Abstract
Background
The burden of herpes zoster has been mitigated through the introduction of two types of vaccines, including zoster vaccine live (ZVL) and recombinant zoster vaccine (RZV). We aimed to compare the occurrence of adverse events within 90 days of vaccination.
Methods
We prospectively enrolled participants who received ZVL or RZV between October 2022 and November 2024 at five tertiary hospitals and nine primary care clinics in South Korea. Data on solicited and unsolicited adverse events were collected using questionnaires at 1, 3, 7, 28, and 90 days after vaccination. Demographic and clinical data including vaccination history, previous episodes of herpes zoster, underlying diseases, and immune status were also collected. Multivariable logistic regression analysis was conducted to assess the risk of solicited adverse events according to clinical variables.
Results
In total, 1,527 participants were enrolled, with 487 receiving ZVL, 632 receiving the first RZV dose, and 408 receiving the second RZV dose. In multivariable logistic regression analysis after adjusting clinical variables, the adjusted odds ratios (ORs) for the risk of solicited adverse events at day 1 were significantly lower in 11 categories for the ZVL group compared to the first-dose RZV group. However, for the second-dose RZV group, the adjusted ORs were significantly higher in 9 categories when compared to the first-dose RZV group. No life-threatening vaccine-related events occurred in the unsolicited adverse event reports between days 8 and 90.
Conclusion
After adjusting for clinical variables, the risks of many solicited adverse events were highest in the second-dose RZV group, followed by the first-dose RZV group, and were lowest in the ZVL group. However, the differences in risk diminished from day 1 to day 7. No fatal events occurred in either group. Clinicians should be aware of early reactogenicity of RZV.
Keywords: Herpes Zoster Vaccine, Zoster Vaccine Live, Recombinant Zoster Vaccine, Vaccination, Adverse Effects
Graphical Abstract
INTRODUCTION
Herpes zoster, a viral infection caused by the reactivation of the varicella-zoster virus (VZV), is associated with significant disease in adults, particularly older adults and those with underlying medical conditions, leading to severe complications and sequelae.1 The lifetime risk of herpes zoster is estimated to be approximately 30%, with over one million cases reported annually in the United States of America.2 In South Korea, the incidence of herpes zoster is reported to be 10.4/1,000 person-years, which increases with age.3 Herpes zoster develops by the reactivation of latent VZV, which remains in the sensory/autonomic ganglia following primary infection. This reactivation may be attributed to decline in VZV-specific cell-mediated immunity with advancing age and comorbidities. VZV immunity can reverse upon contact with the virus antigen, which forms the basis for the development of vaccines against herpes zoster.4
The zoster vaccine live (ZVL) was initially approved from the U.S. Food and Drug Administration (FDA) in 2006 and recommended for immunocompetent adults aged 60 and above. Two kinds of ZVL are available in South Korea, including Zostavax® (Merck, Rahway, NJ, USA) and SKYZoster® (SK Bioscience, Incheon, Korea). Subsequently, the age recommendation expanded to include individuals aged 50 and above in 2011.4 Recently in 2017, a more efficacious AS01B-adjuvanted recombinant zoster vaccine (RZV; Shingrix®, GlaxoSmithKline, London, UK) containing glycoprotein E antigen (50 μg) has replaced ZVL. Contrary to ZVL, RZV can be administered to immunocompromised patients, and its safety and effectiveness have been proven in clinical trials and post-marketing surveillance (PMS) for patients with hematologic malignancies and solid cancers.5,6,7 In South Korea, RZV was introduced in late 2022. Currently, both ZVL and RZV are available, but are not included in the Korean National Immunization Program (NIP). Therefore, healthcare provider and recipients must select a vaccine, with adverse reactions being one of the key considerations.
In the ZOE-50 trial, the proportion of solicited and unsolicited adverse events within 7 days after RZV vaccination was higher compared to placebo (84.4% vs. 37.8%) and greater than the incidence observed with the previously reported ZVL (58.1%).8,9 This increased rate might be attributable to adjuvants included in the RZV. However, the occurrence of adverse events may vary depending on several factors, including prior exposure to VZV antigens, immune status, age and sex. Furthermore, despite the population eligible for RZV has been expanded relative to ZVL, there has been no comparative analysis of the adverse event profiles between these two vaccines with accounting for these variables.
In this study, we aim to evaluate the incidence of adverse events within 90 days of vaccine administration with either ZVL or RZV, utilizing patient surveys. We will analyze the differences in the rates of solicited and unsolicited adverse events between two vaccines, considering relevant clinical variables. This research will elucidate the burden of vaccine-related adverse events associated with each vaccine and to provide objective safety data tailored to clinical contexts, thereby reducing vaccine-related hesitancy.
METHODS
Study design and adverse event data collection
This study was conducted to establish a safety monitoring system for vaccines not included in the NIP in Korea.10 We prospectively collected data on adverse events from individuals vaccinated with ZVL or RZV between October 2022 and November 2024 at five tertiary hospitals and nine primary care clinics. After obtaining informed consent, participants were asked to complete a questionnaire regarding the occurrence of adverse events at 1, 3, 7, 28, and 90 days after vaccination. On days 1, 3, and 7, questions were asked about solicited and unsolicited adverse events that occurred locally or systemically. On days 28 and 90, open questions were asked only about unsolicited adverse events that had occurred up to the time of the survey. For solicited adverse events, the local reactions (injection site pain, redness and limited motion) and systemic reactions (fever, chilling, headache, myalgia, fatigue, joint pain, nausea and vomiting, rash or urticaria, diarrhea, dyspnea, angioedema, paralysis and anaphylaxis) were graded to mild (grade 1), moderate (grade 2), severe (grade 3), and potentially life threatening (grade 4) according to the toxicity grading scale of U.S. FDA (Supplementary Table 1).11 The questionnaire uniform resource locator was sent to a mobile phone, and participants were asked to complete it. If they found it difficult to handle or did not complete the questionnaire, the survey was conducted over phone.
Participant data collection
Participants’ age, sex, administered vaccine type, date of vaccination, injection site, and simultaneous vaccination were collected. The research group did not intervene in deciding which vaccine to administer and followed the decisions of the attending physician and participants. We also collected information on discomfort before vaccination (individuals with physical discomfort were encouraged to report freely), previous ZVL vaccination history, history of vaccinations other than zoster within 3 months, history of herpes zoster within 5 years, and underlying diseases. Immunosuppression was defined as an autoimmune disease, solid cancer, hematologic malignancy, organ transplant recipient, or human immunodeficiency virus infection.
Statistical analysis
Categorical variables were compared using the χ2 and Fisher’s exact tests. Mean values were compared using the Mann–Whitney U test. To evaluate the risk of solicited adverse events according to age, sex, vaccine type, immunosuppression, ZVL vaccination history, and herpes zoster history, multivariable logistic regression analysis was performed according to the solicited adverse events. Since both previous ZVL vaccination history and herpes zoster episodes can be considered reactions that cause immune reversion to the VZV antigen, they were considered as the same variable. A 95% confidence interval was confirmed for adjusted odds ratios (ORs), and a P value < 0.05 was defined as statistically significant. All analyses were conducted using RStudio with R version 4.3.2 (Boston, MA, USA).
Ethics statement
This study was reviewed and approved by the Institutional Review Board (IRB) of each participating hospital: IRB No. Korea University Guro Hospital, 2022GR0339; Kangnam Sacred Heart Hospital, 2022-07-014; Korea University Ansan Hospital, 2022AS0238; International St. Mary’s Hospital, IS22ENME0051; and Ajou University Hospital, AJOURIRB-OB-2024-170. Informed consent was submitted by all subjects when they were enrolled.
RESULTS
In total, 1,527 participants were enrolled, with 487 receiving ZVL, 632 receiving the first RZV dose, and 408 receiving the second RZV dose. The baseline characteristics of the vaccinated groups are presented in Table 1. There were more women in all groups, and the average age in the ZVL group was 63.3 years, which was higher than that in the first (56.7 years) and second (56.3 years) dose of RZV. The proportion of previous ZVL vaccinations within 5 years in the RZV group was 6.8% (n = 43) and 6.1% (n = 25) in the first- and second-dose groups, respectively. The underlying medical conditions were more common in the RZV group than in the ZVL group. In particular, the difference in immunosuppression was more remarkable, with 212 (33.5%) patients in the first-dose RZV group, 115 (28.2%) in the second-dose RZV group, and 26 (5.3%) in the ZVL group (P < 0.001). Participants who received simultaneous vaccinations (n = 22 in ZVL, n = 54 in first RZV dose, and n = 27 in second RZV dose) were excluded in the following analysis.
Table 1. Baseline characteristics of vaccinated participants.
| Variables | ZVL (n = 487) | RZV dose 1 (n = 632) | RZV dose 2 (n = 408) | P value | |
|---|---|---|---|---|---|
| Sex, female | 269 (55.2) | 381 (60.3) | 240 (58.8) | 0.229 | |
| Age, yr | 63.3 ± 10.6 | 56.7 ± 10.2 | 56.3 ± 10.0 | < 0.001 | |
| 19–49 | 26 (5.3) | 113 (17.9) | 71 (17.4) | < 0.001 | |
| 50–59 | 172 (35.3) | 285 (45.1) | 189 (46.3) | ||
| 60–69 | 154 (31.6) | 172 (27.2) | 116 (28.4) | ||
| 70–79 | 95 (19.5) | 58 (9.2) | 29 (7.1) | ||
| ≥ 80 | 40 (8.2) | 4 (0.6) | 3 (0.7) | ||
| Discomfort before vaccination | 7 (1.4) | 24 (3.8) | 9 (2.2) | 0.041 | |
| ZVL vaccination history within 5 yr | 1 (0.2) | 43 (6.8) | 25 (6.1) | < 0.001 | |
| Other vaccination history within 3 mon (except zoster vaccine) | 126 (25.9) | 101 (16.0) | 80 (19.6) | < 0.001 | |
| Herpes zoster reactivation history within 5 yr | 44 (9.0) | 65 (10.3) | 45 (11.0) | 0.004 | |
| Underlying conditions | 240 (49.3) | 406 (64.2) | 229 (56.1) | < 0.001 | |
| Diabetes | 78 (16.0) | 85 (13.4) | 43 (10.5) | 0.058 | |
| Hypertension | 165 (33.9) | 155 (24.5) | 101 (24.8) | 0.001 | |
| Tuberculosis history | 9 (1.8) | 12 (1.9) | 3 (0.7) | 0.283 | |
| Stroke | 4 (0.8) | 13 (2.1) | 5 (1.2) | 0.208 | |
| Chronic heart disease | 17 (3.5) | 41 (6.5) | 26 (6.4) | 0.062 | |
| Chronic respiratory disease | 8 (1.6) | 22 (3.5) | 15 (3.7) | 0.117 | |
| Chronic kidney disease | 10 (2.1) | 65 (10.3) | 26 (6.4) | < 0.001 | |
| Chronic liver disease | 1 (0.2) | 16 (2.5) | 7 (1.7) | 0.008 | |
| Neuromuscular disease | 2 (0.4) | 14 (2.2) | 5 (1.2) | 0.035 | |
| Immunosuppression | 26 (5.3) | 212 (33.5) | 115 (28.2) | < 0.001 | |
| Autoimmune disease | 7 (1.4) | 143 (22.6) | 85 (20.8) | < 0.001 | |
| Solid cancer | 20 (4.1) | 32 (5.1) | 15 (3.7) | 0.530 | |
| Hematologic malignancy | 0 | 12 (1.9) | 7 (1.7) | 0.011 | |
| Hematopoietic stem cell transplantation | 0 | 5 (0.8) | 4 (1.0) | 0.111 | |
| Solid organ transplantation | 0 | 21 (3.3) | 8 (2.0) | < 0.001 | |
| HIV infection | 0 | 14 (2.2) | 8 (2.0) | 0.005 | |
| Injection site | 0.072 | ||||
| Left deltoid | 424 (87.1) | 529 (83.7) | 357 (87.5) | ||
| Right deltoid | 61 (12.5) | 103 (16.3) | 51 (12.5) | ||
| Another site | 2 (0.4) | 0 | 0 | ||
| Simultaneous vaccination | 22 (4.5) | 54 (8.5) | 27 (6.6) | 0.029 | |
Values are presented as number (%) or mean ± standard deviation.
ZVL = zoster vaccine live, RZV = recombinant zoster vaccine, HIV = human immunodeficiency virus.
The incidence rates of the solicited adverse events on days 1, 3, and 7 are shown in Fig. 1 and Supplementary Tables 2, 3, 4. On day one, local solicited adverse events (especially grade 2 adverse events) were more common in the RZV group than in the ZVL group. These findings were consistent with most of the systemic solicited adverse events (fever, chilling, headache, myalgia, fatigue, joint pain, nausea/vomiting, rash/urticaria and diarrhea). However, dyspnea, angioedema, and paralysis were reported in a small number of patients (Supplementary Table 2). On days 3 and 7, the incidence of solicited adverse events decreased rapidly in both vaccination groups (Fig. 1B and C, Supplementary Tables 3 and 4). On day 7, there were no statistically significant differences between the vaccination groups, except for injection site pain, injection site limited motion, headache, and fatigue (Fig. 1C, Supplementary Table 4). Clinically confirmed anaphylaxis has not been reported.
Fig. 1. Occurrence rate of solicited adverse events by the type of zoster vaccines (ZVL, RZV dose 1 and RZV dose 2) at day 1 (A), day 3 (B), and day 7 (C). Note that the limit of y-axis is 30% at day 7 to clearly represent the decreased occurrence rate of adverse events.
ZVL = zoster vaccine live, RZV = recombinant zoster vaccine.
Multivariable logistic regression analysis was conducted to reveal the risk of solicited adverse events after adjusting clinical variables (Table 2). The results of the crude ORs are presented in the Supplementary Table 5. Most adverse events demonstrated lower adjusted ORs in men and older age. On day 1, among recipients of ZVL, the adjusted ORs for 11 adverse event categories (excluding rash or urticaria) were significantly lower compared to those of first-dose RZV, with OR values ranging from 0.03 to 0.39. Conversely, among recipients of second-dose RZV, the adjusted ORs for nine adverse event categories (excluding injection site pain and limited motion, nausea/vomiting) were significantly higher than those of first-dose RZV, with OR values ranging from 1.55 to 1.99. Participants with immunosuppression exhibited a significantly reduced risk in four adverse event categories (chilling, headache, fatigue and joint pain) on day 1; however, this difference diminished by days 3 and 7. For individuals with a history of previous episode of herpes zoster or prior ZVL vaccination, the risk of diarrhea was significantly lower on days 1 and 3, and the risk of chilling and headache were significantly higher on day 7.
Table 2. Adjusted odds ratios and 95% confidence interval for solicited adverse events calculated by multivariable logistic regression analysis.
| Adverse events | Sex (male) | Age | Vaccination type | Immuno-suppression | Previous episode of HZ or prior ZVL vaccination | |||
|---|---|---|---|---|---|---|---|---|
| ZVL | RZV 1st dose | RZV 2nd dose | ||||||
| Day 1 | ||||||||
| Injection site pain | 0.50 (0.36–0.70) | 0.95 (0.94–0.97) | 0.04 (0.02–0.06) | Ref | 0.89 (0.47–1.67) | 1.74 (0.96–3.14) | 0.73 (0.43–1.26) | |
| Injection site redness | 0.50 (0.39–0.63) | 0.97 (0.96–0.98) | 0.26 (0.20–0.36) | Ref | 1.55 (1.17–2.05) | 0.84 (0.62–1.12) | 1.07 (0.77–1.50) | |
| Injection site limited motion | 0.71 (0.54–0.94) | 0.94 (0.93–0.96) | 0.10 (0.07–0.13) | Ref | 1.39 (0.99–1.95) | 1.08 (0.75–1.53) | 1.14 (0.77–1.70) | |
| Fever | 0.80 (0.60–1.07) | 0.98 (0.96–0.99) | 0.03 (0.01–0.08) | Ref | 1.63 (1.23–2.16) | 0.86 (0.63–1.19) | 1.17 (0.80–1.69) | |
| Chilling | 0.89 (0.68–1.17) | 0.96 (0.95–0.98) | 0.05 (0.03–0.09) | Ref | 1.46 (1.12–1.92) | 0.65 (0.48–0.88) | 0.95 (0.67–1.37) | |
| Headache | 0.59 (0.45–0.77) | 0.97 (0.96–0.98) | 0.12 (0.08–0.19) | Ref | 1.57 (1.19–2.06) | 0.64 (0.47–0.86) | 0.95 (0.67–1.35) | |
| Myalgia | 0.87 (0.66–1.14) | 0.93 (0.92–0.95) | 0.08 (0.06–0.12) | Ref | 1.66 (1.20–2.31) | 0.84 (0.60–1.18) | 1.14 (0.77–1.69) | |
| Fatigue | 0.66 (0.51–0.85) | 0.97 (0.95–0.98) | 0.11 (0.08–0.16) | Ref | 1.70 (1.26–2.30) | 0.68 (0.49–0.92) | 1.16 (0.81–1.67) | |
| Joint pain | 0.56 (0.43–0.73) | 0.99 (0.97–1.00) | 0.10 (0.07–0.16) | Ref | 1.99 (1.51–2.61) | 0.59 (0.43–0.80) | 0.98 (0.69–1.40) | |
| Nausea and vomiting | 0.54 (0.38–0.77) | 0.99 (0.98–1.01) | 0.22 (0.12–0.38) | Ref | 1.21 (0.86–1.71) | 1.14 (0.78–1.65) | 0.72 (0.44–1.16) | |
| Rash or urticaria | 0.56 (0.31–1.01) | 0.98 (0.95–1.00) | 0.75 (0.35–1.62) | Ref | 1.96 (1.10–3.52) | 0.94 (0.50–1.77) | 1.32 (0.66–2.64) | |
| Diarrhea | 0.94 (0.55–1.59) | 0.99 (0.97–1.02) | 0.39 (0.17–0.90) | Ref | 1.85 (1.07–3.19) | 1.36 (0.76–2.44) | 0.33 (0.12–0.94) | |
| Day 3 | ||||||||
| Injection site pain | 0.46 (0.36–0.60) | 0.97 (0.95–0.98) | 0.14 (0.10–0.19) | Ref | 1.10 (0.79–1.55) | 1.17 (0.82–1.67) | 0.88 (0.61–1.29) | |
| Injection site redness | 0.35 (0.27–0.45) | 0.97 (0.96–0.98) | 0.39 (0.29–0.53) | Ref | 1.34 (1.01–1.77) | 0.77 (0.57–1.03) | 0.81 (0.58–1.13) | |
| Injection site limited motion | 0.47 (0.37–0.60) | 0.97 (0.96–0.98) | 0.19 (0.13–0.26) | Ref | 1.00 (0.76–1.31) | 1.18 (0.88–1.58) | 0.78 (0.55–1.09) | |
| Fever | 0.58 (0.39–0.84) | 1.00 (0.98–1.02) | 0.08 (0.03–0.18) | Ref | 1.18 (0.82–1.68) | 1.14 (0.77–1.69) | 0.78 (0.47–1.28) | |
| Chilling | 0.59 (0.42–0.83) | 0.99 (0.98–1.01) | 0.12 (0.07–0.22) | Ref | 0.94 (0.67–1.31) | 0.86 (0.59–1.24) | 1.11 (0.73–1.70) | |
| Headache | 0.41 (0.30–0.57) | 0.98 (0.97–1.00) | 0.20 (0.12–0.32) | Ref | 1.27 (0.93–1.72) | 0.79 (0.56–1.11) | 1.03 (0.69–1.52) | |
| Myalgia | 0.69 (0.54–0.88) | 0.96 (0.95–0.98) | 0.20 (0.14–0.28) | Ref | 1.08 (0.82–1.41) | 0.82 (0.61–1.10) | 1.12 (0.80–1.57) | |
| Fatigue | 0.49 (0.38–0.63) | 0.98 (0.97–0.99) | 0.17 (0.12–0.25) | Ref | 1.11 (0.84–1.46) | 0.67 (0.49–0.90) | 1.10 (0.79–1.55) | |
| Joint pain | 0.40 (0.28–0.55) | 1.00 (0.98–1.01) | 0.21 (0.13–0.34) | Ref | 1.24 (0.91–1.71) | 0.93 (0.66–1.32) | 1.13 (0.76–1.68) | |
| Nausea and vomiting | 0.45 (0.28–0.72) | 1.00 (0.98–1.02) | 0.25 (0.13–0.49) | Ref | 1.14 (0.73–1.77) | 0.93 (0.57–1.51) | 0.66 (0.35–1.24) | |
| Rash or urticaria | 0.58 (0.34–0.99) | 0.97 (0.95–1.00) | 1.07 (0.57–2.00) | Ref | 1.27 (0.72–2.25) | 0.93 (0.51–1.71) | 0.88 (0.42–1.83) | |
| Diarrhea | 0.74 (0.42–1.29) | 1.00 (0.97–1.02) | 0.19 (0.08–0.48) | Ref | 0.97 (0.55–1.72) | 0.68 (0.35–1.35) | 0.09 (0.01–0.66) | |
| Day 7 | ||||||||
| Injection site pain | 0.63 (0.46–0.87) | 1.00 (0.98–1.01) | 0.40 (0.26–0.60) | Ref | 0.93 (0.66–1.30) | 0.91 (0.63–1.30) | 1.08 (0.72–1.63) | |
| Injection site redness | 0.41 (0.29–0.59) | 0.97 (0.95–0.98) | 0.74 (0.49–1.12) | Ref | 1.04 (0.72–1.50) | 0.79 (0.53–1.17) | 0.97 (0.62–1.53) | |
| Injection site limited motion | 0.68 (0.45–1.02) | 1.00 (0.98–1.02) | 0.34 (0.20–0.60) | Ref | 1.00 (0.66–1.53) | 0.75 (0.46–1.20) | 1.12 (0.67–1.88) | |
| Fever | 0.96 (0.39–2.33) | 0.96 (0.92–1.00) | 0.38 (0.10–1.41) | Ref | 0.51 (0.18–1.43) | 1.27 (0.49–3.28) | 1.97 (0.74–5.24) | |
| Chilling | 0.79 (0.42–1.46) | 1.00 (0.97–1.03) | 0.51 (0.23–1.13) | Ref | 0.71 (0.35–1.43) | 1.12 (0.56–2.23) | 2.13 (1.09–4.16) | |
| Headache | 0.34 (0.20–0.56) | 0.99 (0.96–1.01) | 0.59 (0.33–1.05) | Ref | 1.28 (0.81–2.02) | 0.86 (0.51–1.41) | 1.78 (1.08–2.94) | |
| Myalgia | 0.58 (0.38–0.87) | 0.99 (0.97–1.01) | 0.61 (0.37–1.01) | Ref | 1.14 (0.74–1.76) | 0.70 (0.43–1.13) | 1.45 (0.88–2.38) | |
| Fatigue | 0.44 (0.31–0.63) | 0.99 (0.98–1.01) | 0.38 (0.25–0.60) | Ref | 1.08 (0.76–1.52) | 1.12 (0.78–1.61) | 0.86 (0.56–1.34) | |
| Joint pain | 0.46 (0.27–0.77) | 0.99 (0.97–1.01) | 0.71 (0.38–1.31) | Ref | 1.53 (0.92–2.55) | 0.73 (0.41–1.29) | 1.57 (0.89–2.79) | |
| Nausea and vomiting | 0.30 (0.11–0.81) | 1.02 (0.98–1.06) | 0.37 (0.14–1.01) | Ref | 0.56 (0.22–1.45) | 0.58 (0.21–1.61) | 1.22 (0.45–3.29) | |
| Rash or urticaria | 0.52 (0.25–1.08) | 0.95 (0.92–0.98) | 0.84 (0.37–1.93) | Ref | 0.92 (0.43–1.99) | 0.51 (0.21–1.22) | 1.78 (0.78–4.04) | |
| Diarrhea | 1.01 (0.56–1.80) | 1.01 (0.99–1.04) | 0.38 (0.16–0.88) | Ref | 1.12 (0.60–2.10) | 1.26 (0.65–2.43) | 1.13 (0.53–2.39) | |
The results highlighted in bold indicate statistically significant values with P < 0.05.
ZVL = zoster vaccine live, RZV = recombinant zoster vaccine, HZ = herpes zoster, Ref = reference value.
The unsolicited adverse events from days 8 to 90 are summarized in Table 3. Unsolicited adverse events were reported more frequently in the first (9.3% [n = 54] at days 8 to 28, 6.6% [n = 39] at days 29 to 90) and second (8.7% [n = 33] at days 8 to 28, 5.2% [n = 20] at days 29 to 90) doses of the RZV groups compared to the ZVL group (3.0% [n = 14] from days 8 to 28, 2.2% [n = 10] from days 29 to 90). Ureter stones, severe diarrhea, trauma, spinal stenosis and COVID-19 were reported in the ZVL group but were not considered to be related to vaccination because they were not immune-mediated diseases. In comparison, one case of multiple cranial neuropathy was reported after the first dose of RZV, which could be related to vaccination.
Table 3. Unsolicited adverse events and diagnosis between day 8 and day 90.
| Adverse events | ZVL (n = 465) | RZV dose 1 (n = 578) | RZV dose 2 (n = 381) | P value | ||
|---|---|---|---|---|---|---|
| Day 8–28 | ||||||
| Unsolicited adverse events | 14 (3.0) | 54 (9.3) | 33 (8.7) | < 0.001 | ||
| Hospitalization or outpatient clinic | 4 (0.9) | 12 (2.1) | 7 (1.8) | 0.013 | ||
| Diagnosis (No.) | - Ureter stone (1)a | - COVID-19 (3) | - COVID-19 (2) | |||
| - Severe diarrhea (1) | - Chest pain (1)b | - Herpes zoster (1) | ||||
| - Spinal stenosis (1) | - Herpes zoster (1)c | - Hip joint arthritis (1) | ||||
| - Tibia fracture due to trauma (1) | - Nasal skin erosion (1) | - Sore throat and rhinorrhea (1) | ||||
| - Skin rash (1) | - Allergic skin rash (1) | |||||
| - Fall down (1)d | - Pleuritis (1) | |||||
| - Shoulder pain (1) | ||||||
| - Allergic rhinitis (1) | ||||||
| - Common cold (1) | ||||||
| - Dizziness (1) | ||||||
| Day 29–90 | ||||||
| Unsolicited adverse events | 10 (2.2) | 38 (6.6) | 20 (5.2) | 0.004 | ||
| Hospitalization or outpatient clinic | 4 (0.9) | 16 (2.8) | 8 (2.1) | 0.047 | ||
| Diagnosis (No.) | - Ureter stone (1)a | - Pneumonia (1) | - Influenza (2) | |||
| - COVID-19 (3) | - COVID-19 (2) | - Herpes zoster (1) | ||||
| - Menopausal symptoms (1) | - Fever of unknown origin (1) | |||||
| - Angina pectoris (1)b | - Allergic symptom (1) | |||||
| - Spinal stenosis (1) | - Hypertension (1) | |||||
| - Shoulder tendinitis (1)e | - COPD (1) | |||||
| - Sore throat and rhinorrhea (1) | - Lower limb myositis (1)e | |||||
| - Herpes simplex (1) | ||||||
| - WPW syndrome (1) | ||||||
| - DM foot ulcer (1)d | ||||||
| - Diarrhea (1) | ||||||
| - Knee osteoarthritis (1) | ||||||
| - Multiple cranial neuropathy (1) | ||||||
| - Traumatic lumbar disc herniation (1) | ||||||
| - Postherpetic neuralgia (1)c | ||||||
Values are presented as number (%).
ZVL = zoster vaccine live, RZV = recombinant zoster vaccine, COVID-19 = coronavirus disease 19, WPW syndrome = Wolff-Parkinson-White syndrome, DM = diabetes mellitus, COPD = chronic obstructive pulmonary disease.
a-eEach number indicates same individual patients. ‘Patient a’ received second RZV vaccination after 84 days of first dose.
DISCUSSION
In this study, we compared and analyzed the adverse events following zoster vaccination in 1,527 participants. We found that, after adjusting for clinical variables, most solicited adverse events were least frequent in the ZVL group and most frequent in the second-dose RZV group during the early post-vaccination period; however, the differences diminished by day 3 and 7. The risks of many solicited adverse events were higher in the female and younger age groups; however, aside from a few categories, there was no clear association with immunosuppression, prior episodes of herpes zoster, and vaccination history of ZVL. Unsolicited adverse events were more frequent in the RZV group; however, no fatal adverse events were reported. The results of this study are consistent with the previous safety analyses of clinical trials involving RZV and ZVL.8,9,12
In particular, we observed a significantly higher incidence of early solicited adverse events in RZV recipients than in ZVL recipients. A previous trial on RZV showed 84.4% solicited or unsolicited adverse events within 7 days of vaccination.8 In comparison, a previous trial of ZVL showed that 58.1% of all adverse events occurred within 42 days after vaccination, including 48.3% injection site reactions and 24.7% systemic events.9 RZV contains the AS01B adjuvant system (monophosphoryl lipid A and QS-21), known to enhance immunogenicity and increase reactogenicity also, which might contribute to the higher reactogenicity.13 Given that this tendency decreases to levels similar to those of ZVL after one week, healthcare providers and patients need to be aware of the early reactogenicity of RZV.
The risks of solicited adverse events were significantly higher in the female, younger age and RZV groups, whereas they were mostly not affected by immunosuppression, prior ZVL vaccination, or previous herpes zoster episodes. Sex-based risk differences were observed in both previous ZVL and RZV studies. In a 10-year PMS study on ZVL, adverse events in females accounted for 70% of cases.14 In previous RZV trials, there was a tendency for more frequent reactogenicity in females than in males: for local reactions, 84.2% vs. 75.5%, and for systemic reactions, 69.2% vs. 58.1%.15 Previous ZVL vaccination history, herpes zoster history, and immunosuppression might be associated with VZV-specific cellular immunity, but they do not seem to be related to reactogenicity, as presented in this study. A meta-analysis has reported that an immunocompromised state does not significantly affect vaccine safety.16
No cases of Guillain-Barré syndrome (GBS) or autoimmune disease flare-ups were identified until day 90. In particular, the U.S. FDA recommends adding a warning regarding the potential association of GBS with RZV.17 However, other large-scale safety studies of RZV safety reported no clear relationship between vaccination and GBS.18,19 In Korean studies involving RZV or ZVL recipients, no severe vaccine-related adverse events were observed.20,21 The higher number of unsolicited adverse event reports with RZV could be partially interpreted as a heightened participant interest in the new vaccine. Herpes zoster reactivation following RZV vaccination was reported in this study, which is consistent with the findings of previous studies on both ZVL and RZV. In a 10-year PMS study of ZVL, 3,943 cases of herpes zoster were reported, with the majority occurring within one week of vaccination.14 In addition, 837 cases of herpes zoster were reported in PMS studies of RZV.15
This study had several limitations. First, the type and grade of adverse events relied on surveys based on on-line questionnaires and telephone follow-ups, rather than physician assessments, which may have compromised the accuracy. Second, while data collection was prospective, the vaccine type was not randomized, and selection depended on physician’s discretion, potentially introducing bias in the vaccination groups. Given that RZV was introduced in South Korea during the study period, many immunocompromised individuals who had not received ZVL were vaccinated. Conversely, owing to the relatively higher cost of RZV, some participants may have opted for ZVL as an alternative. Finally, this study was conducted to evaluate the early safety of RZV after its introduction in South Korea compared to the ZVL. However, rare adverse events of special interest, such as autoimmune diseases or GBS, could not be appropriately evaluated because of the small number of participants. A safety analysis of zoster vaccines that combines vaccination data and National Health Insurance claims data would be effective.
In conclusion, our study revealed a higher risk of solicited adverse events in the early post-vaccination period in the second-dose RZV group than in the first-dose RZV group, and lowest risk in the ZVL group, after adjusting age, sex, vaccination history of ZVL, prior herpes zoster reactivation and immune status. However, this difference diminished gradually following vaccination and no fatal adverse events occurred. Although RZV administration is safe, it is important to note its higher early reactogenicity compared to that of ZVL.
Footnotes
Funding: This study was funded by the Ministry of Food and Drug Safety of Korea (Grant No. 22183MFDS435).
Disclosure: The authors have no potential conflicts of interest to disclose.
- Conceptualization: Cheong HJ.
- Data curation: Yoon JG.
- Formal analysis: Yoon JG.
- Funding acquisition: Cheong HJ.
- Investigation: Yoon JG, Nham E, Choi YJ, Choi WS, Choi MJ, Seo YB, Lee J, Hyun H, Heo JY, Noh JY, Song JY.
- Methodology: Yoon JG, Nham E, Choi MJ, Seo YB, Lee J, Choi WS, Noh JY, Song JY, Cheong HJ.
- Validation: Yoon JG.
- Writing - original draft: Yoon JG.
- Writing - review & editing: Yoon JG, Nham E, Choi YJ, Choi WS, Choi MJ, Seo YB, Lee J, Hyun H, Heo JY, Noh JY, Song JY, Cheong HJ.
SUPPLEMENTARY MATERIALS
Grade of local and systemic solicited adverse events
Solicited adverse events at day 1
Solicited adverse events at day 3
Solicited adverse events at day 7
Crude odds ratios and 95% confidence interval for solicited adverse events
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Grade of local and systemic solicited adverse events
Solicited adverse events at day 1
Solicited adverse events at day 3
Solicited adverse events at day 7
Crude odds ratios and 95% confidence interval for solicited adverse events