Post-marketing surveillance study of the safety of the HPV-16/18 vaccine in Korea (2017–2021)

ABSTRACT

Human papillomavirus (HPV) infection is associated with the risk of developing certain cancers, including cancers of the cervix, vulva, vagina, penis, anus, rectum, and oropharynx. In 2016, the bivalent HPV-16/18 vaccine was included in the Korea National Immunization Program. This vaccine protects against HPV types 16 and 18 and other oncogenic HPV types predominant in cervical and anal cancers. This post-marketing surveillance (PMS) study assessed the safety of the HPV-16/18 vaccine in Korea. The study was conducted in males and females aged between 9 and 25 years, from 2017 to 2021. Safety was measured in terms of frequency and intensity of adverse events (AEs), adverse drug reactions (ADRs), and serious adverse events (SAEs) after each vaccine dose. The safety analysis included all participants who were vaccinated as per prescribing information and who completed a 30-day follow-up after at least one dose. Data were collected using individual case report forms. The total safety cohort included 662 participants. A total of 220 AEs were reported in 144 subjects (21.75%), and there were 158 ADRs in 111 subjects (16.77%), with the most common being injection site pain in all cases. No SAEs or serious ADRs were reported. Most AEs were reported after the first dose and were injection site reactions with mild intensity that recovered. No individuals required hospitalization or an emergency department visit. Safety results showed that the HPV-16/18 vaccine was generally well tolerated in the Korean population, and no safety concerns were identified.

ClinicalTrials.gov Identifier: NCT03671369.

Plain Language Summary

What is the context?

• Infection with human papillomavirus (HPV) is linked to the development of certain cancers.

• More specifically, HPV types 16 and 18 are predominant in cervical and anal cancers.

• In 2016, the HPV-16/18 vaccine was included in the National Immunization Program of Korea.

What is new?

• The objective of this study was to evaluate the safety of the HPV-16/18 vaccine following its introduction in Korea.

• The study was conducted from 2017 to 2021 in young Korean men and women between 9 and 25 years of age.

• The study analyzed 662 participants, of whom:

  • ∘ 144 reported 220 adverse events

  • ∘ 111 reported 158 adverse drug reactions

  • ∘ None reported serious adverse events

• The safety of the vaccine was measured after each dose as the number and intensity of:

  • ∘ Adverse events, which are side-effects or unwanted reactions that might be associated with the use of the vaccine

  • ∘ Adverse drug reactions, which are side-effects or unwanted reactions associated with the use of the vaccine

  • ∘ Serious adverse events, which are reactions resulting in death, disability, are life-threatening, or require hospitalization (or prolongation of it).

• Most adverse events occurred following the first dose, were mild in intensity, and the participants recovered after a few days. Injection site pain was the most common adverse event following vaccination.

What is the impact?

• The study showed that the HPV-16/18 vaccine is safe and generally well tolerated in Korean participants.

KEYWORDS:

• HPV
• bivalent vaccine
• AS04-adjuvanted HPV-16/18 vaccine
• HPV-16/18
• safety
• post-marketing surveillance
• Korea

Introduction

Infection with human papillomavirus (HPV) is associated with a risk of developing certain cancers, including cancers of the cervix, vulva, vagina, penis, anus, rectum, and oropharynx. More than 80% of all HPV-associated cancers occur in the cervix.¹ Recent data from the HPV Information Centre shows that 570,000 women are diagnosed with cervical cancer annually, and 311,000 die from it; most cases occur in low- and middle-income countries.² Approximately 70% of cervical cancers are associated with HPV-16 and/or HPV-18 infection.²

Anal cancer, on the other hand, is rare in the general population, with 50,000 new cases worldwide in 2020.³ Its incidence is higher in high-income countries, where it has increased substantially in both men and women in recent years.^2,4 Available data show HPV infection to be associated with approximately 90% of anal cancers.^5,6 Anal cancer incidence is higher among immunosuppressed individuals, including individuals infected with human immunodeficiency virus (HIV),⁷ populations of men who have sex with men,⁸ women with a history of cervical or vulvar cancer,⁹ and individuals with certain lifestyle factors such as smoking or a high number of sexual partners (>5).¹⁰ Currently, in South Korea, anal cancer accounts for 0.1% of total cancer cases; however, the high-risk population is increasing.^11,12

Thanks to novel technologies that enable the detection of HPV in cancers other than those of the cervix (i.e., anus, vulva, vagina, and penis), data documenting the presence of HPV in anogenital cancers are accumulating.^2,13 This association makes these cancers potentially preventable through strategies similar to those currently applied for cervical cancer.² Preventive strategies against HPV infection include the use of HPV vaccines.^14,15 In 2008, the Ministry of Food and Drug Safety (MFDS) approved the use of the bivalent HPV-16/18 vaccine (Cervarix, GSK) in South Korea. Later, in 2016, it was included in South Korea’s National Immunization Program for the vaccination of 12-year-old girls in a two-dose schedule.^11,16

Following the analysis of four immunogenicity and safety trials assessing the HPV-16/18 vaccine in females (Studies HPV-010, NCT00423046; and HPV-071, NCT01462357)^17,18 and males (Studies HPV-011, NCT00309166; and HPV-040, NCT00534638),^19–21 the MFDS approved the amended vaccine indication to include anal cancer caused by HPV types 16 and 18 and extended its use to males.²² As required by the MFDS, post-marketing surveillance (PMS) was performed to collect safety data in relation to the use of the HPV-16/18 vaccine. In the present study, we analyze the safety of the HPV-16/18 vaccine in individuals aged 9 to 25 years under PMS conditions.

Participants and methods

Study design and setting

This was a prospective, observational, non-comparative, self-contained, multi-center, post-marketing surveillance study of the HPV-16/18 vaccine, conducted in South Korea (ClinicalTrials.gov Identifier: NCT03671369). Continuous surveillance of the vaccine safety in males and females aged 9 to 25 years was conducted from July 2017 to July 2021, in 29 surveillance sites (see Table S1). Safety was measured in terms of the frequency and intensity of adverse events (AEs) and serious adverse events (SAEs).

Study population

Participants were Korean males and females aged 9 to 25 years and who were eligible for vaccination according to the local prescribing information (PI).²² Participants (or their parents/legal representatives) were required to sign an informed consent form (ICF) and be able to comply with the requirements of the protocol (e.g., complete diary cards, follow-up visits). The participant or the participant’s parents/legal representatives purchased the vaccine.

Individuals with contraindications according to the PI or the judgment of the physician, who had previously received an HPV vaccine other than the HPV-16/18 vaccine, or were children in care (i.e., placed under the control and protection of an agency, organization, institution, or entity by the courts), were excluded from the study.

Definitions

An AE was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of the vaccine.

An adverse drug reaction (ADR) was defined as any adverse, unintended reaction from normal administration whose causality due to the vaccine could not be ruled out.

An SAE was defined as any medical occurrence that results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability, or is a congenital anomaly.

AEs, ADRs, and SAEs were classified as expected (i.e., described in the approved PI) or unexpected (not described in the PI) at the time of the statistical analysis.

Study procedures

The HPV-16/18 vaccine was administered outside of the study according to the local PI. Male and female participants aged 9 to 14 years were vaccinated with two doses at a 0 and 6 to 12 months schedule. If the second dose was administered before 5 months, a third dose was required. Participants aged 15 to 25 years were vaccinated with three doses at 0, 1, and 6 months (the second dose could also be administered at 1 to 2.5 months and the third at 5 to 12 months).

Data were collected using individual case report forms (CRFs). CRFs collected data on demographics (age, gender), physical examination (weight and height), medical history, concomitant medication (within 30 days after vaccine administration), concomitant vaccination or use of investigational medication (from 30 days before first vaccination until 30 days after the last vaccine dose), vaccination information, and safety data on AEs, ADRs, and SAEs.

The detailed procedure followed during each visit is shown in the supplementary material, Table S2.

Safety monitoring

Safety analysis was performed on the total safety cohort (TSC), which included all participants who were vaccinated as per PI and completed a 30-day follow-up after at least one dose, regardless of the number of doses.

Medication taken, AEs, SAEs, ADRs, and pregnancy were recorded in diary cards by the participants. Any AEs during a 30-day period after each vaccine dose were recorded. Any SAEs, ADRs, and pregnancies were recorded for an uninterrupted period from the first vaccine dose until 30 days after the last one. Information recorded in the diary cards was collected and transcribed by physicians into the CRFs.

The intensity of AEs and SAEs was categorized as mild (i.e., easily tolerated and not interfering with everyday activities), moderate (i.e., discomforting and interfering with everyday activities), or severe (i.e., prevents everyday activities). Fever intensity was graded as mild (≥37.5°C to≤38.0°C), moderate (>38.0°C to≤39.0°C), or severe (>39.0°C). Pregnancy during the study was not counted as an AE or SAE. However, pregnancy was followed-up to determine the outcome.

The assessment of causality and outcome was performed by physicians according to the MFDS guidelines. Causality was classified as: (1) certain, (2) probable/likely, (3) possible, (4) unlikely, (5) conditional/unclassified, and (6) unassessable/unclassifiable. Outcome was classified as: (1) recovered, (2) not recovered, (3) recovering, (4) resolved with sequelae, (5) fatal, and (6) unknown.

Endpoints and statistical analysis

Two main endpoints were defined. The first was the occurrence of AEs during the follow-up period after each vaccine dose. The second was the occurrence of SAEs throughout the study and up to 30 days after the last vaccine dose.

According to MFDS guidelines, the minimum sample size for a safety evaluation is 600 subjects. Therefore, 670 individuals were enrolled, assuming a dropout rate of 10%. Participants were enrolled in sequential order after the date of contract and until the agreed number of individuals was reached.

Participants’ demographic characteristics (age, gender, and ethnicity), as well as weight, height, and distribution by surveillance center, were tabulated using descriptive statistics. Mean, standard deviation (SD), median, minimum, and maximum were calculated for continuous variables, while frequency and percentage were calculated for categorical variables. The medical history by disease classification and per past/current status, and vaccination history of the vaccinated individuals was also determined.

Analyses of AE/SAE data reported after each dose were performed separately. AEs and SAEs were analyzed and classified as expected or unexpected. The number and percentage (with 95% confidence interval, CI) of any AEs reported was tabulated, for each dose, for overall doses, and by the number of subjects. AEs collected during the study were coded using MedDRA version 24.0.

Withdrawal

Withdrawal was defined as any subject who did not return for the final study visit. However, all data collected until the date of withdrawal were used for the safety analysis. Any information relating to a withdrawal was documented in the CRFs.

According to the protocol, withdrawals due to SAEs/AEs were clearly distinguished from withdrawals for other reasons, and physicians were tasked with following up any individuals who withdrew, until the resolution of the event. Individuals who withdrew were not replaced.

Regulatory and ethical considerations

This study was designed and conducted in accordance with the ICH guidelines for Good Clinical Practice, the ICH Harmonized Tripartite Guidelines for clinical investigation of medicinal products in the pediatric population (ICH E11), all applicable individual privacy requirements, and the guiding principles of the Declaration of Helsinki. The study protocol was reviewed and approved by an Institutional Review Board/Independent Ethics Committee. The ICF for this study did not include consent for vaccination, as vaccination was undertaken at the discretion of participants’ (or their parent(s)/legal representatives) and a physician.

Results

Demographics

From the initially enrolled cohort in this PMS of 670 participants, 669 of them received at least one vaccine dose. Out of those 669 subjects, 5 did not meet the inclusion/exclusion criteria and 2 were not vaccinated, according to the local PI. Therefore, 662 participants were included in the total safety cohort. Among them, 378 participants received the second or third dose of the vaccine according to their age based on the local PI, and completed the study. A total of 289 participants received at least one vaccine dose but withdrew from the study for causes not related to AEs or SAEs. Two individuals received at least one vaccine dose but were withdrawn due to protocol deviation. Most of the subjects in the total safety cohort were females (n = 639; 96.53%). The majority of the subjects were 9 to 14 years old (n = 595; 89.88%) (Table 1), with just 55 participants (8.31%) being adults (≥18 years of age). Participants’ mean age was 12.93 (SD 2.76) years, and their mean body mass index was 20.19 (SD 3.35).

Table 1. Demographics and incidence of adverse events by demographics.

		AEs by demographics
	Total safety cohort (N = 662) n (%)^a	Subjects with AEs n (%)^b [95% CI]	AEs (n)	p-value
Age group
9–14 years	595 (89.88)	134 (22.52) [19.22, 26.09]	208	.1531
15–25 years	67 (10.12)	10 (14.93) [7.40, 25.74]	12	.1531
Female	639 (96.53)	141 (22.07) [18.91, 25.48]	216	.3028
Number of vaccine doses received
1	469 (70.85)	83 (17.70) [14.35, 21.46]	126	<.0001
2	167 (25.23)	58 (34.73) [27.54, 42.47]	90	<.0001
3	26 (3.93)	3 (11.54) [2.45, 30.15]	4	<.0001
Medical history
Past	67 (10.12)	29 (43.28) [31.22, 55.96]	48	<.0001
Current	70 (10.57)	24 (34.29) [23.35, 46.60]	34	.0072
Medication
Prior^c	24 (3.63)	6 (25.00) [9.77, 46.71]	6	.6944
Concomitant	91 (13.75)	61 (67.03) [56.39, 76.53]	101	<.0001
After 1^st dose	62 (13.57)	39 (62.90) [49.69, 74.84]	64	<.0001
After 2^nd dose	37 (9.51)	26 (70.27) [53.02, 84.13]	45	<.0001
After 3^rd dose	3 (8.57)	1 (33.33) [0.84, 90.57]	1	.3132
Vaccination^d
Prior^c	56 (8.46)	16 (28.57) [17.30, 42.21]	22	.1961
Concomitant	191 (28.85)	52 (27.23) [21.05, 34.12]	77	.0297
After 1^st dose	154 (33.70)	45 (29.22) [22.18, 37.08]	67	.0089
After 2^nd dose	43 (11.05)	10 (23.26) [11.76, 38.63]	15	.6116
After 3^rd dose	0 (0.00)	0 (0) [0.00, 0.00]	0	NA
Bivalent HPV vaccination status prior to study start
Yes	205 (30.97)	43 (20.98) [15.62, 27.20]	70	.7456
1 dose	197 (96.10)	42 (21.32) (15.82, 27.71)	69
2 doses	8 (3.90)	1 (12.50) (0.32, 52.65)	1

^a% = (n/N) × 100, where N = total safety cohort, and n = number of subjects in a given category;

^b% = (n/N) × 100, where N = number of subjects in a given category, and n = number of subjects with an AE in a given category;

^cwithin 30 days prior HPV vaccination;

^dvaccination other than the bivalent HPV vaccine; 95% confidence intervals for the percentage of subjects with an AE were calculated by Exact Methods.

Abbreviations: AE, adverse event; CI, confidence interval; HPV, human papillomavirus.

The vast majority of participants had no past or concomitant medical history or medication (see Table 1, Table S3, and Table S4 for detailed information). Fifty-six individuals (8.46%) had received a vaccine other than the bivalent HPV vaccine within 30 days prior to their HPV vaccination. A total of 191 subjects (28.85%) were administered any vaccines other than the bivalent HPV vaccine within 30 days of vaccination.

Incidence of AEs, ADRs, and SAEs

Incidence of AEs

A total of 144 out of 662 (21.75%) participants reported at least one AE. Overall, 220 AEs were reported in these 144 individuals. Most AEs occurred at the administration site, were of mild to moderate intensity, and recovered. A total of 50 events needed a visit to medical personnel, but no AEs needed hospitalization or a visit to an emergency department (see Table S5). Among the 220 reported AEs, 217 resolved (reported by 143 subjects), 196 were of mild intensity, while the remaining 24 AEs were of moderate intensity (see Table S5). The most frequently reported AEs were injection site pain (9.06% [60/662 subjects]; 68 events), followed by injection site erythema (4.68% [31/662 subjects]; 34 events), and injection site swelling (1.96% [13/662 subjects]; 13 events) (Table 2). Fever was the most frequent systemic AE (1.81% [12/662 subjects]; 12 events). Among all subjects, 2.27% (15/662) reported 21 AEs that were unexpected. The most frequent unexpected AE by preferred terms (PTs) was allergic rhinitis in 0.76% of the subjects (5/662; 5 events), followed by asthma (0.45% [3/662 subjects]; 3 events) (Table 2). All 21 unexpected AEs but one were classified as unlikely caused by the vaccine according to investigators. Only one case, chronic sinusitis, was categorized as “unassessable/unclassifiable.” None of the unexpected AEs were considered to be vaccine-related by the investigator.

Table 2. Incidence of adverse events and adverse drug reactions by disease.

	Adverse events		Adverse drug reactions
	Subjects with an AE n (%)^a [95% CI]	AEs n	Subjects with an ADR n (%)^b [95% CI]	ADRs n
Total	144 (21.75) [18.67, 25.09]	220	111 (16.77) [14.00, 19.84]	158
General disorders and administration site conditions	107 (16.16) [13.44, 19.19]	141	105 (15.86) [13.16, 18.87]	138
Injection site pain	60 (9.06) [6.99, 11.51]	68	60 (9.06) [6.99, 11.51]	68
Injection site erythema	31 (4.68) [3.20, 6.58]	34	31 (4.68) [3.20, 6.58]	34
Injection site swelling	13 (1.96) [1.05, 3.33]	13	13 (1.96) [1.05, 3.33]	13
Fever^c	12 (1.81) [0.94, 3.14]	12	10 (1.51) [0.73, 2.76]	10
Injection site pruritus	4 (0.60) [0.16, 1.54]	4	4 (0.60) [0.16, 1.54]	4
Injection site bruising	2 (0.30) [0.04, 1.09]	2	2 (0.30) [0.04, 1.09]	2
Injection site paresthesia	2 (0.30) [0.04, 1.09]	2	2 (0.30) [0.04, 1.09]	2
Pain	2 (0.30) [0.04, 1.09]	2	1 (0.15) [0.00, 0.84]	1
Fatigue	1 (0.15) [0.00, 0.84]	1	1 (0.15) [0.00, 0.84]	1
Injection site edema	1 (0.15) [0.00, 0.84]	1	1 (0.15) [0.00, 0.84]	1
Injection site rash	1 (0.15) [0.00, 0.84]	1	1 (0.15) [0.00, 0.84]	1
Injection site warmth	1 (0.15) [0.00, 0.84]	1	1 (0.15) [0.00, 0.84]	1
Infections and infestations	32 (4.83) [3.33, 6.76]	33	3 (0.45) [0.09, 1.32]	3
Tonsillitis	7 (1.06) [0.43, 2.17]	7	0 (0.00) [0.00, 0.56]	0
Nasopharyngitis	5 (0.76) [0.25, 1.75]	5	0 (0.00) [0.00, 0.56]	0
Pharyngitis	4 (0.60) [0.16, 1.54]	4	0 (0.00) [0.00, 0.56]	0
Bronchitis	3 (0.45) [0.09, 1.32]	3	0 (0.00) [0.00, 0.56]	0
Rhinitis	3 (0.45) [0.09, 1.32]	3	1 (0.15) [0.00, 0.84]	1
Upper respiratory tract infection	3 (0.45) [0.09, 1.32]	3	1 (0.15) [0.00, 0.84]	1
Chronic sinusitis^d	2 (0.30) [0.04, 1.09]	2	1 (0.15) [0.00, 0.84]	1
Paronychia^d	2 (0.30) [0.04, 1.09]	2	0 (0.00) [0.00, 0.56]	0
Pneumonia	2 (0.30) [0.04, 1.09]	2	0 (0.00) [0.00, 0.56]	0
Conjunctivitis	1 (0.15) [0.00, 0.84]	1	0 (0.00) [0.00, 0.56]	0
Impetigo^d	1 (0.15) [0.00, 0.84]	1	0 (0.00) [0.00, 0.56]	0
Gastrointestinal disorders	10 (1.51) [0.73, 2.76]	10	2 (0.30) [0.04, 1.09]	2
Gastroenteritis	2 (0.30) [0.04, 1.09]	2	0 (0.00) [0.00, 0.56]	0
Nausea	2 (0.30) [0.04, 1.09]	2	2 (0.30) [0.04, 1.09]	2
Diarrhea	1 (0.15) [0.00, 0.84]	1	0 (0.00) [0.00, 0.56]	0
Enteritis	1 (0.15) [0.00, 0.84]	1	0 (0.00) [0.00, 0.56]	0
Functional gastrointestinal disorder^d	1 (0.15) [0.00, 0.84]	1	0 (0.00) [0.00, 0.56]	0
Gastritis^d	1 (0.15) [0.00, 0.84]	1	0 (0.00) [0.00, 0.56]	0
Gastrointestinal inflammation	1 (0.15) [0.00, 0.84]	1	0 (0.00) [0.00, 0.56]	0
Vomiting	1 (0.15) [0.00, 0.84]	1	0 (0.00) [0.00, 0.56]	0
Nervous system disorders	10 (1.51) [0.73, 2.76]	11	7 (1.06) [0.43, 2.17]	8
Headache	6 (0.91) [0.33, 1.96]	6	5 (0.76) [0.25, 1.75]	5
Dizziness	4 (0.60) [0.16, 1.54]	4	3 (0.45) [0.09, 1.32]	3
Syncope	1 (0.15) [0.00, 0.84]	1	0 (0.00) [0.00, 0.56]	0
Musculoskeletal and connective tissue disorders	7 (1.06) [0.43, 2.17]	7	7 (1.06) [0.43, 2.17]	7
Myalgia	6 (0.91) [0.33, 1.96]	6	6 (0.91) [0.33, 1.96]	6
Back pain	1 (0.15) [0.00, 0.84]	1	1 (0.15) [0.00, 0.84]	1
Respiratory, thoracic, and mediastinal disorders	6 (0.91) [0.33, 1.96]	8	0 (0.00) [0.00, 0.56]	0
Allergic rhinitis^d	5 (0.76) [0.25, 1.75]	5	0 (0.00) [0.00, 0.56]	0
Asthma^d	3 (0.45) [0.09, 1.32]	3	0 (0.00) [0.00, 0.56]	0
Eye disorders	3 (0.45) [0.09, 1.32]	3	0 (0.00) [0.00, 0.56]	0
Chalazion	1 (0.15) [0.00, 0.84]	1	0 (0.00) [0.00, 0.56]	0
Dry eye	1 (0.15) [0.00, 0.84]	1	0 (0.00) [0.00, 0.56]	0
Ocular discomfort^d	1 (0.15) [0.00, 0.84]	1	0 (0.00) [0.00, 0.56]	0
Skin and subcutaneous tissue disorders	3 (0.45) [0.09, 1.32]	3	0 (0.00) [0.00, 0.56]	0
Dermatitis atopic	1 (0.15) [0.00, 0.84]	1	0 (0.00) [0.00, 0.56]	0
Keratosis pilaris^d	1 (0.15) [0.00, 0.84]	1	0 (0.00) [0.00, 0.56]	0
Urticaria	1 (0.15) [0.00, 0.84]	1	0(0.00) [0.00, 0.56]	0
Immune system disorders	2 (0.30) [0.04, 1.09]	2	0 (0.00) [0.00, 0.56]	0
Lip swelling^d	1 (0.15) [0.00, 0.84]	1	0 (0.00) [0.00, 0.56]	0
Swelling of eyelid^d	1 (0.15) [0.00, 0.84]	1	0 (0.00) [0.00, 0.56]	0
Injury, poisoning, and procedural complications	2 (0.30) [0.04, 1.09]	2	0 (0.00) [0.00, 0.56]	0
Burns, second degree^d	1 (0.15) [0.00, 0.84]	1	0 (0.00) [0.00, 0.56]	0
Limb injury^d	1 (0.15) [0.00, 0.84]	1	0 (0.00) [0.00, 0.56]	0

^a% = (n/N) × 100, where N = total safety cohort, and n = number of subjects with AEs in a given category;

^b% = (n/N) × 100, where N = number of subjects in a given category, and n = number of subjects with ADRs in a given category;

^cFever is defined as a temperature ≥ 37.5°C on oral, axillary, or tympanic setting, or ≥ 38.0°C on rectal setting;

^dUnexpected AE/ADR.

Abbreviations: AE, adverse event; ADR, adverse drug reaction; CI, confidence interval; HPV, human papillomavirus.

Regarding the incidence data by vaccine dose (Table S6), the highest incidence of AEs was recorded after the second dose (18.77% [73/389 individuals]; 106 events), followed by the first dose (17.72% [81/457 individuals]; 113 events) and third dose (2.86% [1/35 individuals]; 1 event). Across doses (Table S6), the most frequently reported AE was injection site pain. The respective incidence proportions of injection site pain were 6.78% after the first dose (31/457 individuals; 31 events), 9.00% after the second dose (35/389 individuals; 36 events), and 2.86% after the third dose (1/35 individuals; 1 event).

Incidence of ADRs

The incidence proportion of ADRs was 16.77% (111/662 individuals; 158 events). The most frequently reported ADRs were injection site pain (9.06% [60/662 individuals]; 68 events), injection site erythema (4.68% [31/662 individuals]; 34 events), and injection site swelling (1.96% [13/662 individuals]; 13 events). One event was reported as an unexpected ADR (chronic sinusitis) (Table 2).

Incidence data by vaccine dose (Table S7) showed that most ADRs were reported after the second dose. The respective incidence proportions of ADRs were 13.57% after the first dose (62/457 individuals; 76 events), 14.91% after the second dose (58/389 individuals; 81 events), and 2.86% after the third dose (1/35 individuals; 1 event).

No SAEs, serious ADRs, pregnancies, or individuals who experienced liver or renal disease were reported during the study period.

A detailed record (per system organ class, preferred term, seriousness, administration site, outcome, intensity, causality, medical visit, and expectedness) of all AEs and ADRs registered during the study is provided in the Supplementary Material, Table S8.

Discussion

In this PMS study, a total safety cohort of 662 individuals, 9 to 25 years of age, who received the HPV-16/18 vaccine was included. A total of 220 AEs were reported in 144 individuals (21.75%), while there were 158 ADRs in 111 individuals (16.77%), the most common being injection site pain in all cases. Most AEs were recorded after the first dose (113 events in 81 individuals), at the administration site (126 events), with mild intensity (196 events in 138 individuals), and recovered as an outcome (217 events in 143 individuals). No individuals required hospitalization or an emergency department visit. No SAEs or serious ADRs were reported.

The current PMS results showed similar AE, ADR, and SAE incidences to those reported in previous local studies. Setiawan et al.’s meta-analysis confirmed that the safety profile of the HPV-16/18 vaccine was acceptable for Asian populations, and vaccination had a low risk of AEs. Local AEs, mainly injection site reactions (i.e., pain, erythema, and swelling), were the most common. Most AEs were mild and resolved within 5 to 7 days, or in our case, during the study period.²³ Comparable results were also reported in a previous South Korean PMS study, where 3,084 South Korean females aged 10 to 25 years were vaccinated. Throughout that study, 20.5% of individuals reported at least one AE (21.7% in our study), primarily after the first dose (18.2%; 17.7% in our study); again, the most common was injection site pain (10.4%; 9.1% in our study).²⁴ Furthermore, a recent nationwide cohort study performed in Korea found no association between HPV vaccination and SAEs, which is in agreement with our PMS results, where no SAEs or serious ADRs were registered.²⁵

Safety results therefore show that the HPV-16/18 vaccine is generally well tolerated in Korea; this safety profile is consistent with data from other regions of the world, as exemplified by studies conducted in the UK²⁶ and Finland.²⁰ A meta-analysis by Descamps et al. again showed that injection site reactions are the main AEs following HPV-16/18 vaccination; they concluded that the vaccine had a favorable safety profile, with no clinically relevant differences between the HPV-16/18 vaccine and pooled control groups in rates of SAEs.²⁷ In a long-term follow-up trial performed in Brazil, all reported SAEs and pregnancy outcomes were also considered to be unrelated to the vaccine.²⁸ Similar results were reported by Einstein et al. in 2011, when a comparison with the quadrivalent HPV vaccine was performed; they concluded that both vaccines were generally well tolerated.¹⁷

The present study had several limitations. First, the lack of a control group calls for caution when interpreting the results. Second, gender representation was not balanced; the number of male participants (3.47% of the total cohort) was considerably lower than that of females, hence, safety results in males might be underrepresented. Moreover, from 662 individuals included in the study, only 378 of them received all vaccine doses. This implies that the safety cohort and data analyzed after the second (167 individuals) and third (26 individuals) vaccine dose were reduced when compared with the first one. Finally, additional limitations inherent to all PMS studies, including underreporting, reporting biases, or quality and completeness of the reported events are important to note. However, as the number of individuals analyzed was large, it was considered that these limitations were mitigated. Furthermore, the large number of study sites should mitigate the risk of selection bias.

Conclusion

The results of this PMS study of 662 individuals aged 9 to 25 years in South Korea showed the HPV-16/18 vaccine to be generally well tolerated and with a favorable safety profile. The incidence of reported events was similar to those of the currently approved local PI, as well as other PMS studies conducted locally or in other countries. Thus, this PMS study adds to the body of evidence on the overall safety profile of the HPV-16/18 vaccine.

Abbreviations

ADR	=	Adverse drug reaction
AE	=	Adverse event
CI	=	Confidence interval
CRF	=	Case report form
GCP	=	Good clinical practice
HIV	=	Human immunodeficiency virus
HPV	=	Human papillomavirus
ICF	=	Informed consent form
IEC	=	Independent ethics committee
IRB	=	Institutional review board
KFDA	=	Korea Food and Drug Administration
MFDS	=	Ministry of Food and Drug Safety
PI	=	Prescribing information
PMS	=	Post-marketing surveillance
SAE	=	Serious adverse event
TSC	=	Total safety cohort

Contributorship

All authors participated in the design or 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.

Trademark

Cervarix is a trademark owned by or licensed to GSK.

Acknowledgments

The authors would like to thank the global and regional teams of GSK, in particular Naveen Karkada and Raghavendra Devadiga, for their contribution to the protocol as part of the statistical team and Sarah Welby (Epidemiologist) for the coordination of the study. The authors would like to thank Business & Decision Life Sciences platform for editorial assistance and manuscript coordination, on behalf of GSK. Leire Iralde Lorente, on behalf of GSK, provided medical writing support.

Disclosure statement

EB, SX, HK and DB are employed by GSK. HK and DB hold shares in GSK. All authors declare no other financial and non-financial relationships, activities and no other conflicts of interest.

Data availability statement

Anonymized individual participant data and study documents can be requested for further research from www.clinicalstudydatarequest.com.

Supplementary material

Supplemental data for this article can be accessed on the publisher’s website at https://doi.org/10.1080/21645515.2023.2184756.

Additional information

Funding

GlaxoSmithKline Biologicals SA funded this study and took in charge all costs associated with the development and publication of this manuscript.