The comparison of seroconversion rates among different varicella vaccines administered Turkish children; MAV/06 and vOka

ABSTRACT

Varicella is a vaccine-preventable disease, and the incidence of varicella has declined since the introduction of varicella vaccine campaigns. A wild type of varicella zoster virus (VZV) was isolated from a 33-month-old child with varicella in Korea in 1989, a different strain (MAV/06). A live-attenuated varicella vaccine containing strain (MAV/06), Suduvax®, was developed in South Korea in 1994. Turkey introduced the varicella vaccine containing the MAV/06 strain (Varicella Vaccine-GCC, Green Cross, South Korea) in January 2019. Therefore, we aimed to compare the seroconversion rates among MAV/06 vaccine- and vOka-administered children. We prospectively collected blood samples from 98 received vOKA and 98 received MAV/06 children 6 weeks after administration, and seroconversion rates were determined by an indirect fluorescence assay (Anti-VZV IIFT IgG, Euroimmun, Germany). Seroconversion rate was significantly higher in vOka group than MAV/06 group (82.7% vs. 64.3%; p = .004). Of the children vaccinated with vOka strain, 17 children did not develop antibodies, 12 were weakly positive, and the remaining 69 children were strongly positive. Of the children who were administered MAV/06 strain, 35 were negative, 20 were weakly positive, and 43 were strongly positive. In conclusion, this study demonstrated that MAV/06 varicella vaccine had lower seroconversion rates and the strong seropositive cases were less common than vOka-administered children. Larger and prospective studies are needed.

KEYWORDS:

• Varicella
• varicella vaccine
• Suduvax
• MAV/06
• vOka
• seroconversion

Introduction

Varicella-zoster virus (VZV) belongs to alpha herpes viruses. VZV has 125-kb double-stranded DNA genome with at least 71 open-reading frames. VZV causes two clinical forms of the disease: varicella (chickenpox) and herpes zoster (shingles).^1,2 Varicella is an acute, common, and highly contagious vaccine-preventable disease, and the incidence of varicella has declined since the introduction of varicella vaccine campaigns.³ Several live-attenuated varicella vaccines are currently available worldwide, either as a monovalent Oka or MAV/06 strain vaccine or as a component of quadrivalent vaccines (Oka strain only), given in combination with the measles-mumps-rubella vaccine.⁴ The first live-attenuated varicella vaccine known as vOka was derived from wild-type VZV from a child with typical varicella and developed through the serial passage by Takahashi in 1974.⁵

The vaccine was licensed for use in the United States in 1995, and the United States became the first country to introduce a universal varicella vaccination program.⁶ Currently, approximately 40 countries have included the varicella vaccine as part of their national immunization program. The effectiveness for one dose of Oka strain varicella vaccines was estimated to be 81% against all varicella and 98% against moderate/severe varicella.⁶ A wild type of VZV was isolated from a 33-month-old child with varicella in Korea in 1989, a different strain (MAV/06). A live-attenuated varicella vaccine containing strain (MAV/06), Suduvax®, was developed in South Korea in 1994.⁷ The vaccine strain (MAV/06) was obtained through the serial passage of wild-type virus in cell culture. The virus was attenuated by 10 passages in HEL cells, 12 passages in guinea pig embryonic lung cells, and passaged five times in HEL cells to prepare an attenuated strain, designated MAV/06, for vaccine production.⁸ The MAV/06 strain varicella vaccine has been used throughout Latin American countries where publicly funded varicella immunization programs have been available.⁹ Although the MAV/06 and Oka strains are included in the VZV clade 2 genotype, they are molecularly different and have different genome sequences.⁸ Next-generation sequencing was performed to evaluate the single nucleotide polymorphisms among vaccine strains of VZV showed 24 vaccine-specific loci. The number of vaccine-specific sites where the frequency of wild-type sequence was higher than 10% was more common in Varivax and Varilrix than Suduvax. Therefore, the effectiveness of the vaccines containing different strains in preventing varicella may be different. In Turkey, Oka strain varicella vaccines have been available in the private sector since 2000. The varicella vaccine was implemented within the Turkish National Immunization Program in January 2013 (a single dose at 12 months).¹⁰ The Oka strain varicella vaccine (Varivax, Meck, USA) was administered from 2013 to December 2018 in Turkey, with vaccination coverage, reported to be >95% for children 12–36 months of age. In January 2019, Turkey initiated the varicella vaccine containing the MAV/06 strain (Varicella Vaccine-GCC, Green Cross, South Korea). Currently, MAV/06 strain varicella vaccine is administered in a universal vaccination program in Turkey. This change was the decision of the Turkish Ministry of Health. In this study, we aimed to determine the immunogenicity of a single dose of a new varicella vaccine containing MAV/06 strain in healthy Turkish children aged 13–15 months and compare the children’s seropositivity rates MAV/06 strain or vOka strain.

Patients and methods

Study population and setting

A prospective clinical trial on varicella vaccines was conducted from October 2018 to April 2019. Following the announcement by the Turkish Ministry of Health in July 2018 of a change in the national immunization schedule from vOKA to MAV/06 vaccine from January 2019, we enrolled children attending the outpatient clinics of Children’s Hospital of Ege University in Izmir, Turkey, in a clinical trial. Children vaccinated from October to December 2018 received vOka vaccine, and children vaccinated from January to April 2019 received MAV/06 . Parental approval to participate in the study was obtained for 98 healthy children in each period. All children with a doctor-confirmed varicella history, underlying immunosuppressive conditions, chronic medical conditions, and children who already received one dose of any varicella vaccines were excluded. The patients who received any dose of intravenous immunoglobulin for Kawasaki disease and other reasons were excluded. All demographic characteristics, including age, gender, prior medical history, and varicella exposure or history, were recorded.

Vaccine recipients were immunized with Varivax™ (1350 pfu/dose, Merck, White Station, USA) and the MAV strain of Varicella Vaccine – Suduvax™ (1400 pfu/dose, Green Cross Corporation, Yongin, Korea). The mean age at vaccination was 13.7 months, and the mean elapsed time between vaccination and extraction of blood samples was 6.4 weeks (range 6–8 weeks). All the blood samples were stored at −200 C until the Elisa tests were performed. The number of girls was 40 and 46 in vOka administered and MAV/06 administered children.

Microbiological methods

According to kit instructions, VZV IgG antibody was evaluated by an indirect fluorescence assay (Anti-VZV IIFT IgG, Euroimmun, Germany). Wells coated with VZV-infected cells were incubated with 30 μl (1/10 diluted) serum samples. In a second step, the attached antibodies were stained with fluorescein-labeled anti-human antibodies and made visible with the fluorescence microscope (×20/×40). Fluorescence pattern was characteristic of the infected cells predominantly located in the cytoplasm and seldom in the cell nuclei when IgG antibody was positive. The evaluation was reported negative, weak positive, and strong positive.

Statistical analysis

Statistical analyses were performed using SPSS for Windows (version 22.0, IBM Corp., Armonk, NY, USA). Chi-square test and Fischer exact tests were used to compare the outcomes. Comparisons were referred to as statistically significant at p < .05.

Ethical approvals

This study had the Ethics Board of Ege University (ethical decision number: 20–2.3/17) and the Turkish Ministry of Health approvals.

Written consent was received from all enrolled patients or their parents.

Results

Seropositivity rate was significantly higher in vOka group than MAV/06 group (82.7% vs. 64.3%; p = .004). The comparison of the groups according to seropositivity degree showed that the rate of strongly positive children was higher in vOka group. Of the children vaccinated with vOka strain, 17 children did not develop antibodies, 12 were weakly positive, and the remaining 69 children were strongly positive. Of the children who were administered MAV/06 strain, 35 were negative, 20 were weakly positive, and 43 were strongly positive. The number of strong positive cases was higher in the vOka group (70.4% vs. 43.9%), and the distribution of strong and weak positive cases is shown in Table 1.

Table 1. Classification of seropositive patients according to degree of seropositivity

Vaccine strain	Strong positive (n,%)	Weak positive (n,%)	Negative	P level
vOka (n:98)	69 (70.4)	12(12.2)	17(17.3)	0.001
MAV/06 (n:98)	43 (43.9)	20(20.4)	35(35.7)

Discussion

This is the first study that evaluated the immunogenicity of MAV/06 strain and compared it with the vOKA strains in Turkey.

Since varicella vaccines were introduced in national immunization programs of many developed countries, a dramatic decline was observed, but breakthrough cases can still have occurred.^11–14 Declined varicella incidence has also been observed in infants not eligible for varicella vaccination and adults with low vaccination levels due to herd immunity.³ Turkey introduced a single-dose vOka strain varicella vaccine in the national immunization program in 2013 with vOKA but since 2019 MAV-06 strain took place. Therefore, we aimed to compare the immunogenicity at 6 weeks after vaccination of these two strains (vOka and MAV/06) and found that the immunogenicity rate was higher and strong positivity rates were higher in children administered vOka strain than MAV/06 administered patients. Few reports in English literature evaluated MAV/06 strain, and only one study compared the immunogenicity of MAV/06 with vOKA strain.^6,15–20 A recent study from South Korea that evaluated the seroconversion rates following immunization with the MAV/06 varicella vaccine found that 76.7% of the children had seroconversion 6 weeks after vaccination, which was higher than our study. ¹⁵ The second published study on MAV/06 immunogenicity evaluated 754 healthy and 89 immunocompromised children (31 leukemia, 40 solid tumor, and 18 nephrotic syndrome). They demonstrated 100% of seroconversion rates by using fluorescent antibody to membrane antigen assay (FAMA) in both immunocompromised and healthy children.¹⁸ Our study did not include immunocompromised children; therefore, we cannot compare these findings. Choi et al.¹⁹ evaluated 35 children for seropositivity rates among MAV/06 strain and Oka strain (Vari-L, Changchun Institute of Biological Products, Changchun, China) vaccines. They showed that the MAV vaccine was not inferior to the Oka vaccine in providing immunity against VZV. In their study, the sample size and the clinical information of the study groups were limited.

However, various clinical trials suggest that the MAV/06 strain varicella vaccine is poorly immunogenic and does not lessen disease severity.^15,20,21 A prospective clinical case-control study conducted in South Korea showed almost no impact of varicella vaccine introduction, possibly due to insufficient immunogenicity of vaccine based on MAV strain.¹⁵

MAV/06 strain has been predominately used vaccine strain in Korea. A single dose of varicella vaccine was introduced in the national vaccination program of South Korea in 2005.²² A recent study reported an increase in the incidence of varicella in South Korea, where the MAV strain varicella vaccine is predominantly used, despite the universal varicella vaccination.¹⁶ Lee et al.¹⁶ figured an increasing trend in varicella incidence, and the peak incidence has changed from 4 to 6 years old. Another recent study evaluated the effectiveness of varicella vaccines and demonstrated the lowest efficacy [−5% (95% CI, −61.9–31.9)] for MAV/06 strain compared with other vOka strains.²³ They also demonstrated that both MAV and Oka vaccines had higher seropositivity in the sixth year of vaccination, which can be explained with undiagnosed breakthrough cases over the study period. Oh et al.¹⁵ compared breakthrough cases and unvaccinated cases and found no difference in clinical symptoms between the groups; however, the parent-reported moderate disease severity was significantly more common in unvaccinated patients. These can be related to the unvaccinated group was also more likely to have inpatient care than the breakthrough group; however, the unvaccinated group contains only 13 cases, who were younger than the vaccinated group, so this may impact hospitalization rates. They concluded that the varicella vaccine has almost no effect in disease presentation on the severity of disease in Korea. A recent survey from Turkey evaluated the breakthrough infections those required hospitalization reported 1939 hospitalization due to varicella.²⁴

A recent letter remarked that varicella’s seemingly increasing incidence rate results from improved doctors’ reporting rate of nationally notifiable infectious diseases, including varicella, rather than an actual increase in varicella incidence during 2006–2017 in Korea.¹⁶ It is hard to conclude because it was based on medical billing data conducted in one area, and also, the incidence rate of varicella has been reported to be substantially decreased after the introduction of the varicella NIP in 2005.²⁵

A historical study followed the children vaccinated with vOka strain for 10 years. It demonstrated that the seroconversion rate was 85.7% at 6 weeks in the first year, which changed in the following 10 years (first year: 86.9%, ninth year: 95.3%).²⁶ This may be explained by misdiagnosed breakthrough infections, which can be observed as a very mild disease. However, they reported that the exact role played by exogenous vs. endogenous boosting in the persistence of varicella antibodies in that population could not be established.

In conclusion, this study showed that the seropositivity rate was lower in MAV/O6-administered children. The time elapsed between the introduction of MAV/06 vaccine in Turkey is too short. Therefore, further well-designed studies should be designed for evaluating the effectiveness of MAV/06 vaccine and the severity of disease in breakthrough cases.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.