Seroepidemiological Study of Varicella Zoster Virus in Korea, 2023

Abstract

Background

Seroprevalence studies monitor changes in the immune status of populations. During the coronavirus disease 2019 (COVID-19) pandemic, public health measures such as social distancing and mask-wearing led to significant changes in the epidemiology and transmission patterns of many infectious diseases. In the post-pandemic period, outbreaks of various infectious diseases have been reported globally. In this context, this study evaluated changes in varicella zoster virus (VZV) seroepidemiology in the Republic of Korea after the COVID-19 pandemic.

Methods

Residual serum samples were collected from specimens referred to Seoul Clinical Laboratories in 2023. Serum samples were collected after anonymization, with all identifiable information excluded except for date, age, sex, and region. Samples were collected evenly by age group in 5-year intervals. The evaluation of anti-VZV IgG antibodies was performed using a chemiluminescence immunoassay analyzer (Liaison^®XL; Diasorin).

Results

The study population comprised 995 participants including 581 males and 414 females. The overall VZV IgG seropositivity rate was 82.9%. The seropositivity rates of VZV IgG antibodies were 88.1% in males and 75.6% in females. VZV IgG seroprevalence showed variations across different age groups. VZV IgG seropositivity was 80% in the 1–4 year age group, declined to 53% in the 5–9 year age group, and reached its lowest at 43% in 10–14 year-olds. Seropositivity rates steadily increased from 71% in the 15–19 year-olds, to 85% in the 25–29 year group, and exceeded 95% in subjects ≥ 40 year of age.

Conclusion

Seropositivity rates in children (5–19 year) and adults (20–39 year) were lower than in previous studies in the Republic of Korea, likely due to reduced community exposure to varicella during the pandemic. These findings highlight a potential need to reinforce infection control measures and vaccination policies to address vulnerable age groups.

Graphical Abstract

INTRODUCTION

Varicella zoster virus (VZV), a double-stranded DNA virus classified within the Herpesviridae family, is highly contagious, with humans serving as its sole reservoir of infection.1 VZV infection causes varicella (chickenpox), which is characterized by symptoms such as fever, fatigue, and vesicular rash, potentially resulting in complications including bacterial superinfection, pneumonia, or encephalitis. Even after recovery, reactivation of latent VZV in the sensory ganglia results in herpes zoster, which is associated with considerable morbidity, such as post-herpetic neuralgia, ophthalmic complications, and meningoencephalitis.

In the Republic of Korea, the VZV vaccine was introduced in 1988 and included in the national immunization program in 2005. According to national insurance claims, varicella cases declined from approximately 210,000 cases/year in 2006 to 80,000 cases/year in 2019.2 Recently, during the coronavirus disease 2019 (COVID-19) pandemic, nonpharmaceutical interventions and social distancing measures further reduced cases to 18,615 cases/year in 2022. Nonetheless, sporadic cases continue to occur, especially in children aged 5–9 years, 0–4 years, and more recently in children aged 10–14 years.3 Moreover, outbreaks continue to occur year-round in childcare centers and elementary schools.4 However, the impact of these changes on VZV seroepidemiology in the Republic of Korea are not well characterized.

It is well established that the COVID-19 pandemic led to substantial changes in the epidemiology of various infectious diseases. These changes have likely influenced population-level immunity, raising concerns about the potential for outbreaks in the post-pandemic period. To prepare for such scenarios, it is imperative to assess the current immune status of the population. In particular, a comprehensive evaluation of VZV immunity across all age groups is warranted in the post-pandemic context. Seroprevalence studies monitor changes in the immune status of populations and provide evidence for vaccination strategies and public health policies by identifying vulnerable age groups. Although several studies on VZV seropositivity have been conducted in the Republic of Korea, most have focused on specific subpopulations such as healthcare workers, female nurses, military personnel, or individuals within a limited age range. Therefore, there is a need for comprehensive analysis across all age groups in the general population.5,6,7,8,9,10 In light of these considerations, we designed this study to evaluate changes in VZV seroepidemiology in the general Korean population after the COVID-19 pandemic.

METHODS

Study design

We conducted a serological survey to assess the seroprevalence of VZV. Residual serum samples were collected from specimens referred for testing from July to October, 2023 at Seoul Clinical Laboratories (SCL) in Yongin, the Republic of Korea. Serum samples were collected after anonymization, with all personally-identifiable information excluded except for date, age, sex, and region. Samples were collected evenly by age group at 5-year intervals, with a total of 995 samples: 75 participants in the 1–4 year group, 80 per group from 5–49 years, 50 per group for 50–59 year, and 100 participants aged 60 years or older.

VZV serology testing

The evaluation of anti-VZV IgG antibodies was performed using a chemiluminescence immunoassay (CLIA) analyzer (Liaison^®XL; Diasorin, Cypress, CA, USA).

Samples with serum IgG concentrations below 150.0 mIU/mL were considered negative, whereas those ≥ 150.0 mIU/mL were classified as positive. The lower limit of detection for VZV IgG was 10 mIU/mL; therefore, values below this limit were rounded off to 10 mIU/mL. Serological testing was conducted at the Seoul Clinical Laboratories in Yongin, Gyeonggi-do, Republic of Korea.

Statistical analysis

Seroprevalence data for different sexes and age groups were analyzed and are presented as percentages with 95% confidence intervals (95% CIs). The geometric mean titer (GMT) of VZV IgG was analyzed according to age and sex. The χ² test was used to assess differences between sex and age groups. Statistical analysis was performed using SPSS Statistics (version 27.0; SPSS Inc., Armonk, NY, USA), and P < 0.05 was considered statistically significant.

Ethics statement

The study protocol was exempted from review by the Institutional Review Board (IRB) of Seoul National University Bundang Hospital (IRB No. X-2307-839-901). It was also reviewed and approved by the IRB of SCL (IRB No. 23-035). Informed consent was waived by both IRBs due to the retrospective nature of this study and the use of anonymized clinical data.

RESULTS

Study population and seroprevalence of VZV

The study population comprised 995 participants, including 581 males and 414 females. Of the 995 participants, 825 tested positive and 170 tested negative, with an overall VZV IgG seropositivity rate of 82.9%. VZV IgG seroprevalence varied across the age groups. VZV IgG seropositivity was 80% in the 1–4 year age group, declined steadily to 53% in the 5–9 year age group, and reached its lowest point by 43% in 10–14 year-olds. A steady increase followed, reaching 71% in the 15–19 year group, 76% in 20–24 year-olds, 85% in the 25–29 year group, 93% in the 30–34 year group, and 94% in the 35–39 year group. Seropositivity rates of VZV IgG consistently exceeded 95% in subjects older than 40 years (Fig. 1A). The seropositivity rate for VZV IgG antibodies was 88.1% (512/581, 95% CI, 85.2–90.5) in males and 75.6% (313/414, 95% CI, 71.2–79.5) in females (Fig. 2). The odds ratio for the difference in antibody positivity rates between males and females was 2.40 (P < 0.001).

Fig. 1. Varicella zoster virus IgG in 2023 according to age group. (A) Seroprevalence, (B) geometric mean titers (mIU/mL). Bars indicate 95% confidence interval.

Fig. 2. Varicella zoster virus IgG seroprevalence in 2023 according to sex.

Overall, the GMT for VZV IgG was 500.5 mIU/mL. Across different age groups, it was 360.4 mIU/mL in the 1–4 year age group, decreased to 153.8 mIU/mL in the 5–9 year age group, and reached its lowest point at 107.6 mIU/mL in the 10–14 year age group. Subsequently the GMT continued to rise, reaching 1,013.8 mIU/mL in the 40–44 year age group, and then slightly decreased to 899.7 mIU/mL in the 45–49 year age group. GMT reached its peak at 1,295.59 mIU/mL in the 55–59 year age group and was 1,166.2 mIU/mL in subjects ≥ 60 years of age (Fig. 1B). The GMT was 641.7 mIU/mL for males and 353.1 mIU/mL for females.

Compared to a previous report in 2010, marked differences were found across the various age groups (Fig. 3).11 The seropositivity rate among children aged 1–4 years in 2023 was 80%, which was substantially higher than the 67% in 2010. However, for the 5–9 year and 10–14 year age groups, rates that had previously risen from 78% to 94% in 2010 decreased sharply to 53% and 43%, respectively, in 2023. Seropositivity rates were consistently lower throughout the 5–39 year age groups in 2023 compared to 2010. Seropositivity rates did not differ in subjects older than 40 years of age between 2010 and 2023 (96–100%).

Fig. 3. Varicella zoster virus IgG seroprevalence in ▲2010 (Lee et al., 2013)11 vs. ●2023.

DISCUSSION

We performed a seroepidemiology study on VZV to assess changes in susceptibility in age groups in relation to the changes in VZV epidemiology due to the COVID-19 pandemic. The overall VZV IgG seropositivity rate was 82.5%. The seropositivity rate was high (80%) in 1–4 years of age but decreased gradually to 53% in 5–9-year-olds and reached its lowest value of 43% in 10–14-year-olds. Subsequently, VZV IgG seropositivity consistently increased to 71% in 15–19-year-olds, 76% in 20–24-year-olds, and reached > 95% after 40 years of age.

In the Republic of Korea, the national immunization program recommends a single dose of the VZV vaccine at 12–15 months of age. According to a previous study, the vaccine effectiveness of one-dose universal varicella vaccination was 86.1% during the first year following vaccination, but declined to 49.9% over a six-year follow-up period, corresponding to an annual decrease in effectiveness of approximately 7.2%.12 Therefore the decrease in the VZV IgG antibody positivity rate and GMT up to the age of 5–14 years can be interpreted as the result of waning immunity after vaccination at 12–15 months. In addition, the epidemiology of VZV infections in the Republic of Korea has changed since the COVID-19 pandemic. According to the Korean Disease Control and Prevention Agency, VZV cases decreased substantially during the COVID19 pandemic from over 80,000 cases/year in 2019 to 18,547 cases/year in 2022.3 Therefore, COVID-19-related social distancing measures and non-pharmaceutical interventions possibly contributed to the decrease in seropositivity in young children and young adults as the result of decreased opportunities for exposure to VZV.

This study identified substantial differences in age-specific seroprevalence compared to previous studies in the Republic of Korea. Although direct comparisons are limited by variability in assay sensitivity and specificity, age-related trends have shifted over time. Choi et al.13 reported an overall varicella seropositivity of 87.6% in 887 participants, increasing from 50% at 1–2-year-olds, 75% in 5–6-year-olds, to > 90% after 11 years of age. Similarly, Lee et al.11 (2009–2010) observed an 85.8% overall seropositivity in 1,302 participants, with rates rising from 67.3% at 1–4 years, 78.0% at 5–9 years, to 94.2% in 10–14-year-olds. This increase in older children was attributed to natural varicella exposure. In contrast, our study showed declining seropositivity in children aged 5–9 years and 10–14 years.

A similar decline in VZV seropositivity among young children was observed in a 2018–2021 study. Ji et al.14 reported overall seropositivity rates of 82.0% using the fluorescent antibody to membrane antigen (FAMA) test and 80.0% using the glycoprotein enzyme-linked immunosorbent assay (gpELISA) in 400 participants. Both assays, known for high sensitivity, showed the lowest seropositivity rates at ages 5–9 years (FAMA: 58.0%; gpELISA: 52.0%), followed by an increase in the 10–19-year group (FAMA: 72.0%; gpELISA: 64.0%). This decline was attributed to reduced VZV circulation after the introduction of the VZV vaccine in the national immunization program.

In the 2023 study, the 10–14-year age group, corresponding to the 5–9-year group in the 2018–2021 study, exhibited the lowest seropositivity rate (43%), suggesting evidence of age shifting. This decline aligns with the reduced natural VZV exposure that was exacerbated during the COVID-19 pandemic. Historically, seropositivity among teenagers is higher, exceeding 90% after age 11 in 2008 and reaching 94% in the 10–19-year age group by 2010.11,13 The lower seropositivity rates in 20–29-year-olds also raises concerns about an increasingly susceptible population, particularly among women of reproductive age, potentially heightening risks of complications like congenital varicella syndrome.

The changes in age-group-specific seropositivity rates seen in the current study correlate with recent changes in VZV epidemiology in Korea. Before the pandemic, the majority of reported cases were in the 5–9-year age group, accounting for 52.2% of cases in 2019. However, following the pandemic, the proportion of cases in the 10–14-year age group increased substantially, rising from 19.1% in 2019 to 30.2% in 2023, approaching the 35.9% in the 5–9-year age group during the same period.3

The seropositivity rates for VZV IgG antibodies were higher in males (87.8%) than in females (75.0%). These findings differ from previous studies, which reported no significant difference in seroprevalence between male and female subjects across age groups.11,15 However in the age- and sex-specific analysis, a notable difference was observed in the 10–14-year age group, where the seropositivity rate was 52.4% in males and 31.6% in females. Thus, the lower seropositivity rates in this age group may be overrepresented. Further larger-scaled studies may be necessary to further address this issue.

Seroepidemiological studies highlight variations in epidemiology and vaccination policies across different countries. A recent study conducted in Italy from 2019–2020 reported a high overall seroprevalence of 91.6%, with an increasing trend observed across age groups: 84.1% in children aged 6–9 years, 89.3% in adolescents aged 15–19 years, 91.7% in adults aged 20–39 years, and 97.0% in individuals over 40 years.16 Compared to earlier studies (1996–1997, 2003–2004, 2013–2014), seroprevalence in children was higher. Notably, since 2017, Italy has implemented mandatory varicella vaccination for all children, administering two doses at 13–15 months and again at 5–6 years of age, which may have contributed to the high seroprevalence observed in younger age groups. Despite a three-year gap, Italy’s seropositivity rates were substantially higher than those in the current study, underscoring the need for country-specific and periodic seroepidemiological studies to guide public health strategies.

As of 2021, 44 countries have introduced the varicella vaccine as part of universal vaccination programs, with 28 countries recommending a two-dose schedule.17 Despite high coverage of the first dose and reductions in morbidity and mortality, the Centers for Disease Control and Prevention (CDC) surveillance data showed that varicella case numbers either remained steady or declined minimally, with ongoing outbreaks in certain areas. As a result, the CDC currently recommends two doses of the varicella vaccine: the first dose at 12–15 months, and the second at 4–6 years.18 In Europe, Hungary, Italy, and Latvia mandate two doses, whereas the national health systems of Finland, Germany, Greece, Iceland, Liechtenstein, Luxembourg, and Spain recommend them.19 Similarly, Japan advises two doses, administered at 12–15 months and 6–12 months later.20

According to the 2023 vaccination coverage report in Korea, vaccination rates were high across age groups: 97.0% for children born in 2021 (2 years-old), 97.2% for children born in 2020 (3 years-old), and 97.6% for children born in 2017 (6 years-old).21 Similar to the United States, outbreaks continue to occur in South Korea despite high vaccination coverage. Notably, age groups previously identified as vulnerable have consistently shown low seroprevalence in the present study as well. This study found lower antibody positivity rates among children 5–14 years than in previous Korean studies, highlighting the need for infection control measures and vaccination policies targeting these age groups. These findings suggest implementing a two-dose strategy may enhance population immunity and reduce the risk of future outbreaks.

This study had several limitations. First, patient ages were categorized into 5-year intervals rather than 1-year increments. A more detailed analysis using 1-year intervals may have provided further insights into specifically vulnerable age groups. Second, IgG antibody tests were conducted using CLIA, which is known as an easy-to-operate, automated process with a short runtime, suitable for high-throughput laboratories but may show lower sensitivity compared to FAMA or gpELISA.22 According to the package insert, the LIAISON assay has a sensitivity and specificity of 97.4% and 100% respectively. The sensitivity and specificity of the LIAISON assay compared to VZV-time resolved fluorescence immunoassay was 67% and 100% respectively.23 Thus, the low seropositivity rates in younger age groups may attribute to the low sensitivity of the assay. Despite variations in sensitivity and specificity among commercial anti-VZV assays, our findings align with recent changes in the age distribution of varicella cases in Korea. Third, this study was conducted retrospectively using residual blood samples, which were evenly collected across age groups. However, the samples were not stratified according to age, sex or regional distribution, they may not be representative of the general population. One of the limitations of our study is the unequal sex distribution across age groups in the collected samples, which may have influenced the analysis of seropositivity by sex. To enable accurate comparisons between sexes in future studies, it is essential to collect samples with balanced sex ratios within each age group during the sampling phase. In addition, the lack of data on the patients’ varicella vaccination history and prior varicella infections limited our ability to analyze these factors comprehensively. For these reasons, future large-scale trials may provide more robust and generalizable evidence, with careful consideration to ensure balanced recruitment across age groups and sexes.

In this study, a seroepidemiological study of VZV was conducted after the COVID-19 pandemic. Seroprevalence in the 5–9-year and 10–14-year age groups tended to decrease and lower seroprevalence was found in the 15–39-year groups compared to earlier studies. These findings likely reflect a decrease in natural exposure to varicella during the pandemic and potentially waning immunity from a single vaccine dose administered at 12–15 months of age. Therefore, a second varicella vaccination may be warranted. The study provides valuable insights into post-pandemic trends, which inform vaccination policies and highlight a potential need to reinforce infection control measures for varicella in the community. Ongoing surveillance of national epidemiology and seroprevalence is necessary.