Effects of One-Dose Varicella Vaccination On Disease Severity in Children During Outbreaks in Seoul, Korea

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J Korean Med Sci.

2019 Mar 18;34(10):e83


https://doi.org/10.3346/jkms.2019.34.e83
eISSN 1598-6357·pISSN 1011-8934

Original Article
Infectious Diseases,
Effects of One-dose Varicella
Microbiology & Parasitology Vaccination on Disease Severity in
Children during Outbreaks in Seoul,
Korea
Young Hwa Lee ,1,2 Young June Choe ,3 Sung-Il Cho ,1,2 HyeKyung Park ,4
Ji Hwan Bang ,2,5 and Jong-koo Lee 2,6
1
Department of Epidemiology, Seoul National University Graduate School of Public Health, Seoul, Korea
2
Institute of Infectious Disease, Seoul National University College of Medicine, Seoul, Korea
Division of Pediatric Infectious Diseases, The Warren Alpert Medical School of Brown University,
3

Providence, RI, USA


4
Division of Infectious Disease Surveillance, Center for Control of Infectious Diseases, KCDC, Osong, Korea
Division of Infectious Diseases, Seoul Metropolitan Government-Seoul National University Boramae
5

Medical Center, Seoul, Korea


6
Department of Family Medicine, Seoul National University College of Medicine, Seoul, Korea

Received: Oct 26, 2018


Accepted: Feb 22, 2019
ABSTRACT
Address for Correspondence: Background: In Korea, the incidence of varicella has increased despite the introduction of
Jong-koo Lee, MD, PhD a universal one-dose vaccination for children aged 12–15 months in 2005. A previous study
Department of Family Medicine, Seoul demonstrated that the vaccine effectiveness was insufficient to prevent against varicella. We
National University College of Medicine, 71
assessed the effect of the varicella vaccination on disease severity.
Ihwajang-gil, Jongno-gu, Seoul 03087, Korea.
E-mail: docmohw@snu.ac.kr
Methods: Epidemiologic investigation of varicella cases in Seoul metropolitan area from
2015 to 2017 were used. Varicella-related symptoms such as rash were determined by the
© 2019 The Korean Academy of Medical clinical practitioners. Disease severity of patients was assessed by the number of skin lesions
Sciences.
and divided into mild (≤ 50) and moderate (51–249) to severe (≥ 250). Unconditional logistic
This is an Open Access article distributed
under the terms of the Creative Commons
regression analysis was performed and age was controlled.
Attribution Non-Commercial License (https:// Results: Among a total of 1,008 varicella cases reported, 869 cases were breakthrough cases
creativecommons.org/licenses/by-nc/4.0/) and 139 were unvaccinated cases. The risk for occurrence of moderate-to-severe disease in the
which permits unrestricted non-commercial breakthrough group was 0.57 times less than that of the unvaccinated group.
use, distribution, and reproduction in any Conclusion: These data suggest that national varicella vaccination may have a significant
medium, provided the original work is properly
effect on attenuation of disease severity in children.
cited.

ORCID iDs Keywords: Varicella; Chickenpox; Vaccination; Breakthrough; Severity


Young Hwa Lee
https://orcid.org/0000-0003-2073-993X
Young June Choe
https://orcid.org/0000-0003-2733-0715
INTRODUCTION
Sung-Il Cho
https://orcid.org/0000-0003-4085-1494 Since the introduction of a universal varicella vaccination program, countries such as the United
HyeKyung Park States, Germany, and Taiwan have experienced a reduced incidence rate of varicella.1-3 However,
https://orcid.org/0000-0002-3263-8776 in Korea—where one-dose of varicella vaccination for all children aged 12–15 months was
Ji Hwan Bang
recommended by the National Immunization Program (NIP) in 2005, and the coverage had reached
https://orcid.org/0000-0002-7628-1182
Jong-koo Lee up to 98.9% in 20124—the incidence rate of varicella has been continuously rising from 22.5 per
https://orcid.org/0000-0003-4833-1178 100,000 persons to 154.8 from 2006 to 2017.5 A previous study demonstrated that the vaccine
immunogenicity may be not sufficient to provide effective immunity against varicella infection.6,7

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Effectiveness of Varicella Vaccination on Disease Severity

Disclosure To our knowledge, there has been no population-based study to assess the disease severity of
The authors have no potential conflicts of varicella cases after adoption of a universal one-dose varicella vaccination to the NIP. In this
interest to disclose.
study, we aimed to investigate the effect of vaccination on the disease severity of varicella.
Author Contributions
Conceptualization: Lee YH, Choe YJ, Cho SI,
Lee JK. Formal analysis: Lee YH. Methodology: METHODS
Lee YH, Cho SI. Software: Lee YH. Supervision:
Lee JK. Validation: Lee YH, Park H, Bang JH,
Lee JK. Writing - original draft: Lee YH. Writing
Study population and data collection
- review & editing: Lee YH, Choe YJ, Cho SI, In this study, 1,125 cases from 94 varicella outbreaks reported as part of epidemiologic
Park H, Bang JH, Lee JK. investigation of varicella from January 2015 to December 2017 in the Seoul metropolitan
area were used. Data were provided by the Korea Centers for Disease Control and Prevention
(KCDC). According to the KCDC guidelines, an epidemiologic investigation is required if
varicella outbreaks, including index cases, occur in more than 5% of students in a classroom
within a 3-week period in schools, kindergartens, or day care centers. When a varicella
outbreak is reported, public health centers should conduct an epidemiologic investigation
within 3 days, collecting data from the patient's parent with the help of the school health
teacher. The information includes the name, gender, date of birth, date of diagnosis,
vaccination status, and related clinical symptoms such as rash (the number skin lesions),
fever, headache, and arthralgia. Varicella-related symptoms were determined by the clinical
practitioners through a physical examination of the patients. Disease severity of patients was
assessed by the number of skin lesions as used in a previous study.8-11

Mild cases were defined as those having less than or equal to 50 skin lesions; moderate cases
were defined as those having 51–249 skin lesions; and severe cases were defined as those
having more than or equal to 250 skin lesions. We excluded 117 cases: 3 cases were excluded
because the patient was infected before 12 months of age; 12 cases were excluded for having
varicella within 42 days after the vaccination (breakthrough varicella is infection with
varicella-zoster virus occurring in a vaccinated person more than 42 days after vaccination); 4
were excluded for being vaccinated with 2 doses of vaccine; and 98 cases because the patient
was born before 2004.

Statistical analysis
We used t-test and χ2 to compare the difference in distribution in general characteristics, clinical
symptoms, and disease severity in the vaccinated (breakthrough) and unvaccinated groups.
Binary unconditional logistic regression analysis was performed to examine the differences in
disease severity between the two groups, controlling for the factor of age. All statistical analyses
were performed using SAS software, version 9.3 (SAS Institute, Cary, NC, USA). P < 0.05 was
considered significant, and all tests of statistical significance were two-sided.

Ethics statement
The present study protocol was reviewed and approved by the Institutional Review Board
(IRB) of Seoul National University (IRB No. E-1808-062-965). Informed consent was waived
by the board because this was a retrospective study.

RESULTS
Among a total of 1,008 varicella cases in Seoul, Korea, 869 cases (86.2%) were breakthrough
cases and 139 (13.8%) were unvaccinated cases. The mean age for the breakthrough cases

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Effectiveness of Varicella Vaccination on Disease Severity

Table 1. General characteristics of breakthrough cases and unvaccinated cases


Characteristics Breakthrough cases Unvaccinated cases χ2 P value
(n = 869) (n = 139)
Age, yr
Mean ± SD 7.72 ± 1.86 8.82 ± 2.04 6.33a < 0.001
Age group, No. (%) 50.58 < 0.001
1–3 15 (1.7) 2 (1.4)
4–6 210 (24.2) 14 (10.1)
7–9 487 (56.0) 62 (44.6)
10–12 157 (18.1) 61 (43.9)
Sex, No. (%) 0.4972 0.481
Male 478 (55.0) 72 (51.8)
Female 391 (45.0) 67 (48.2)
Reporting source, No. (%) 4.1068 0.128
Kindergarten 131 (15.1) 13 (9.4)
Elementary school 724 (83.3) 122 (87.8)
Unknown 14 (1.6) 4 (1.6)
SD = standard deviation.
a
t-value.

was younger than for the unvaccinated cases (7.72 vs. 8.82 years; P < 0.001). No significant
differences were observed in gender and reporting source distributions between the two
groups. Of these cases, about half were male and 83% to 88% cases were elementary school
students (Table 1).

There was no difference in clinical symptoms between the two groups. Among patients,
rash was the most common symptom in both the breakthrough and unvaccinated groups
(99.5% and 100%) and rash onset was on most of the body (54.1% and 43.7%; P = 0.001).
Fever was the second most common symptom (33.8% and 36.7%; P = 0.510); headache was
the third most common (7.3% and 10.1%; P = 0.245); and arthralgia was a rare symptom
(1.2%, only in the breakthrough group). Disease severity differed between the two groups.
In the breakthrough group, the proportion of cases with moderate-to-severe symptoms
was less than that in the unvaccinated group (14.6% vs. 25.8%; P = 0.002). The risk for
occurrence of moderate-to-severe disease in the breakthrough group was less than roughly
half that of the unvaccinated group (odds ratio [OR], 0.570; 95% confidence interval [CI],
0.365–0.890) (Table 2).

Table 2. Comparison of the epidemiology and disease severity between the breakthrough and unvaccinated cases
Variables Breakthrough Unvaccinated P value OR (95% CI)
cases (n = 869) cases (n = 139)
Clinical symptoms, No. (%)a
Rash 865 (99.5) 139 (100.0) - -
Affected part of rash onset
Face and neck 333 (38.5) 56 (40.3)
Body 468 (54.1) 60 (43.2)
Arms and legs 64 (7.4) 23 (16.5)
Fever 294 (33.8) 51 (36.7) 0.510 0.888 (0.602–1.309)
Headache 63 (7.3) 14 (10.1) 0.245 0.975 (0.517–1.838)
Arthralgiab 10 (1.2) 0 (0.0) - -
Severity, No. (%)
Mild (< 50) 742 (85.4) 104 (74.8) 0.002 0.570 (0.365–0.890)
Moderate to severe (≥ 50) 127 (14.6) 35 (25.8) - -
Moderate (50–249) 114 (89.8) 32 (91.4)
Severe (≥ 250) 13 (10.2) 3 (8.6)
OR = odds ratio, CI = confidence interval.
a
Every clinical symptom was detected and recorded; bContinuity-adjusted χ2 test was used because one of the
cell frequencies was equal to zero.

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Effectiveness of Varicella Vaccination on Disease Severity

DISCUSSION
The results of the present study showed that a one-dose vaccination was associated with
the attenuation of disease severity in pediatric varicella cases. We found that the risk of
severe illness was significantly decreased in the breakthrough group compared with the
unvaccinated group (14.6% vs. 25.8%; OR, 0.570). In other words, the vaccine effectiveness
(1–OR) of one-dose of varicella vaccine administered at 12–15 months of age was 43% (95%
CI, 11.0%–63.5%) against moderate-to-severe varicella.

This finding is consistent with results from previous studies reported elsewhere. An OR for
illness that was of a severity more than mild in breakthrough cases than in unvaccinated cases
was noted in Germany (12.5% vs. 68.2%; OR, 0.183),10 the United States (14.3% vs. 52.4%;
OR, 0. 273),9 and China (25.6% vs. 44.8%; OR, 0.446).11

Our data may be contrasted with the results from studies on varicella vaccine effectiveness
that suggest an insufficient immunogenicity of the vaccine in Korea. In a clinical-based study,
the effectiveness of one varicella vaccine product (Suduvax, Green Cross, Seoul, Korea) was
estimated as 54% (CI, 0.10–2.05) in a case-control study, and the seroconversion rate was
76.67% by the classical fluorescent antibody to membrane antigen assay.6 In a population-
based study in Seoul, Korea, the effectiveness of the varicella vaccine was 13% (CI, −17.3–35.6)
and the vaccine-induced immunity rapidly decreased three years after the vaccination,
suggesting waning of the immunity.7

From these findings, we could suggest that a universal one-dose varicella vaccination
program may have limited effectiveness to decrease in the incidence rate of varicella, but have
positive effects in attenuating the disease severity in pediatric varicella cases. Two clinical
studies on the severity of varicella in Korea demonstrated that a milder pattern of rash was
observed in the breakthrough group versus the unvaccinated group12 and that the number of
lesions detected were significantly fewer in the breakthrough group than in the unvaccinated
group.13 From the perspective of a vaccinated patient, milder symptoms by attenuation of
the disease severity are benefit. Contrarily, from the perspective of a population health care
management, patients with breakthrough varicella can also transmit varicella to others
despite that they generally have a lower rate of infectivity than those who are unvaccinated.
Mild symptoms often lead to a failure to isolate patients and lead to outbreaks among those
in close contact such as children in kindergarten or elementary school.

Our study has several limitations. A relatively small number of unvaccinated cases were
identified due to a high level of vaccine coverage, which may cause selection bias. A tendency
for a patient who is infected with varicella in their later years and develops severe disease
could be confounded in our study because the mean age of the unvaccinated group is
significantly higher than that of the breakthrough group (8.82 vs. 7.72 years). To alleviate this
selection bias, however, we used age as a confounder in the logistic model. There could be
also recall bias because the reporter would fill out the epidemiological survey depending on
his or her memory. In addition, in the epidemiological survey form, the questionnaire about
the number of lesions only requests the range of the number with a broad bracket (< 50,
50–249, 250–499, ≥ 500) rather than a concrete number of lesions, which makes it impossible
to precisely distinguish disease severity. The exact impact of a universal one-dose varicella
vaccination on disease severity could not be assessed due to a lack of previous population-
based data on varicella vaccination and its effect on disease severity before adoption of the

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Effectiveness of Varicella Vaccination on Disease Severity

universal vaccination. Furthermore, we could not estimate changes in disease severity over
time because there was no data on the annual incidence of varicella cases categorized by
disease severity. Despite these limitations, the present study is the first population-based
study to assess a universal one-dose varicella vaccination on disease severity in Korea after
introduction of the national varicella vaccination program.

In conclusion, our study suggests that employing a universal one-dose varicella vaccination
has had a significant effect on attenuating the disease severity in children. Additional
research is necessary to assess the longitudinal effect of the varicella vaccination program on
changing the epidemiology of varicella in Korea.

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