Prospective, multi-center post-marketing surveillance cohort study to monitor the safety of the human papillomavirus-16/18 AS04-adjuvanted vaccine in Chinese girls and women aged 9 to 45 years, 2018–2020

ABSTRACT

Following the approval of Cervarix for the immunization of girls and women in China against high-risk human papillomavirus types 16 and 18, a non-interventional post-authorization safety study was performed. A multi-center prospective cohort study assessed safety following Cervarix vaccination of Chinese girls and women aged 9–45 years between 31 May 2018 and 3 December 2020. Adverse events following immunization (AEFIs), potential immune-mediated diseases (pIMDs), and pregnancy-related outcomes were collected up to 12 months from the third immunization or 24 months from the first immunization, whichever came first. Among 3,013 women who received 8,839 Cervarix doses, 167 (5.5%) reported ≥ 1 any AEFI, and 22 (0.7%) reported 40 serious AEFIs. During the 30 days after each dose, 147 women (4.9%) reported 211 medically attended AEFIs, including 3 serious AEFIs reported by 1 woman (0.03%). One woman reported a pIMD. Cervarix was inadvertently administered to 65 women (2.2%) within 60 days before conception or during pregnancy. Of these women, 34 (52.3%) gave birth to live infant(s) with no apparent congenital anomalies, and 1 (1.5%) woman gave birth to a live infant with a congenital anomaly. No serious AEFIs or pIMDs were considered to be related to the vaccination. In Chinese women aged 9–45 years, immunization with the Cervarix three-dose schedule was well tolerated. Overall, no safety concerns were identified, although rare adverse events may have been missed due to the study sample size.

Clinical trial registration: NCT03438006.

HIGHLIGHTS

• Infection with high-risk human papillomavirus is a prerequisite for cervical cancer

• Cervarix is a human papillomavirus-16/18 AS04-adjuvanted vaccine

• Multi-centre prospective cohort study to monitor safety of Cervarix immunisation

• Safety was monitored in 3,013 girls/women aged 9–45 years in China (8,839 doses)

• Cervarix was well tolerated, and no safety concerns were identified

KEYWORDS:

• China
• HPV-16/18 AS04-adjuvanted vaccine
• human papillomavirus
• post-marketing
• pregnancy
• safety

Introduction

Cervical cancer ranks as the fourth leading cause of cancer among women worldwide. More than 600,000 new cervical cancer cases are diagnosed annually, and there were 341,831 deaths in 2020.¹ The major prerequisite of cervical cancer is persistent infection with high-risk human papillomavirus (HPV) types.^2–4 There are more than 100 HPV types, and 13 of these are high-risk types that can cause cancer. Worldwide, the high-risk HPV types 16 and 18 account for approximately 70% of cervical cancer cases.⁵

In China, 109,741 new cervical cancer cases and 59,060 deaths due to cervical cancer were reported in 2020.⁶ Cervical cancer incidence was highest in women aged 45–59 years, followed by women aged 30–44 years.⁷ Regional prevalence of cervical or cervicovaginal HPV infection ranged from 9.3% to 25.8%, while the prevalence of high-risk HPV types ranged from 7.4% to 15.6%.^8–12 HPV infection prevalence differed among age groups, with younger women having a higher prevalence.^9,10

In 2016, the HPV-16/18 AS04-adjuvanted vaccine (Cervarix, GSK) was approved in China for the prevention of cervical cancer, cervical intraepithelial neoplasia grades 1, 2, and 3, and adenocarcinoma in situ caused by high-risk HPV types 16 and 18, in girls and women aged 9–25 years; in 2018, this approval was extended to women aged up to 45 years.^13,14 Cervarix is based on HPV-16 and HPV-18 L1 proteins formulated with AS04 adjuvant (comprising aluminum hydroxide [Al(OH)₃] and 3-O-desacyl-4’−monophosphoryl lipid A).¹⁵ The clinical efficacy of Cervarix has been demonstrated in clinical trials, and real-world data have provided further evidence for the vaccine’s effectiveness against cervical advanced premalignant lesions (i.e., grade 3 cervical intraepithelial neoplasia) and cervical cancer.^16–18

This post-marketing surveillance study assessed the safety of Cervarix among Chinese girls and women aged 9–45 years who were vaccinated voluntarily as per standard practice according to the prescribing information. At the time, a three-dose schedule was licensed. The primary objective of the study was to assess the safety of Cervarix in terms of medically attended adverse events following immunization (AEFIs) occurring within 30 days following each immunization in all participants. The secondary objectives were to assess the safety of Cervarix in terms of (1) serious AEFIs and (2) potential immune-mediated diseases (pIMDs) detected during the period from the first immunization to either 12 months following the third immunization or 24 months following the first immunization (whichever occurred first) in all participants; and (3) pregnancy outcomes and (4) congenital anomalies when administered inadvertently within 60 days before conception or any time during pregnancy.

Materials and methods

Study design

This post-marketing surveillance study (NCT03438006) comprised a multi-center prospective cohort study that aimed to involve approximately 3,000 participants for the Cervarix safety assessment in China, as per Chinese regulation requirements. Participants were girls and women aged 9–45 years, vaccinated voluntarily with Cervarix as per routine clinical practice and according to the official prescribing information for China. Participants were expected to receive three doses of Cervarix at 0, 1, and 6 months. The second and third doses could be administered 1–2.5, and 5–12 months, respectively, after the first dose. The vaccine was administered intramuscularly in the deltoid region. The enrollment was open from 19 May 2018 to 5 December 2018, and data was collected from 31 May 2018 to 3 December 2020. The study protocol, any amendments, the informed consent, and other information that required approval were reviewed and approved by the Medical Research Ethical Committee of Fudan University’s School of Public Health (approval numbers IRB#2018-01-0659 and IRB#2018-12-0722).

Participants

Girls and women were recruited at vaccination centers. Participants were asked to take part in the study if they had received voluntary Cervarix vaccination as per standard practice and satisfied the inclusion criteria: (1) they were Chinese girls or women aged 9–45 years at the time of the first dose; (2) the investigator believed that they and/or their parent(s)/legally acceptable representative(s) (LAR[s]) could and would comply with the protocol’s requirements (e.g., return for subsequent doses and follow-up visits); and (3) they gave written informed consent, or, for participants who were below the legal age of consent, their parent(s)/LAR(s) gave written informed consent, and informed assent was obtained from the participants. Children in care were excluded.

Participant selection and recruitment was performed by on-site investigators and local well-trained staff. The sampling technique consisted of asking all women between 9 and 45 years old who had just been vaccinated if they would like to participate. Less than 10% of eligible women declined study participation or did not respond. No data was collected on the number of participants who were invited but did not enroll or on their demographic characteristics or baseline information.

Data sources

Data were collected using both active surveillance and enhanced passive surveillance methods, i.e., (1) participant interview and observation by the principal investigator at each of the three immunization visits or at events that occurred since the previous visit(s) or just after the visit; (2) structured telephone follow-up by the investigator or a study team member 31–45 days after dose 2 (call one) and dose 3 (call two) and 12 months after dose 3 or 24 months after dose 1 (whichever occurred first) (call three); (3) direct reporting by participants or their parent(s)/LAR(s); (4) reporting by a physician who was not part of this study, this could be any physician the participant visited or consulted. At least three attempts to contact a participant had to be made before they were considered lost to follow-up.

In this way, information was collected about AEFIs, pIMDs, and pregnancies 1 month after dose 1 (at the second immunization visit), approximately 1 month after dose 2 (by telephone, 31–45 days after dose 2), and approximately 1 month after dose 3 (by telephone, 31–45 days after dose 3).

Data collected on the first visit were participants’ demographic data, medical and vaccination history, physical examination data, and concomitant medication or vaccination.

Definition of AEFI and AEFI intensity

An AEFI was defined as any untoward medical occurrence following immunization regardless of whether it was considered related to the vaccine. A medically attended AEFI was defined as any event leading to an unscheduled visit to or from medical personnel for any reason, including emergency room visits. If a medically attended AEFI led to hospitalization (or met any other criteria of a serious AEFI), it was reported as a serious AEFI. A serious AEFI was defined as any event that resulted in death, was life-threatening (an event in which the participant was at risk of death), required hospitalization or prolongation of existing hospitalization, or resulted in disability/incapacity. Any congenital anomaly in a participant’s offspring was included in this category.

The intensity of AEFIs was graded as: no discomfort (0); mild discomfort not interfering with everyday activities (1); moderate discomfort, interfering with normal everyday activities (2); and severe discomfort, preventing normal everyday activities such as attending work or school and requiring treatment (3).

Outcome measures

Follow-up was performed from enrollment until either 12 months after the third immunization or 24 months after the first immunization with Cervarix (whichever occurred first). Any AEFIs were assessed throughout the follow-up period and evaluated for their clinical relevance and relationship to vaccination as per the investigator’s judgment.

Pregnancy outcomes and congenital anomalies were summarized when Cervarix was administered within 60 days before conception or any time during pregnancy. For this purpose, these women and their offspring were followed-up for a maximum of 12 months post-delivery. Possible congenital anomalies were diagnosed at pregnancy outcome and during the first 12 months of the child’s life. All of these pregnancy outcomes and congenital anomalies were investigated to determine a potential association with vaccination.

The occurrence of pIMDs was summarized through the follow-up in all participants. pIMDs were defined as AEFIs that included autoimmune diseases and other inflammatory and/or neurologic disorders of interest, which may or may not have an autoimmune etiology. A list of pIMDs we looked for is provided in Table S1.

Data were collected via an electronic case report form (eCRF). As per Chinese regulations, safety information was collected from approximately 3,000 participants for the post-marketing surveillance study. This sample size was deemed to be plausible for both medically significant AEs and serious AEs based on an efficacy clinical trial that evaluated the efficacy of Cervarix, with a 72-month follow-up period conducted in China.¹⁹ In that trial the percentage of participants reporting at least one medically significant AE was 6.1% (95% CI: 5.3%–7.1%).¹⁹ The follow-up of the medically attended AEFI for this study was 30 days after each dose of the vaccine, therefore 90 days in total after three doses. Under a conservative assumption of constant incidence of AE’s during the 72-months follow-up period, the percentage of participants reporting at least one medically attended AEFI during the 90-day follow-up period of our study was assumed to be 0.25%. As a decreasing incidence rate medically significant AEs with time from vaccination was plausible, a range of percentage from 0.20% (95% CI: 0.07%–0.43%) to 1.0% (95% CI: 0.68%–1.42%) medically significant AE was assumed. In the above-mentioned clinical trial that evaluated the efficacy of Cervarix in China it was also found that the percentage of participants reporting at least one severe adverse event was 1.9% (95% CI: 1.4%–2.4%).¹⁹ The follow-up of serious AEFIs in our study was at least 18 months after the first dose of vaccine for a participant who completed the full course of vaccinations. Therefore, the percentage of participants reporting serious AEFI was assumed to be 0.5%.

For causality assessment, the principal investigator used the method endorsed by the Council for International Organizations of Medical Sciences,²⁰ which is the standard method used for causality assessment in the pharmaceutical industry. It is a binary tool that uses the question “Is there a reasonable possibility that the AEFI/serious AEFI/pIMD may have been caused by the vaccine?” with the possible answers being “Yes, there is a reasonable possibility that the vaccine contributed to the AEFI/pIMD” and “No, there is no reasonable possibility that the vaccine contributed to the AEFI/pIMD. There are other, more likely causes and administration of the vaccine is not suspected to have contributed to the AEFI/pIMD.” Possible contributing factors to include in the causality assessment are medical history, other medication, the procedure required by the protocol, other procedures not required by the protocol, erroneous administration of the vaccine, or other cause.

Statistical analysis

All analyses were performed using data from women who had been vaccinated at least once (Exposed Set). Participants’ demographics (age, ethnicity, and pregnancy status) and baseline characteristics were tabulated. The percentage of participants with ≥1 medically attended AEFI occurring within the 30-day follow-up period (days 1–30) was tabulated with the exact 95% confidence interval (CI) after each dose and overall. The tabulation was performed based on the Medical Dictionary for Regulatory Activities (MedDRA) classification of System Organ Class and Preferred Term.

All statistical analyses were conducted with Statistical Analysis Systems software (SAS Inst., Cary, NC, USA). Secondary endpoints (serious AEFIs, pIMDs, pregnancy outcomes) were summarized by the percentage of participants reporting the endpoint with the exact 95% CI.

Results

Participants and characteristics

A total of 3,016 women were enrolled in the study, meeting the sample size requirement of 3,000 individuals, 3,013 of these women had been vaccinated at least once (Exposed Set). At dose 1, the mean age was 30.6 years (standard deviation 9.2), with a range of 9–45 years (median 32.0). Most (72.8%, n = 2,193/3,013) were 26–45 years old, and all were of East Asian heritage (Table 1).

Table 1. Summary of demographic characteristics – exposed set.

	Vaccinated participants, N = 3,013
	n (%)	Mean age (SD)	Median age	Age range	Missing^a, n
At least 1 dose of HPV vaccine	3,013 (100)	30.6 (9.2)	32.0	9–45	0
Age category
9–15 years	301 (10.0)
16–17 years	49 (1.6)
18–25 years	470 (15.6)
26–45 years	2,193 (72.8)
≥46 years	0 (0.0)
At least 2 doses of HPV vaccine	2,956 (98.1)	30.6 (9.2)	32.0	9–46	57
Age category
9–15 years	299 (10.1)
16–17 years	46 (1.6)
18–25 years	456 (15.4)
26–45 years	2,153 (72.8)
≥46 years	2 (0.1)
All 3 doses of HPV vaccine	2,870 (95.3)	31.1 (9.3)	32.0	9–46	143
Age category
9–15 years	292 (10.2)
16–17 years	43 (1.5)
18–25 years	414 (14.4)
26–45 years	2,114 (73.7)
≥46 years	7 (0.2)
Ethnicity
East Asian heritage	3,013 (100)
Other	0 (0)
Pregnancy during the study
Yes	65 (2.2)
No	2,948 (97.8)

HPV, human papillomavirus; N, number of participants vaccinated with at least one dose of Cervarix; n, number of participants in a given category; SD, standard deviation; %, n/N × 100.

Age was computed using 15 as the day of birth, as only month and year of birth were collected. ^a Dose 2/dose 3 not received.

Of the 3,013 participants who had received Cervarix, 2,870 (95.3%) participants had received three doses, 86 (2.9%) had received two doses, and 57 (1.9%) had received a single dose.

The women were enrolled at eight vaccination centers, ranging from 9 to 1,026 women enrolled per center. There were 100 (3.3%) participants who had other vaccines co-administered with Cervarix as part of their routine healthcare. Of the 3,013 women, 2,895 completed the study, and 118 withdrew. The most common reasons for withdrawal were that the women were lost to follow-up with an incomplete vaccination course (n = 48), and consent was withdrawn but not due to an adverse event (n = 47).

Occurrence of medically attended AEFIs

During the 30-day follow-up period after vaccination, the majority (95.1%, n = 2,866/3,013) of participants did not report any medically attended AEFIs after 8,839 vaccine doses. A total of 147 participants (4.9%, n = 147/3,013) reported 211 medically attended AEFIs following 160 vaccine doses (1.8%, n = 160/8,839) (Table 2 and Table S2). Fifty-five medically attended AEFIs were reported by 49 participants (1.6%) post-dose 1; 71 by 55 participants (1.9%) post-dose 2; and 85 by 56 participants (2.0%) post-dose 3 (Table 2).

Table 2. Number of participants who reported AEFIs following each dose of Cervarix and overall – exposed set.

	Any AEFI in the entire study period			Medically attended AEFI within 30 days		Serious AEFI in the entire study period
	N	n	%	n	%	n	%
Dose 1	3,013	57	1.9	49	1.6	5	0.2
Dose 2	2,956	64	2.2	55	1.9	9	0.3
Dose 3	2,870	59	2.1	56	2.0	8	0.3
Overall/dose	8,839	180	2.0	160	1.8	22	0.2
Overall/participant	3,013	167	5.5	147	4.9	22	0.7

AEFI, adverse event following immunization.

For each dose and overall/participant: N, number of participants with at least one administered dose; n, number of participants reporting at least one type of symptom; %, n/N × 100.

For overall/dose: N, number of administered doses; n, number of doses followed by at least one type of symptom; %, n/N × 100.

AEFIs reported above exclude the AEFIs reported for offspring.

The reported medically attended AEFIs within 30 days of vaccination were mainly in the Primary System Organ Class “Infections and infestations,” of which 118 events were reported by 96 participants (3.2%, 95% CI: 2.6–3.9) following 104 doses (1.2%, 95% CI: 1.0–1.4). These were not causally related to vaccination as per the investigator’s judgment. The most frequently reported medically attended AEFIs were upper respiratory tract infections, with 32 events reported by 30 participants (1.0%, 95% CI: 0.7–1.4); and bronchitis, with 27 events reported by 25 participants (0.8%, 95% CI: 0.5–1.2). All other medically attended AEFIs were each reported by between 1 and 12 (≤0.4%) participants. Each individual medically attended AEFI was reported after at most 0.4% of all 8,839 doses (Table 3 and Table S2).

Table 3. Summary of occurrences and participants with at least one medically attended AEFI with onset within 30 days of vaccination with Cervarix classified by MedDRA Primary system Organ class and Preferred Term – exposed set.

MedDRA Primary System Organ Class (Code) Preferred Term (Code)	Occurrences and participants, N  = 3,013
	events	n	% (95% CI: LL – UL)
Any	211	147	4.9 (4.1–5.7)
Infections and infestations (10021881)	118	96	3.2 (2.6–3.9)
Upper respiratory tract infection (10046306)	32	30	1.0 (0.7–1.4)
Bronchitis (10006451)	27	25	0.8 (0.5–1.2)
Tonsillitis (10044008)	12	12	0.4 (0.2–0.7)
Pharyngitis (10034835)	9	9	0.3 (0.1–0.6)
Gastroenteritis (10017888)	5	5	0.2 (0.1–0.4)
Pneumonia (10035664)	5	5	0.2 (0.1–0.4)
Urinary tract infection (10046571)	5	5	0.2 (0.1–0.4)
Nasopharyngitis (10028810)	4	4	0.1 (0.0–0.3)
Acute sinusitis (10001076)	3	3	0.1 (0.0–0.3)
Pelvic inflammatory disease (10034254)	3	3	0.1 (0.0–0.3)
Helicobacter infection (10054263)	2	2	0.1 (0.0–0.2)
Vaginal infection (10046914)	2	2	0.1 (0.0–0.2)
Conjunctivitis (10010741)	1	1	0.03 (0.0–0.2)
Gingivitis (10018292)	1	1	0.03 (0.0–0.2)
Herpangina (10019936)	1	1	0.03 (0.0–0.2)
Influenza (10022000)	1	1	0.03 (0.0–0.2)
Otitis media chronic (10033081)	1	1	0.03 (0.0–0.2)
Paronychia (10034016)	1	1	0.03 (0.0–0.2)
Periodontitis (10034539)	1	1	0.03 (0.0–0.2)
Urethritis (10046480)	1	1	0.03 (0.0–0.2)
Vulvovaginal mycotic infection (10064899)	1	1	0.03 (0.0–0.2)
Gastrointestinal disorders (10017947)	15	15	0.5 (0.3–0.8)
Gastritis (10017853)	5	5	0.2 (0.1–0.4)
Abdominal pain (10000081)	2	2	0.1 (0.0–0.2)
Chronic gastritis (10008882)	2	2	0.1 (0.0–0.2)
Enteritis (10014866)	2	2	0.1 (0.0–0.2)
Gastritis erosive (10017865)	1	1	0.03 (0.0–0.2)
Mouth ulceration (10028034)	1	1	0.03 (0.0–0.2)
Stomatitis (10042128)	1	1	0.03 (0.0–0.2)
Tooth impacted (10044042)	1	1	0.03 (0.0–0.2)
General disorders and administration site conditions (10018065)	15	14	0.5 (0.3–0.8)
Pyrexia (10037660)	10	10	0.3 (0.2–0.6)
Influenza like illness (10022004)	5	4	0.1 (0.0–0.3)
Skin and subcutaneous tissue disorders (10040785)	10	10	0.3 (0.2–0.6)
Eczema (10014184)	3	3	0.1 (0.0–0.3)
Urticaria (10046735)	3	3	0.1 (0.0–0.3)
Dermatitis allergic (10012434)	2	2	0.1 (0.0–0.2)
Acne (10000496)	1	1	0.03 (0.0–0.2)
Dermatitis contact (10012442)	1	1	0.03 (0.0–0.2)
Reproductive system and breast disorders (10038604)	7	7	0.2 (0.1–0.5)
Menstruation irregular (10027339)	3	3	0.1 (0.0–0.3)
Adenomyosis (10056268)	1	1	0.03 (0.0–0.2)
Breast hyperplasia (10006256)	1	1	0.03 (0.0–0.2)
Polymenorrhea (10036086)	1	1	0.03 (0.0–0.2)
Vaginal hemorrhage (10046910)	1	1	0.03 (0.0–0.2)
Respiratory, thoracic and mediastinal disorders (10038738)	7	7	0.2 (0.1–0.5)
Rhinitis allergic (10039085)	3	3	0.1 (0.0–0.3)
Cough (10011224)	2	2	0.1 (0.0–0.2)
Asthma (10003553)	1	1	0.03 (0.0–0.2)
Respiratory disorder (10038683)	1	1	0.03 (0.0–0.2)
Musculoskeletal and connective tissue disorders (10028395)	5	5	0.2 (0.1–0.4)
Arthritis (10003246)	1	1	0.03 (0.0–0.2)
Back pain (10003988)	1	1	0.03 (0.0–0.2)
Costochondritis (10011219)	1	1	0.03 (0.0–0.2)
Intervertebral disc protrusion (10050296)	1	1	0.03 (0.0–0.2)
Spinal osteoarthritis (10041591)	1	1	0.03 (0.0–0.2)
Nervous system disorders (10029205)	5	5	0.2 (0.1–0.4)
Diabetic neuropathy (10012680)	1	1	0.03 (0.0–0.2)
Dizziness (10013573)	1	1	0.03 (0.0–0.2)
Headache (10019211)	1	1	0.03 (0.0–0.2)
Migraine (10027599)	1	1	0.03 (0.0–0.2)
Neuritis (10029240)	1	1	0.03 (0.0–0.2)
Psychiatric disorders (10037175)	5	5	0.2 (0.1–0.4)
Insomnia (10022437)	2	2	0.1 (0.0–0.2)
Sleep disorder (10040984)	2	2	0.1 (0.0–0.2)
Anxiety (10002855)	1	1	0.03 (0.0–0.2)
Renal and urinary disorders (10038359)	4	4	0.1 (0.0–0.3)
Calculus urinary (10007027)	1	1	0.03 (0.0–0.2)
Diabetic nephropathy (10061835)	1	1	0.03 (0.0–0.2)
Nephrolithiasis (10029148)	1	1	0.03 (0.0–0.2)
Stress urinary incontinence (10066218)	1	1	0.03 (0.0–0.2)
Eye disorders (10015919)	3	3	0.1 (0.0–0.3)
Chalazion (10008388)	1	1	0.03 (0.0–0.2)
Conjunctival edema (10010726)	1	1	0.03 (0.0–0.2)
Dry eye (10013774)	1	1	0.03 (0.0–0.2)
Hepatobiliary disorders (10019805)	3	2	0.1 (0.0–0.2)
Hepatic function abnormal (10019670)	1	1	0.03 (0.0–0.2)
Hepatic steatosis (10019708)	1	1	0.03 (0.0–0.2)
Hyperbilirubinemia (10020578)	1	1	0.03 (0.0–0.2)
Blood and lymphatic system disorders (10005329)	2	2	0.1 (0.0–0.2)
Anemia (10002034)	1	1	0.03 (0.0–0.2)
Lymphadenopathy (10025197)	1	1	0.03 (0.0–0.2)
Cardiac disorders (10007541)	2	2	0.1 (0.0–0.2)
Sinus node dysfunction (10075889)	1	1	0.03 (0.0–0.2)
Tachycardia (10043071)	1	1	0.03 (0.0–0.2)
Ear and labyrinth disorders (10013993)	2	2	0.1 (0.0–0.2)
Ear pruritus (10052138)	1	1	0.03 (0.0–0.2)
Tinnitus (10043882)	1	1	0.03 (0.0–0.2)
Injury, poisoning and procedural complications (10022117)	2	2	0.1 (0.0–0.2)
Animal scratch (10002519)	1	1	0.03 (0.0–0.2)
Ligament rupture (10065433)	1	1	0.03 (0.0–0.2)
Metabolism and nutrition disorders (10027433)	2	2	0.1 (0.0–0.2)
Hyperuricemia (10020903)	2	2	0.1 (0.0–0.2)
Congenital, familial and genetic disorders (10010331)	1	1	0.03 (0.0–0.2)
Type V hyperlipidemia (10060755)	1	1	0.03 (0.0–0.2)
Endocrine disorders (10014698)	1	1	0.03 (0.0–0.2)
Hyperthyroidism (10020850)	1	1	0.03 (0.0–0.2)
Immune system disorders (10021428)	1	1	0.03 (0.0–0.2)
Hypersensitivity (10020751)	1	1	0.03 (0.0–0.2)
Pregnancy, puerperium and perinatal conditions (10036585)	1	1	0.03 (0.0–0.2)
Ectopic pregnancy (10014166)	1	1	0.03 (0.0–0.2)

AEFI, adverse event following immunization; CI, confidence interval; events, number of medically attended AEFIs with onset within 30 days; LL, lower limit; MedDRA, Medical Dictionary for Regulatory Activities; N, number of participants vaccinated with at least one dose of Cervarix; n, number of participants who reported the medically attended AEFI with onset within 30 days in a given category; UL, upper limit; %, n/N × 100.

AEFIs reported above exclude the AEFIs reported for offspring.

During the 30-day follow-up period after vaccination, 2 of the 10 cases of pyrexia were the only medically attended AEFIs the investigator considered causally related to vaccination. These two pyrexia cases were reported by two participants (0.1%, 95% CI: 0.0–0.2), one each after doses 2 and 3.

During the 30-day follow-up period after each vaccination, three medically attended AEFIs of grade 3 intensity were reported by one participant (0.03%, 95% CI: 0.0–0.2). These were pyrexia, bronchitis, and allergic rhinitis. The investigator considered that these AEFIs were not causally related to vaccination.

During the entire study, 167 participants (5.5%, n = 167/3,013) reported ≥ 1 of any AEFIs following 180 doses (2.0%, n = 180/8,839) (Table 2).

Occurrence of serious AEFIs in the entire study period

During the entire follow-up period, 40 serious AEFIs were reported by 22 participants (0.7%, 95% CI: 0.5–1.1) following 22 doses (Table 4 and Table S3). The most frequently reported serious AEFIs were pneumonia and ectopic pregnancy, each reported four times by four participants (0.1% each, 95% CI: 0.0–0.3). All other serious AEFIs were reported only once or twice (Table 4).

Table 4. Summary of occurrences and participants with at least one serious AEFI^a in the entire study period classified by MedDRA Primary system Organ class and Preferred Term – exposed set.

MedDRA Primary System Organ Class (Code) Preferred Term (Code)	Occurrences and participants, N  = 3,013
	events	n	% (95% CI: LL – UL)
Any	40	22	0.7 (0.5–1.1)
Infections and infestations (10021881)	9	8	0.3 (0.1–0.5)
Pneumonia (10035664)	4	4	0.1 (0.0–0.3)
Bronchitis (10006451)	2	2	0.1 (0.0–0.2)
Mastitis (10026883)	1	1	0.03 (0.0–0.2)
Pelvic inflammatory disease (10034254)	1	1	0.03 (0.0–0.2)
Viral hepatitis carrier (10047458)	1	1	0.03 (0.0–0.2)
Pregnancy, puerperium and perinatal conditions (10036585)	8	7	0.2 (0.1–0.5)
Ectopic pregnancy (10014166)	4	4	0.1 (0.0–0.3)
Abortion missed (10000230)	1	1	0.03 (0.0–0.2)
Gestational diabetes (10018209)	1	1	0.03 (0.0–0.2)
High-risk pregnancy (10052744)	1	1	0.03 (0.0–0.2)
Premature delivery (10036595)	1	1	0.03 (0.0–0.2)
Hepatobiliary disorders (10019805)	3	2	0.1 (0.0–0.2)
Hepatic function abnormal (10019670)	1	1	0.03 (0.0–0.2)
Hepatic steatosis (10019708)	1	1	0.03 (0.0–0.2)
Hyperbilirubinemia (10020578)	1	1	0.03 (0.0–0.2)
Metabolism and nutrition disorders (10027433)	3	3	0.1 (0.0–0.3)
Electrolyte imbalance (10014418)	1	1	0.03 (0.0–0.2)
Hyperuricemia (10020903)	1	1	0.03 (0.0–0.2)
Hypoproteinemia (10021083)	1	1	0.03 (0.0–0.2)
Blood and lymphatic system disorders (10005329)	2	2	0.1 (0.0–0.2)
Anemia (10002034)	1	1	0.03 (0.0–0.2)
Thrombocytopenia (10043554)	1	1	0.03 (0.0–0.2)
Congenital, familial and genetic disorders (10010331)	2	2	0.1 (0.0–0.2)
Glycogen storage disease type I (10018464)	1	1	0.03 (0.0–0.2)
Type V hyperlipidemia (10060755)	1	1	0.03 (0.0–0.2)
Neoplasms benign, malignant and unspecified (including cysts and polyps) (10029104)	2	2	0.1 (0.0–0.2)
B-cell lymphoma (10003899)	1	1	0.03 (0.0–0.2)
Colon cancer (10009944)	1	1	0.03 (0.0–0.2)
Renal and urinary disorders (10038359)	2	2	0.1 (0.0–0.2)
Diabetic nephropathy (10061835)	1	1	0.03 (0.0–0.2)
Stress urinary incontinence (10066218)	1	1	0.03 (0.0–0.2)
Reproductive system and breast disorders (10038604)	2	2	0.1 (0.0–0.2)
Cervical dysplasia (10008263)	1	1	0.03 (0.0–0.2)
Uterine scar (10074527)	1	1	0.03 (0.0–0.2)
Surgical and medical procedures (10042613)	2	2	0.1 (0.0–0.2)
Abortion induced (10000220)	2	2	0.1 (0.0–0.2)
Gastrointestinal disorders (10017947)	1	1	0.03 (0.0–0.2)
Gastritis (10017853)	1	1	0.03 (0.0–0.2)
Musculoskeletal and connective tissue disorders (10028395)	1	1	0.03 (0.0–0.2)
Intervertebral disc protrusion (10050296)	1	1	0.03 (0.0–0.2)
Nervous system disorders (10029205)	1	1	0.03 (0.0–0.2)
Diabetic neuropathy (10012680)	1	1	0.03 (0.0–0.2)
Psychiatric disorders (10037175)	1	1	0.03 (0.0–0.2)
Sleep disorder (10040984)	1	1	0.03 (0.0–0.2)
Vascular disorders (10047065)	1	1	0.03 (0.0–0.2)
Venous thrombosis (10047249)	1	1	0.03 (0.0–0.2)

AEFI, adverse event following immunization; CI, confidence interval; events, number of serious AEFIs reported by a participant; LL, lower limit; MedDRA, Medical Dictionary for Regulatory Activities; N, number of participants vaccinated with at least one dose of Cervarix; n, number of participants who reported serious AEFIs in a given category; UL, upper limit; %, n/N × 100.

^aSerious AEFIs that occurred within 12 months following the third immunization or 24 months following the first immunization (whichever occurred first).

All AEFIs reported exclude the AEFIs reported for offspring.

All 40 serious AEFIs were classified as such due to hospitalization or prolongation of hospitalization. In terms of intensity, 20 events (50.0%, n = 20/40) were moderate, 15 (37.5%, n = 15/40) were mild, and two (5.0%, n = 2/40) were severe. Severity information was missing for three events (7.5%, n = 3/40). At the time of this report, 95% (n = 38/40) of the serious AEFIs were recovered/resolved, and 5.0% (n = 2/40) were recovering/resolving. No serious AEFI that the investigator considered to be causally related to vaccination was reported during the study.

Occurrence of pIMDs

One woman (0.03%, 95% CI: 0.0–0.2) reported a pIMD, neuritis, following dose 2. The neuritis was mild (grade 1) and resolved after treatment. This neuritis was the only pIMD following 8,839 doses (0.01%, 95% CI: 0.0–0.1) and was considered by the investigator not to be causally related to vaccination.

Pregnancy outcomes and congenital anomalies

Among the 3,013 participants who received Cervarix, 65 participants (2.2%, n = 65/3,013) reported 65 pregnancies where Cervarix was administered within 60 days before conception or any time during pregnancy.

Thirty-five pregnancies resulted in live infant(s) who were followed up until the child’s first birthday: 34 women (52.3%, n = 34/65) had infants with no apparent congenital anomalies, and one woman (1.5%, n = 1/65) had an infant with a congenital anomaly. The congenital anomaly was a left subependymal cyst that was diagnosed at birth. Other pregnancy outcomes were: an elective termination with no apparent congenital anomaly in 20 women (30.8%, n = 20/65); ectopic pregnancy in four women (6.2%, n = 4/65); and one spontaneous abortion with no apparent congenital anomaly (1.5%, n = 1/65). The remaining five women (7.7%, n = 5/65) were lost to follow-up (Table S4).

Discussion

This post-marketing surveillance study assessed the safety of Cervarix among Chinese girls and women aged 9–45 years who were vaccinated with Cervarix voluntarily as per standard practice. The study included 3,013 participants who received 8,839 doses of Cervarix. Administration of Cervarix was well tolerated, and no safety concerns were identified.

Just 4.9% of participants reported medically attended AEFIs within 30 days of vaccination, and these were mainly categorized as”Infections and infestations”. The vast majority of these medically attended AEFIs were non-severe; only two non-serious AEFI cases, namely two cases of pyrexia, were considered to be related to vaccination. During the entire study, 5.5% of participants reported any AEFI, and 40 serious AEFIs were reported by 0.7% of participants. None of these serious AEFIs were considered to be related to vaccination, and most were of moderate or mild severity. All serious AEFIs were recovered/resolved or recovering/resolving at the end of the study. The efficacy, immunogenicity, and safety of Cervarix have previously been assessed in Chinese women aged 18–25 years, in a clinical trial (NCT00779766) that included 6,051 participants, of whom 3,026 received Cervarix and 3,025 received a comparator.^19,21 In that study, 1.9% of Cervarix-vaccinated participants and 2.7% of the controls reported at least one serious adverse event, which is slightly higher than the percentage of serious adverse events reported in the current study (0.7%). This discrepancy may be due to a difference in reporting. In the current study, a combination of active and passive surveillance was used, with a maximum follow-up period of 24 months; in the earlier clinical trial, participants were required to actively complete diary cards for seven days after each vaccination, and follow-up was more intensive over a period of 24–72 months. However, the percentage of pIMDs reported (0.1% in both the vaccinated and control groups), in the previous clinical trial was similar to the percentage we found in our current study (0.03%, 95% CI: 0.0–0.2).^19,21

Although any AEFIs were recorded, only AEFIs (whether anticipated or unanticipated), that required medical attention were analyzed in our study. Multiple previous studies have shown that Cervarix, similar to other vaccines, often causes mild AEFIs, such as injection-site reactions (pain and swelling), that do not require medical attention.²² We chose not to include these mild AEFIs in the analyses as they are well known.

pIMDs are adverse events of interest during the safety assessment of any adjuvanted vaccine, including Cervarix. By the end of our follow-up period, one participant reported a pIMD (neuritis). The investigator considered this pIMD not causally related to the vaccination, and the participant recovered fully after treatment. As our study involved just 3,013 participants, this was, too few individuals to assess the risk of developing pIMDs. However, several large post-marketing studies have assessed the risk of developing pIMDs following Cervarix vaccination. A large, retrospective, observational cohort study in the United Kingdom found no increase in autoimmune disease following Cervarix vaccination. However, when analyzing confirmed cases only, an increased risk of autoimmune thyroiditis (incidence rate ratio 3.75, 95% CI: 1.25–11.31) and a decreased risk of type 1 diabetes (incidence rate ratio 0.30, 95% CI: 0.11–0.83) were found.²³ A study in France found no overall increase in autoimmune diseases among more than 2.2 million girls aged 13–16 years, of whom 37.4% were vaccinated with any HPV vaccine (7% received Cervarix). In that study, an association was found between Cervarix vaccination and thyroiditis and a potential increased risk of Guillain – Barré syndrome (GBS) after any HPV vaccination.²⁴ However, a re-analysis of these data that excluded nonimmune thyroiditis showed that Cervarix vaccination was not associated with an increased risk of autoimmune thyroiditis.²⁵

A subsequent study of all admissions to National Health Service hospitals in England was set up to specifically analyze the risk of GBS following HPV vaccination. The study found no increase in GBS within a year following vaccination, in an analysis of 10.4 million doses of any HPV vaccine in girls aged 12–18 years.²⁶ In a clinical trial in Finland involving girls and boys aged 12–15 years 14,838 participants were vaccinated with Cervarix and 17,338 with a hepatitis B vaccine. In that study, no difference in autoimmune diseases was observed between the groups.²⁷ A meta-analysis of 21 studies involving 154,398 women exposed to Cervarix and 1,504,322 non-exposed women found no increased risk of inflammatory bowel disease and a 1.5-fold increased risk of autoimmune thyroiditis (95% CI: 1.2–1.8). That study design did not allow a conclusion to be drawn about a causal association between Cervarix and GBS; although an 11.1-fold increased risk of GBS (95% CI: 2.0–61.9) was detected, too few GBS cases were detected to draw firm conclusions.²⁸

In our study, pregnancy outcomes were of interest because the target population for immunization against HPV includes women of child-bearing age. In the current study, 2.2% of participants (n = 65) reported having become pregnant and inadvertently vaccinated with Cervarix. Among them, one pregnancy (n = 1/65, 1.5%) resulted in a spontaneous abortion, and one pregnancy (1.5%) resulted in the live birth of a child with a congenital anomaly. Apart from pregnancies lost to follow-up (n = 5/65, 7.7%), the outcomes of the other pregnancies did not suggest that any congenital anomalies were present. In a clinical trial (NCT00779766) in China, approximately 6,000 women were vaccinated with either Cervarix or a comparator. In that trial, 27.7% of Cervarix-vaccinated participants reported a pregnancy during the study, a much higher proportion than in the current study (2.2%), which can be explained by the different age groups of the participants in each study: 18–25 years in the previous clinical trial versus 9–45 years in the current study.^21,29 During the clinical trial, 0.7% (n = 6/837) of the pregnancies in the vaccine group and 0.4% (n = 3/853) of the pregnancies in the control group resulted in an offspring with a congenital anomaly, comparable to the one pregnancy (1.5%) with a congenital anomaly in the current study.²¹ A study in the United Kingdom specifically analyzed pregnancy outcomes by comparing pregnant women aged 15–25 years, who either conceived in the 30 days before to 45 days after Cervarix vaccination (exposed group, n = 207) or between four and 18 months after the last vaccine dose (unexposed group, n = 632). That study found no evidence of an increased risk of spontaneous abortion in women vaccinated around the time of conception (hazard ratio 1.30, 95% CI: 0.79–2.12).³⁰ A pregnancy exposure registry has also been established to collect data on pregnancies exposed to Cervarix vaccination between 60 days before the estimated conception date and the delivery date. An analysis of data from this registry found no suggestion that Cervarix vaccination increased the risk of abnormal pregnancy outcomes or congenital anomalies.³¹

The frequency of congenital anomalies in the current study (1.5%) was of the same magnitude as that in the Chinese population in 2009 (1.5% of over 1.37 million births) and in a global clinical trial (0.8%) of Cervarix.^32,33 Furthermore, the frequency of congenital anomalies in our study was lower than the estimated frequency of birth defects worldwide (6%).³⁴ Although no studies have found that Cervarix vaccination increases the risk of adverse pregnancy outcomes, HPV vaccination is not recommended during pregnancy.³⁵

This study was the first post-marketing safety study of HPV vaccination in China. A strength of the study was to establish prospective follow-up of vaccinated participants for at least 12 months from the third dose or 24 months from the first dose, thus allowing information to also be gathered about potential delayed adverse events. This length of follow-up was appropriate to capture the AEFIs of interest, such as pIMDs, for which the theoretical risk period is at least six months and up to one year after the last dose.³⁶

One limitation of the study is the low representation (11.6%) of the age group 9–17 years, while the age group 26–45 years is overrepresented (72.8%). An earlier clinical trial (NCT00779766) in China only included participants aged 18–25 years (mean 23.0), while the current study mainly included women aged ≥26 years (mean 30.6). Therefore, the safety data from the current study may not be representative of the complete target population (girls and women aged 9–45 years) for the Cervarix vaccine.^19,21 Another limitation is the lack of a control/comparator group or country-wide reference data that would facilitate interpretation of the results. A nationwide electronic data collection system is as yet unavailable in China, although research is ongoing to determine the value of existing electronic healthcare databases for post-marketing drug safety surveillance.³⁷ This precludes the comparison of vaccinated individuals with matched, non-vaccinated individuals. This was, however, not part of our study design. A third limitation is that the sample size of our study was relatively small, with slightly more than 3,000 women, which precludes the identification of rare adverse events.

In conclusion, the administration of Cervarix was well tolerated when administered to Chinese girls and women aged 9–45 years. None of the reported serious AEFIs was considered to be causally related to vaccination. No safety concerns with Cervarix were identified, although rare adverse events may have been missed.

Trademark

Cervarix is a trademark owned by or licensed to GSK.

Contributorship

All authors participated in the design, implementation or analysis, and interpretation of the study; and the development of this manuscript. All authors had full access to the data and gave final approval before submission.

Acknowledgments

The authors would like to thank Pinyada Redlich and Elena Borisova Sharkova who provided support for the study, and Naveen Karkada and Laurence Boquia, who provided statistical analysis support. The authors would also like to thank the Business & Decision Life Sciences platform for editorial assistance and manuscript coordination, on behalf of GSK. Esther van de Vosse provided medical writing support.

Disclosure Statement

AG, KG, YX, KL, YH, NJ, ANT, and DB are employees of GSK. SW and DR were employees of GSK. SW, AG, ANT, DR, and DB hold shares in GSK. HY reports grants from GSK, grants from Yichang HEC Changjiang Pharmaceutical Co., Ltd, grants from Sanofi Pasteur, grants from Shanghai Roche Pharmaceutical Company, grants from Shenzhen Sanofi Pasteur Biological Products Co., LTD., and grants from bioMérieux Diagnostic Product (Shanghai) Co., Ltd, outside the submitted work. The authors declare no other financial or non-financial relationships or activities. QW, MQ, QT, JX, TZ, QW, YP, RZ, JY, XZ, and MZ declare no financial and non-financial relationships and activities and no conflicts of interest.

Data availability statement

To request access to patient-level data and documents for this study, please submit an inquiry via www.clinicalstudydatarequest.com.

Supplementary material

Supplemental data for this article can be accessed on the publisher’s website at https://doi.org/10.1080/21645515.2023.2283912.

Additional information

Funding

GlaxoSmithKline Biologicals SA funded this study (GSK study identifier: 207350 or NCT03438006) and was involved in all stages of study conduct, including analysis of the data. GlaxoSmithKline Biologicals SA also took charge of all costs associated with the development and publication of this manuscript.