Post-marketing surveillance for the safety of the 9-valent human papillomavirus vaccine: a retrospective real-world study in China

ABSTRACT

Background

The 9-valent human papillomavirus (9vHPV) vaccine was introduced in China in 2018. This study was conducted to monitor the occurrence of new-onset autoimmune diseases (AIs) in Chinese women vaccinated with the 9vHPV vaccine and adverse pregnancy outcomes in infants born to mothers with inadvertent pregnancy exposure.

Research design and methods

Women who received the first dose of the 9vHPV vaccine at age 16–26 years in Ningbo between January 2019 and March 2021 were monitored in the Ningbo Regional Health Information Platform. New-onset cases of seven pre-specified AIs diagnosed within six months after vaccination were collected. Cases of stillbirth and 23 major congenital anomalies diagnosed within three months of birth in target infants were collected.

Results

A total of 102,670 doses of the 9vHPV vaccine were administered to 41,609 women who had received no other HPV vaccine. New-onset AIs were diagnosed in 36 women, comprising 21 Hashimoto’s, 11 Graves’, and 4 uveitis disease cases. Among 50 women with maternal vaccination exposure, no stillbirths were observed. One case of microtia was observed.

Conclusions

In this first post-marketing surveillance of the 9vHPV vaccine in China, no safety signals were identified when putting the results in context to published data.

KEYWORDS:

• 9-valent human papillomavirus vaccine
• safety
• product surveillance
• post-marketing
• autoimmune diseases
• pregnancy

1. Introduction

According to the data from the Global Burden of Disease Cancer Collaboration, cervical cancer is the 5^th leading cause of death among women worldwide in 2019 [1]. Based on the Global Cancer Observatory (GLOBOCAN) 2020 estimates, there were an estimated 604,127 cervical cancer cases and 341,831 deaths globally in 2020 [2]. In 2020, approximately 109,741 new cervical cancer cases were diagnosed, and 59,060 cervical cancer deaths occurred in China. Cervical cancer is the 6^th leading cause of female cancer and the 7^th leading cause of cancer deaths in Chinese women [3]. As a measure of primary prevention of cervical cancer, the 9-valent human papillomavirus (9vHPV) vaccine has provided effective and comprehensive protection against the nine HPV types (6/11/16/18/31/33/45/52/58), including the types most commonly associated with cervical cancer. Since 2014, the 9vHPV vaccine (Gardasil 9 [Merck & Co., Inc., Rahway, NJ, USA]) has been licensed in over 80 countries or regions. In mainland China, the 9vHPV vaccine was approved for women aged 16 to 26 years in April 2018 and indication has been extended to girls and women aged 9 to 45 years in August 2022. There is no national HPV immunization program currently implemented in China, girls and women receive the 9vHPV vaccine at their own expense.

A favorable safety profile for the 9vHPV vaccine has been seen in the pre- and post-marketing settings worldwide. Until now, safety of the 9vHPV vaccine has been studied through clinical trials to provide pre-marketing evidence [4–6]. Also, real-world studies were conducted using large databases or adverse events following immunizations (AEFIs) to provide post-marketing evidence on the risk/benefit profile of the 9vHPV vaccine [7–13]. However, the safety of the 9vHPV vaccine administered to Chinese women as part of routine health care has not been studied previously. Therefore, as a commitment to the Center for Drug Evaluation of the Chinese National Medical Products Administration upon licensure of the 9vHPV vaccine (2018), we conducted a surveillance of the safety following routine vaccination with the 9vHPV vaccine in Chinese women.

This study was conducted to monitor the occurrence of seven pre-specified new-onset autoimmune diseases diagnosed within a period of up to six months after vaccination with the 9vHPV vaccine as well as the occurrence of stillbirth and major congenital anomalies in infants of women with pregnancy exposure to the 9vHPV vaccine in China using data from the Ningbo Regional Health Information Platform (NRHIP).

2. Patients and methods

2.1. Data sources and study population

Data from the NRHIP was used in this real-world study. The Ningbo city is an economically developed large coastal city located on the east coastline of China. The NRHIP is an administrative and comprehensive database with healthcare data of the whole city residents from various sources, including all public hospitals and large private hospitals, primary medical institutions, and the center for disease control and prevention in the Ningbo city [14,15]. Data on diagnosis, prescriptions, medical examinations, and lab tests from electronic medical records (EMRs), data on vaccines, dates and sites of vaccination, and dosage from immunization programs, as well as data on prenatal examinations, birth deliveries, and newborn follow-ups from maternal and child management were collected by local physicians and gathered automatically into the NRHIP. And all these data could be linked by unique personal identifiers, such as identification numbers.

Women who received the first dose of the 9vHPV vaccine at age 16 to 26 years in the Ningbo city between 25 January 2019 (the date of the 9vHPV vaccine launch in the Ningbo city) and 31 March 2021 were included in this study. Only women who received the quadrivalent HPV (4vHPV) vaccine or the 9vHPV vaccine before the HPV vaccine were included in the study. Women who received the 4vHPV vaccine followed by the 9vHPV vaccine were defined as women with the receipt of the mixed regimen. And women were censored at the date of vaccination with the bivalent HPV (2vHPV) vaccine. For autoimmune diseases surveillance, women diagnosed with pre-specified autoimmune diseases before receiving the first dose of the 9vHPV vaccine in the NRHIP were excluded. For adverse pregnancy outcomes surveillance, women who had received the 9vHPV vaccine up to 30 days prior to conception or anytime during pregnancy were included for the analysis of the occurrence of stillbirth and congenital anomalies.

2.2. Assessment of vaccine exposure

Vaccination exposure for autoimmune disease surveillance was defined as the receipt of at least one dose of the 9vHPV vaccine in the Ningbo city during the study period. Consistent with previous studies [7], maternal vaccination exposure for adverse pregnancy outcomes surveillance was defined as the receipt of at least one dose of the 9vHPV vaccine within 30 days prior to conception or anytime during pregnancy. The conception date of the study population was re-estimated by obstetricians according to self-reported last menstrual period (LMP) and results of Ultrasound B tests and other available lab tests during pregnancy in NRHIP to minimize the misclassification of maternal vaccination exposure.

2.3. Ascertainment of study outcomes

According to previous studies and local disease composition [14,16], the following autoimmune diseases were selected as outcomes for the study: Graves’ disease, Hashimoto’s thyroiditis, systemic lupus erythematosus (SLE), type 1 diabetes (T1DM), multiple sclerosis, optic neuritis, and uveitis. Adverse pregnancy outcomes included stillbirth and 23 major congenital anomalies that were selected according to the Chinese National Maternal and Child Health Surveillance Manual 2013 and included anencephaly, spina bifida, encephalocele, congenital hydrocephalus, cleft palate, cleft lip, cleft palate with cleft lip, microtia/anotia, other malformations of outer ear, esophageal atresia or stenosis, rectoanal atresia or stenosis, hypospadias, exstrophy of urinary bladder, talipes equinovarus, polydactyly, syndactyly, limb reductions, congenital diaphragmatic hernia, exomphalos, gastroschisis, conjoined twins, down syndrome, and congenital heart diseases [17].

Potential cases of pre-specified autoimmune diseases and adverse pregnancy outcomes were identified using the 10^th revision of the International Classification of Diseases (ICD-10) codes and keywords of diagnosis from emergency room visits, outpatient visits, and hospitalization and confirmed by local clinicians and the safety review committee (Supplementary Table S1). Relevant tests, prescriptions, and surgeries of potential cases that occurred in vaccinated women were reviewed by two or more clinicians to avoid misdiagnosis.

2.4. Statistical analysis

Socio-demographic characteristics (age, sex for infants, residence region, education, and occupation), lifestyle behaviors (tobacco smoking and alcohol consumption), reproductive information (gravidity and parity), and the 9vHPV vaccine vaccination history (year of the first dose and number of doses) of women who received the 9vHPV vaccine were described as frequencies and percentages with means (±standard deviation, SD). New-onset cases of pre-specified autoimmune diseases diagnosed within 6 months after each dose or between two contiguous doses (when time interval <6 months) of the 9vHPV vaccine were reported [18]. Cases of stillbirth in women with maternal exposure to the 9vHPV vaccine were reported. Also, cases of 23 major congenital anomalies which were diagnosed within 3 months from birth in infants whose mothers had maternal vaccination exposure were reported. The incidence and its 95% confidence interval (CI) of pre-specified autoimmune diseases in vaccinated women were calculated. The study population contributed person-years from the date of each dose of the 9vHPV vaccine to the date of the first diagnosis of the pre-specified autoimmune diseases, or 6 months after doses, or subsequent doses (when the time interval for two subsequent doses <6 months), a receipt of other HPV vaccines, or on 31 March 2021, whichever came first. Statistical analyses were performed using Stata (version 14.1, 2013, StataCorp LP., College Station, TX).

3. Results

3.1. Characteristics of vaccinated women

A total of 102,670 doses of the 9vHPV vaccine were administered to 41,609 women aged 16 to 26 years who had not received any other HPV vaccines in the Ningbo city from 25 January 2019 to 31 March 2021 (Table 1). The number of women who received their first dose of the 9vHPV vaccine increased from 10,615 in 2019 to 23,258 in 2020. During the first quarter of 2021, 7,736 women received their first dose of the 9vHPV vaccine. The mean age at first dose was 22.81 (SD = 2.44) years. The mean number of doses received was 2.47 (SD = 0.72). More than 60% of vaccinated women had completed three doses of vaccination at time of data cutoff. The mean time intervals between the first dose and the second dose, and the second dose and the third dose were 2.20 (SD = 0.45) and 4.31 (SD = 0.66) months, respectively.

Table 1. Characteristics of women who received the 9vHPV vaccine between 25 January 2019 and 31 March 2021 in Ningbo.

Characteristics	Only 9vHPV vaccine (n = 41,609)	Mixed regimen (n = 16)
Age at first dose (years), mean±SD	22.81 ± 2.44	23.75 ± 1.53
16–20 years, n (%)	8,972 (21.56)	2 (12.50)
21–26 years, n (%)	32,637 (78.44)	14 (87.50)
Residence region, n (%)
Urban	15,183 (36.49)	8 (50.00)
Rural	18,691 (44.92)	8 (50.00)
Unknown	7,735 (18.59)	0 (0)
Year of first dose, n (%)
2019	10,615 (25.51)	7 (43.75)
2020	23,258 (55.90)	7 (43.75)
2021	7,736 (18.59)	2 (12.50)
Number of doses received, mean±SD	2.47 ± 0.72	3.44 ± 0.73
1 dose, n (%)	5,678 (13.65)	2 (12.50)
2 doses, n (%)	10,801 (25.96)	5 (31.25)
3 doses, n (%)	25,130 (60.40)	9 (56.25)
Time interval between doses (months), mean±SD
Dose 1 and dose 2	2.20 ± 0.45	2.28 ± 0.54
Dose 2 and dose 3	4.31 ± 0.66	4.25 ± 1.06
Dose 3 and the last dose	–	6.70 ± 6.33

During the study period, 16 women received the mixed regimen of both the 4vHPV vaccine and the 9vHPV vaccine. The mean age at first dose was 23.8 (SD = 1.5) years. Nine women received more than three doses of the 4vHPV vaccine and the 9vHPV vaccine. The time interval between the first, second, and third dose was similar in women who received the 9vHPV vaccine only and the mixed regimen.

3.2. Surveillance of autoimmune diseases

Among 41,609 women who were exclusively vaccinated with the 9vHPV vaccine and followed over a median of 0.64 years (26,629.76 million person-years), 36 new-onset cases of pre-specified autoimmune diseases were identified, including 11 cases of Graves’ disease, 21 cases of Hashimoto’s thyroiditis, and four cases of uveitis (Figure 1). The incidence of Graves’ disease, Hashimoto’s thyroiditis, and uveitis were 41.34 (95%CI: 22.89–74,65), 78.94 (95%CI: 51.47–121.08), and 15.03 (95%CI: 5.64–40.05) cases per 100,000 person-years, respectively. No cases of pre-specified autoimmune diseases were identified in women who received the mixed regimen.

Figure 1. Flowchart of new-onset cases of pre-specified autoimmune diseases among women who received the 9vHPV vaccine.

The characteristics of women with new-onset Graves’ disease and Hashimoto’s thyroiditis are summarized in Table 2. The mean age of those women was 23 years. Most of them were urban residents and received their first dose of the 9vHPV vaccine in 2020. Almost all of them had completed three doses of vaccination. Among 11 women with new-onset cases of Graves’ disease, 6 of them were diagnosed after receiving the first dose of the 9vHPV vaccine, and the others were diagnosed after the second dose. Among 21 women with Hashimoto’s thyroiditis, the majority was diagnosed after the second dose of vaccination. No new-onset cases of any of the two diseases were diagnosed after the third dose. The mean time interval between the last dose of vaccination and the date of diagnosis of Graves’ disease and Hashimoto’s thyroiditis was 57.91 (SD = 33.67) and 59.92 (SD = 37.17) days, respectively.

Table 2. Characteristics of women who received with the 9vHPV vaccine only and had new-onset Graves’ disease or Hashimoto’s thyroiditis between 25 January 2019 and 31 March 2021 in Ningbo.

Characteristics	Graves’ disease (n = 11)	Hashimoto’s thyroiditis (n = 21)
Age at first dose (years), mean±SD	23.33 ± 2.20	23.82 ± 1.81
16–20 years, n (%)	3 (27.27)	2 (9.52)
20–26 years, n (%)	8 (72.73)	19 (90.48)
Residence region, n (%)
Urban	6 (54.55)	9 (42.86)
Rural	4 (36.36)	8 (38.10)
Unknown	1 (9.09)	4 (19.05)
Year at first dose, n (%)
2019	3 (27.27)	7 (33.33)
2020	8 (72.73)	13 (61.90)
2021	0 (0)	1 (4.76)
Number of doses received, mean±SD	2.91 ± 0.30	2.90 ± 0.30
Only 1 dose, n (%)	0 (0)	0 (0)
2 doses, n (%)	1 (9.09)	2 (9.52)
3 doses, n (%)	10 (90.91)	19 (90.48)
Diagnosis time, n (%)
After dose 1	6 (54.55)	9 (42.86)
After dose 2	5 (45.45)	12 (57.14)
After dose 3	0 (0)	0 (0)
Time interval between the last dose of vaccination before diagnosis and diagnosis (days)	57.91 ± 33.67	59.29 ± 37.17

Among four women with new-onset cases of uveitis, the mean age at first dose of the 9vHPV vaccine was 23.14 (SD = 3.65) years. Half of them were from urban areas and received their first dose in 2019, and the other two women received it in 2020. One woman had received only two doses of the 9vHPV vaccine during the study period, the three others had been vaccinated with all three doses. One woman was diagnosed with new-onset uveitis after she had received dose 1, and the others were diagnosed after dose 2. The range of the time interval between the date of the last dose of vaccination before diagnosis and the date of diagnosis was 13 to 44 days.

3.3. Surveillance of adverse pregnancy outcomes

A total of 50 women received the 9vHPV vaccine within 30 days prior to conception or during pregnancy (Figure 2 and Table 3). The mean age at their first dose was 24.56 (SD = 0.93) years. Fifty percent of these women were from rural areas and 86.00% of these women had at least a university degree. All these women were non-current smokers and non-regular alcohol drinkers. The mean number of gravidities and parities were 1.28 (SD = 0.73) and 0.02 (SD = 0.14), respectively, and hence most of these women had their first pregnancy and delivery during the study period. Respectively 40 and 10 women had maternal exposure to the 9vHPV vaccine in 2019 and in 2020. More than half of these women (56.00%) had completed three doses of the 9vHPV vaccine. The mean number of doses received was 2.34 (SD = 0.82). Similar proportions of women had their conception before dose 1, after dose 1, after dose 2, and after dose 3. More than half (56.00%) of these women received the first dose of the 9vHPV vaccine in the first trimester of their pregnancy. Only one woman had received her first dose during the third trimester.

Figure 2. Flowchart of adverse pregnancy outcomes among women who received the 9vHPV vaccine.

Table 3. Characteristics of women with maternal exposure to only the 9vHPV vaccine between 25 January 2019 and 31 March 2021 in Ningbo.

Characteristics	9vHPV vaccine (n = 50)
Age at first dose (years), mean±SD	24.56 ± 0.93
16–20 years, n (%)	0 (0.00)
20–26 years, n (%)	50 (100.00)
Residence region, n (%)
Urban	14 (28.00)
Rural	25 (50.00)
Unknown	11 (22.00)
Education, n (%)
University and above	43 (86.00)
Senior high school	6 (12.00)
Junior school and below	1 (2.00)
Occupation, n (%)
Factory worker	9 (18.00)
Agriculture worker	5 (10.00)
Administrator/manager/professional/technical	10 (20.00)
Service worker	3 (6.00)
Other	22 (44.00)
Unknown	1 (2.00)
Cigarette smoking status, n (%)
Non-smoker	50 (100.00)
Smoker	0 (0.00)
Alcohol drinking status, n (%)
Non-drinker	50 (100.00)
Drinker	0 (0.00)
Gravidity, mean±SD	1.28 ± 0.73
1, n (%)	42 (84.00)
2, n (%)	4 (8.00)
≥3, n (%)	4 (8.00)
Parity, mean±SD	0.02 ± 0.14
0, n (%)	49 (98.00)
1, n (%)	1 (2.00)
≥2, n (%)	0 (0.00)
Year at first dose, n (%)
2019	40 (80.00)
2020	10 (20.00)
2021	0 (0.00)
Number of doses received, mean±SD	2.34 ± 0.82
1 dose, n (%)	11 (22.00)
2 doses, n (%)	11 (22.00)
3 doses, n (%)	28 (56.00)
Conception time, n (%)
Before dose 1	15 (30.00)
After dose 1	12 (24.00)
After dose 2	13 (26.00)
After dose 3	10 (20.00)
Vaccination time of the first dose in risk windows, n (%)
Within 30 days prior to conception	18 (36.00)
In the 1^st trimester (0–12 weeks)	28 (56.00)
In the 2^nd trimester (13–28 weeks)	3 (6.00)
In the 3^rd trimester (29–40 weeks or above)	1 (2.00)

Among 50 women with maternal exposure to the 9vHPV vaccine, no stillbirth case was identified. One male infant who was born to an exposed woman was diagnosed with microtia at one month of age. His mother was 23 years old at her first dose of the 9vHPV vaccine. She was an urban resident, nonsmoker, and non-alcohol drinker. This was her first pregnancy, and the gestational age was 39 weeks. She received all three doses of the 9vHPV vaccine in 2019, with the last dose in the first trimester (6 days after conception) of her pregnancy. The time between the last dose and the delivery was 272 days.

No pregnancies were identified among women with maternal exposure to the mixed regimen.

4. Discussion

A total of 36 women were diagnosed with a new-onset case of pre-specified autoimmune diseases among the study population of 41,609 women aged 16 to 26 years who had received at least one dose of the 9vHPV vaccine and no other HPV vaccines in the Ningbo city over the study period from 25 January 2019 to 31 March 2021. Among these 36 women, 11 had Graves’ disease, 21 Hashimoto’s thyroiditis, and four uveitis. No cases of T1DM, SLE, multiple sclerosis, or optic neuritis were identified among the study population. A total of 50 women received the 9vHPV vaccine during their pregnancy or within 30 days before conception. Among these 50 women, no stillbirth was observed. In one infant born to a mother who had been exposed to the 9vHPV vaccine, a case of microtia was diagnosed within 3 months after birth.

4.1. Autoimmune diseases after vaccination with the 9vHPV vaccine

No real-world studies of incident risks of autoimmune diseases following vaccination with the 9vHPV vaccine were identified in China. In this study, we only reported the number and incidence of the new-onset cases of pre-specified autoimmune diseases among women who received the 9vHPV vaccine. We did not assess the occurrence of new-onset AI cases among unvaccinated women or in the general population and did not conduct any comparative analyses between unvaccinated and vaccinated women. However, the results can be put into context using published data of the epidemiology of pre-specified autoimmune diseases in China.

In a prospective cohort study that examined the effect of regional differences in iodine intake on the incidence of thyroid diseases among more than 3000 participants in northeastern China between 1999 and 2004, the 5-year cumulative incidence of Graves’ disease ranged from 0.6% to 0.8%, whereas the incidence of Hashimoto’s thyroiditis ranged between 0.0% and 0.5% in the different regions [19]. According to a surveillance conducted in 505 hospitals across China during 2010–2013, the incidence of T1DM was 0.81 cases per 100,000 person-years in women [20]. The incidence was 1.43, 1.11, and 1.19 cases per 100,000 person-years respectively among subjects aged 15–19, 20–24, and 25–29 years. For SLE and multiple sclerosis, no incidence but prevalence was reported in China previously. The prevalence of SLE was 0.06% among women in the Beijing city [21]. In the Anhui province, the female-specific prevalence of SLE was 28.69 and 83.73 per 100,000 persons in the 10–19 and 20–29 year-old age groups, respectively [22]. According to the data from Basic Medical Insurance for Urban Employee from six provinces in China, the age-standardized prevalence of multiple sclerosis in women was 3.39 per 100,000 persons in 2016 [23]. The female-specific prevalence was 0.72 and 3.44 per 100,000 persons in the 10–19 and 20–29 year-old age groups, respectively. For optic neuritis, the 5-year cumulative incidence was 0.36 and 1.24 cases per 1000 persons among women aged 0–19 and 20–39 years in the Taiwan province from 2000 to 2004 [24]. In the same region between 2003 and 2008, the female-specific incidence of uveitis was 99.6 per 100,000 person-years [25]. The respective incidence was 79.7 and 105.2 per 100,000 person-years among the total population aged 16–25 and 26–35 years.

In our study, 36 new-onset cases were identified following vaccination with the 9vHPV vaccine, including 11 Graves’ disease cases, 21 Hashimoto’s thyroiditis cases, and 4 uveitis cases. No cases of T1DM, SLE, multiple sclerosis, and optic neuritis were identified. The incidence of Graves’ disease, Hashimoto’s thyroiditis, and uveitis was 41.34, 78.94, and 15.03 cases per 100,000 person-years, respectively. Although direct comparisons between the published data and our results were not possible, our study results suggested no increase in the occurrence of all pre-specified autoimmune diseases after vaccination.

4.2. Adverse pregnancy outcomes in infants born to women with inadvertent pregnancy exposure to the 9vHPV vaccine

Although the 9vHPV vaccine is not recommended for use during pregnancy, sometimes it is inadvertently administered. A total of 80 women with maternal exposure to the 9vHPV vaccine were reported to the Vaccine Adverse Event Reporting System in the United States between 2014 and 2017 [11]. Our study also observed a small proportion of women who received the 9vHPV vaccine around pregnancy. The only adverse event that was reported during the study period of more than 2 years in the Ningbo city among the infants born to these mothers was one case of microtia. To date, no unfavorable pregnancy outcomes associated with maternal exposure to the 9vHPV vaccine have been identified. A cohort study analyzing data from seven sites in the Vaccine Safety Datalink found that the 9vHPV vaccine administration during or around the time of pregnancy was uncommon and not associated with structural birth defects [7]. A number of factors may confound the association of the 9vHPV vaccine administration with adverse pregnancy outcomes, including medications taken during pregnancy, occupational exposures, and family history. And the information of these potential confounders is not available in the NRHIP. We therefore did not investigate the association in our study. Data on the epidemiology of microtia in China is limited. In studies conducted in China and worldwide, microtia was reported in approximately 1 to 5 per 10,000 births [26–28].

4.3. Strengths and limitations

Our study is the first study to investigate the post-marketing safety of the 9vHPV vaccine after large-scale use in the Chinese population. However, there were also some limitations in our study. The etiology of incident cases of optic neuritis and uveitis was not investigated in this study, which might be overestimated the incidence attributed to the 9vHPV vaccine. However, cases of uveitis caused by parasites, viruses, and bacteria based on the diagnosis were not included in this study. Besides, with limited information in the NRHIP, the casualization of vaccination with autoimmune diseases could not be investigated. As an administrative and comprehensive database without research purposes, the accuracies of diagnosis with the study outcomes were inconsistent across medical institutions in the NRHIP. To address this issue, algorithms were developed for the identification of study outcomes in the NRHIP, and the cases were validated by relevant experts to avoid underdiagnoses and misdiagnoses. The medical services outside Ningbo could not be recorded in the NRHIP, which might underestimate both the rates of vaccination and the occurrence of the study outcomes. Another limitation is that for some autoimmune diseases, the onset date can precede the actual diagnosis date. In this study, we used the first diagnosis date as a proxy for the onset of pre-specified autoimmune diseases, which might underestimate new-onset cases during follow-up. As the 9vHPV vaccine is an expensive vaccine paid with out-of-pocket expense in China, unvaccinated women might be different in terms of socio-demographic characteristics and health-seeking or other behaviors from vaccinated women. Therefore, a comparison between vaccinated and unvaccinated groups was not applicable in this study. We have put our results into context using data from previous studies, but all these published data were not conducted from the general population in the Ningbo city.

5. Conclusions

In summary, consistent with other global studies, this study did not show any signs of autoimmune diseases and adverse pregnancy outcomes following receipt of the 9vHPV vaccine in Chinese women and their infants.

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A reviewer of this manuscript has disclosed that they were an investigator on the Gardasil9 efficacy trial in young adults. A second reviewer has disclosed that they received support from GSK for an observational, retrospective study unrelated to HPV or HPV vaccines. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose.

Author contributions

Ruogu Meng and Siyan Zhan conceived and designed the study. Rui Ma and Jianmei Wang coordinated the data acquisition and standardization. Ruogu Meng, Peipei Liu, Zuoxiang Liu, Bingjie He, and Zhike Liu analyzed the data. Ruogu Meng drafted the manuscript. Ruogu Meng, Yu Yang, and Siyan Zhan contributed to the interpretation of the results and critical revision of the manuscript for important intellectual content. All authors reviewed and approved the final manuscript.

Ethical approval and patient consent

The study protocol was approved by the ethical review committee of the Peking University Health Science Center (IRB. No: IRB00001052-20101). The requirement for informed consent was waived. The study was conducted in accordance with the Declaration of Helsinki; Good Pharmacoepidemiology Practice Guidelines; and local laws, rules, and regulations.

Acknowledgments

We thank Susanne Hartwig Pharm D, Peng Jiang PhD, Xuedan You PhD, and Carol Koro PhD for their scientific contribution to the study protocol, statistical analysis plan, and manuscript. We also acknowledge the contribution of Yaqun Fu MM MS and Xin Ma MS in providing study management support. MSD did not have access to any patient-level data in the Ningbo Regional Health Information Platform. A relevant abstract entitled “Post-marketing surveillance for the safety of the 9-valent human papillomavirus vaccine in China: a retrospective real-world study” was submitted to the International Conference on Pharmacoepidemiology & Therapeutic Risk Management (ICPE) 2023.

Data availability statement

The data that supports the findings of this study is available from the Ningbo Center for Disease Control and Prevention, but restrictions apply to the availability of these data, which was used under license for the current study, and so is not publicly available. Data is however available from the authors upon reasonable request and with permission of the Ningbo Center for Disease Control and Prevention.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/14760584.2023.2239911.

Additional information

Funding

This manuscript was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (EU PAS register number: EUPAS36132, CDE CTR register number: CTR20210666).