.¹¹ As of November 10, 2025, China provided free HPV vaccination for girls aged 13 and above, in response to the World Health Organization’s (WHO) Global Strategy to Accelerate the Elimination of Cervical Cancer initiative. Since rare events cannot be covered by clinical trials because of their limited potency, surveillance on spontaneous reports on administered doses is fundamental.¹² Analyzing real-world safety data from post-marketing was particularly crucial to identify reactions or new adverse effects not reported in clinical trials, to provide the safety evidence to ensure the smooth implementation of HPV vaccine immunization programs.

Distribution characteristics of the HPV vaccine AEFI

The reporting rate of AEFI and severe AEFI of HPV vaccine from August 2017 to October 2025 in Shandong is lower than that of all vaccines in China from 2021 to 2022 and that in 2023,^13,14 also lower than a passive research of HPV vaccine safety in Italy.¹² The reporting rate of AEFI, mild reaction of HPV vaccine is comparable to the 45 vaccine varieties in Fujian Province in 2022,¹⁵ while the reporting rates of rare reactions were lower than that in Fujian Province. The HPV vaccine in Shandong Province indicated a good safety profile, and monitoring sensitivity is required to improve.

The highest reporting rate of AEFI in the 9–17-age-group is consistent with the results observed in other regions.^16–18 The vast majority of this age group are students in school, living in a collective environment, and any reactions are easier to detect and report. Like other studies,^19,20 the reporting AEFI rate of the first dose was higher than the second and third doses, possibly due to the fact that the recipients were more sensitive to adverse reactions after the first dose and had a stronger willingness to report.²¹ The highest reporting AEFI rate for absorbed HPV is inconsistent with the results observed in Anhui, China.²² There are rarely relevant studies on the differences in AEFI reporting rates among different expression systems, and their differences need to be continuously observed on the later stage. Due to the sparse number of male events (n = 2), formal comparison of sex-specific rates was not performed. This question warrants further investigation using larger post-marketing surveillance datasets with adequate male representation.

In this study, the reporting AEFI rate of 9vHPV was higher than 2vHPV and 4vHPV, consistent with the results reported in China. Further monitoring is needed to determine whether the slightly higher AEFI rate of 9vHPV is related to factors such as the vaccine variety and its introduction time, usage area, and different age groups of vaccination.²³ The reporting AEFI rate varied across cities in Shandong, potentially due to differences in surveillance system sensitivity. To address this variability, the next step is to provide training for vaccination personnel, inform recipients for potential adverse reactions, and standardize AEFI reporting. Notably, the AEFI rate is higher in 2017 than in other years, which is consistent with the trend of a slight increase in sensitivity reported by the population during the initial introduction of the new vaccine, followed by a decrease over time.^24,25

Severe and psychogenic reaction after HPV vaccination

Severe AEFI reporting rate during the study period in Shandong (0.11/100,000 doses) was lower than the monitoring level of severe AEFI of 4vHPV in Australia (3.8/100,000 doses)²⁶ and that of the overall reporting rate from 14 studies (4/100,000 doses).²⁷ The reporting rate of psychogenic reaction was 0.05/100,000 doses, lower than that in the United States (0.47/100,000 doses).²⁸ The main target population for HPV is adolescent females, who are at high risk of psychogenic reactions. So, it is necessary to focus on preventing group psychogenic reactions after large-scale vaccination. If the recipients experience symptoms such as weakness or dizziness after vaccination, they should immediately assume a lying position. Vaccination personnel must respond promptly and appropriately to mitigate the occurrence of serious outcomes.²⁹

During this study, one death case was reported, which was a 24-y-old female who was found dead 44 h after receiving the second dose of HPV vaccine. Autopsy shows: allergic reactions (eosinophilic infiltration in the larynx, trachea, lungs, and liver; mast cell degranulation in the larynx and lungs as shown by toluidine blue staining; bronchospasm in the lungs; pulmonary expansion; pulmonary edema); infiltration of inflammatory cells (predominantly lymphocytes and monocytes) in the heart, lungs, and liver; small focal hemorrhages in the brain and heart (sinoatrial node, myocardium interstitium); congestion and edema in multiple organs; multiorgan putrefaction and autolysis. The investigation and diagnosis expert panel concluded that the vaccinee met the criteria for sudden death induced by an allergic reaction triggered by the entry of sensitizing substances into the body. However, because the death occurred more than 1 d after vaccination, which is inconsistent with the typical onset characteristics of the Type I allergic reaction, it was determined to be unrelated to vaccination.

Symptoms of HPV vaccine AEFI

After HPV vaccination in Shandong Province, the majority of symptoms are mild reactions, accounting for 95.45%. The rare reaction HPV AEFI rate was lower than that of the national HPV²³ and in Jiangxi Province.²⁹ Allergic reactions are the most frequently reported rare reaction, among which allergic rashes was the most commonly reported type. The allergic rashes rate is 0.05 per 100,000 doses, which is lower than the national overall reporting rate (0.96/100,000) for vaccine-related allergic rashes from 2021 to 2022.¹³ Allergic rash is an emergency skin reaction caused by abnormal immune response in patients after exposure to allergens. Like AEFI monitoring nationwide, it is the highest proportion of rare reactions.^13,14 Allergic shock is a severe allergic reaction, with a reporting rate of 0.01/100,000 doses in our study, which is comparable to the estimated overall rate of acute severe allergic reactions after vaccination in the United States from 2009 to 2011 (0.13/100,000).³⁰ Although allergic shock after immunization is rare, its immediate onset (usually within minutes) and life-threatening nature require rapid identification and disposal by vaccination personnel. China requires a 30-min observation in the outpatient department after vaccination, which can ensure timely treatment for the vast majority of allergic shock cases. Three cases of neurological disorders, including optic neuritis, acute myelitis, and acute disseminated encephalomyelitis (ADEM), were reported in this study. Optic neuritis and ADEM are demyelinating diseases of the central nervous system. The pathogenesis is unclear. A plausible explanation is vaccine-induced molecular mimicry, wherein antigenic similarity between vaccine components and endogenous proteins provokes autoimmune responses, leading to disease manifestation.²¹ The occurrence of myelitis after vaccination may be related to abnormal immune reactions that may be caused by vaccination.³¹ Neurological reactions after vaccination are not common. But cases have been reported associated with leprosy and COVID-19 vaccines.^32–34 Research using both cohort analysis and self-controlled risk interval analysis in South Korean indicate that no evidence was found to support an association between HPV vaccination and serious neurological adverse events.³⁵

Four abnormal signals, induration with a diameter greater than 5 cm, myalgia, others mild reaction (including fatigue, drowsiness, dizziness, headache, nausea, diarrhea, abdominal pain, joint pain, and mild rash), and ITP were detected according to the disproportionality analysis method, which were roughly the same as the abnormal signal of HPV vaccine detected by ROR in USA from 2007 to 2017.²⁵ In contrast to most other vaccine recipients in this study, who were infants and young children, the recipients of HPV vaccine were adolescents and adults, who are more sensitive to subjective symptoms such as pain, fatigue, and dizziness and have a stronger propensity to report adverse events. However, most of these reactions were mild and self-limiting, typically resolving spontaneously within 2 or 3 d. This study reported thee cases of ITP. Following assessment by an expert panel, only one case was classified as rare reaction, while the other two were determined to be coincidental event. So, the risk of ITP caused by HPV vaccine is extremely low.

Policy and practice recommendations

A research shows that public trust in vaccines has been increasingly undermined: vaccine hesitancy and controversies pose significant threats to public health³⁶ Public health authorities should launch evidence-based HPV vaccine safety popularization campaigns based on this long-term real-world surveillance data to eliminate public safety anxiety. Meanwhile, continue to promote HPV vaccination. We have not found any rare or unexpected serious safety signals, which provides strong evidence-based support for the continued large-scale vaccination. Regularly summarize and analyze HPV vaccine AEFI to provide high-quality real-world evidence for the revision of national HPV vaccine clinical application guidelines.

Limitations and prospects of this provincial surveillance study

Due to the inadequacy of the passive surveillance system, this study had several limitations. First, the CNAEFIs is a passive reporting system that is susceptible to limitations such as underreporting, reporting biases, and data completeness³⁷; Second, the abnormal signals between vaccination and the AEFI detected through the system did not necessarily indicate causality. Case investigations and epidemiological studies are required to evaluate and identify the causal relationship; Third, inevitable data quality issues are present in routine real-world surveillance data. Missing information, inconsistent entry standards, and non-uniform symptom description classification commonly exist in grassroots data entries. Fourth, critical missing variables limit in-depth subgroup analysis. The current surveillance database lacks detailed individual-level covariates, including participants’ underlying medical conditions, medication history, and allergic history. Fifth, the 27–45 y age group has a wider age span than the other two categories. Although this group contained a large number of vaccination doses and AEFI cases, enabling stable statistical estimates, potential within-group age heterogeneity cannot be fully excluded. This should be considered when interpreting the AEFI rate results. To compensate for the above deficiencies, future studies will adopt an active surveillance design, strictly standardize data collection and follow-up procedures, supplement detailed demographic and clinical covariates, and introduce matched control cohorts to minimize bias and improve the credibility of real-world safety evidence in HPV vaccines.

Conclusions

Overall, HPV vaccines (bivalent, quadrivalent, and nonavalent) administered in routine immunization practice across Shandong Province demonstrated a favorable and acceptable safety profile in large-scale real-world populations, with no unexpected adverse events detected. The most frequently (95.45%) documented AEFIs were fever, swelling, induration, myalgia, fatigue, drowsiness, dizziness, headache, nausea, etc. The most common rare reaction was allergic rash. Severe adverse vaccine reactions were extremely rare, and a relatively higher reporting rate of severe AEFI was observed for 9vHPV in this passive surveillance dataset. Collectively, the long-term real-world safety evidence strongly supports the safe application of the HPV vaccine. Following the inclusion of HPV vaccine into China’s National Immunization Program, it is essential to strengthen AEFI surveillance, ensure proper management of acute allergic reactions and psychogenic responses, to guarantee timely and safe vaccination of age-eligible children.

Biography

Yingjie Zhang, Research Fellow, Institute of Immunization Prevention and Management, Shandong Provincial Center for Disease Control and Prevention, holds a doctoral degree. She is mainly engaged in immunization prevention management and health policy research, and has been selected into the Health Talents Program of Qilu Talent Project.

She concurrently serves as a Member of the Varicella–Zoster Virus Vaccine Special Working Group of the National Immunization Program Technical Working Group, Standing Committee Member of the Immunization Professional Committee of the China Vaccine Industry Association, and Committee Member of the Public Health Economics Professional Committee of the Chinese Health Economics Association, etc.

In recent years, as the task leader, she has participated in 1 National Major Science and Technology Special Project in 2025, and won 3 Third Prizes of Shandong Preventive Medicine Science and Technology, 1 Third Prize of Shandong Medical Science and Technology, 1 Second Prize of Shandong Health Policy Research Project, and 1 Third Prize of Excellent Scientific Research Achievements of Shandong Provincial Department of Human Resources and Social Security, etc.

Funding Statement

This research was funded by the Mount Tai Scholar Project of Shandong Provincial Government [tsqn202103187].

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The original data for the research cannot be released publicly for privacy and ethical reasons.