Changes in the epidemiology of varicella after the introduction of a universal vaccination program in the Republic of Korea

Abstract

Introduction and Objective

Varicella (also known as chickenpox) is an acute and highly contagious disease caused by the varicella-zoster virus (VZV) and is a common childhood disease. The epidemiology of varicella has changed dramatically since introduction of the varicella vaccines that are highly effective in reducing the global incidence and burden of the disease. In the Republic of Korea, however, incidence of varicella has been increasing during 2006 to 2017 despite the implementation of a routine one-dose varicella vaccination program in 2005. This study was to investigate the changes in the epidemiology of varicella following the introduction of vaccination and to evaluate the vaccine effectiveness in Korea. The objectives are as follows:

(1) identify the effect of age, period, and birth cohort on increasing temporal trend of varicella incidence among children in Korea by conducting Age-Period-Cohort(APC) analysis.

(2) identify spatial patterns in varicella incidence and geographical risk factors of the disease by spatial analysis and fitting spatial regression model.

(3) evaluate the effectiveness of universal one-dose vaccination program on the incidence of varicella by performing a matched case-control study.

(4) assess the effect of varicella vaccination on disease severity despite that the vaccination might fail to protect against varicella incidence.

Methods

(1) Varicella incidence from January 2006 to December 2017 was obtained from the National Notifiable Disease Surveillance System data. Population statistics were available from the Korean National Statistics Office. The APC model was used to estimate the age, period, and cohort effects. APC analysis was conducted by the APC Web Tool proposed by Rosenberg.

(2) Varicella incidence of 250 districts (si-gun-gu) from January 2006 to December 2017 was also obtained from the National Notifiable Disease Surveillance System data. Sociodemographic data were available from the Korean National Statistics Office. Global (Morans I) and local (LISA) spatial autocorrelation were calculated. Spatial regression analysis was performed to find sociodemographic predictors of varicella incidence to district level using spatial lag and spatial error model.

(3) The 537 cases and their individually matched controls were collected from the National Notifiable Disease Surveillance System. All confirmed cases were children with varicella in Seoul, Korea, between January 2013 and December 2013. To estimate the effectiveness of one-dose vaccination, conditional logistic regression analysis on the 1:1 matched pairs was performed after adjusting for the effects of possible confounders such as sex and age at vaccination. When calculating the effect of time since vaccination, we used conditional logistic models with dummy-coded variables.

(4) A total of 1,125 varicella cases reported as part of epidemiologic investigation of varicella from January 2015 to December 2017 in Seoul Metropolitan City were used. Data was provided by Korea Centers for Disease Control and Prevention (KCDC). Disease severity of patients was assessed by the number of skin lesions. Binary unconditional logistic regression analysis was performed to examine the differences in disease severity between the two groups with factor of age controlled.

Results

(1) Varicella incidence and age-standardized incidence rates have shown a diagonally upward trend between 2006 and 2017. During the period, the incidence rate also increased for each age strata among children aged 0 to 12–year–old with age peak shifted from 4 to 6 years old. In the APC analysis, period and cohort curves showed similar increasing patterns.

(2) Local spatial clusters with high level of varicella incidence were initially confined to northeast region (Gangwon-do), rural and mountain area. In later, the hot spots gradually spread to their neighboring districts and faded out over time, which led overall increase in incidence across the country. In spatial regression analysis, childhood percentage was risk factors on the incidence of varicella at district level while factors such as population density and number of hospitals have negative effect on the risk. Meanwhile, vaccine coverage rate was an insignificant factor on the incidence of varicella.

(3) In a matched case-control study, the overall effectiveness of one-dose varicella vaccination in preventing confirmed cases of varicella was low (13%, 95% CI: -17.3–35.6) and the vaccine effectiveness sharply declined after the three year of vaccination due to waning of immunity. In specific, The fact that more than half of all vaccinees were immunized with the vaccine based on MAV strain, which only available in Korea, was distinct from the cases in other countries.

(4) 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 risk for severe illness was significantly decreased in breakthrough group than unvaccinated group. The risk for occurrence of moderate-to-severe disease in the breakthrough group was less than roughly half that of the unvaccinated group (OR = 0.570, CI: 0.365–0.890).

Conclusions

(1) The study describes the post-licensure epidemiology of varicella incidence with an aspect of time and age. The increasing trend in varicella incidence may be explained by vaccine failure. The age peak shifting could be associated with secondary failure, which relates to the waning of vaccine-induced immunity over time. The varicella vaccine is merely effective in the early years, but, in later, the incidence of breakthrough infection jumps as immunity rapidly wanes over time.

(2) The second study describes the post-licensure epidemiology of varicella incidence with an aspect of time and space. The result indicated that where have a low population density and a few healthcare providers and a high childhood percentage were vulnerable to varicella outbreak, while vaccine coverage showed no influence on the incidence due to its high vaccination rate. The overall increase in varicella incidence in Korea could be attributed by spread out of varicella from high incidence cluster to its neighboring districts.

(3) The third study was to evaluate the effectiveness of one-dose varicella vaccination program in Korea. A low effectiveness of vaccine and a rapid waning of immunity of administered vaccine in Korea suggested there is primary or/and secondary vaccine failure. This finding may provide a key to understand the increasing trend of varicella incidence following implementation of universal vaccination program in Korea. Due to an insufficient immunogenicity of the vaccine might have limited effectiveness to decrease in the incidence of varicella.

(4) The last study also assessed vaccine effectiveness with an aspect of effects on disease severity. The result suggested that one-dose vaccination was associated with the attenuation of disease severity in children varicella cases. Patients whose mild symptoms can also transmit varicella to others and often cause failure to isolation, leading to outbreaks among those with close contacts in education facilities. Therefore, a recent increase in the incidence rate of varicella in Korea may be associated with a growing number of breakthrough cases