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A Comprehensive Review of MAV/06 Varicella Vaccines: Safety, Immunogenicity, and Effectiveness

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29 April 2024

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29 April 2024

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Abstract
Varicella (chickenpox) is one of the most common infectious diseases in preschool children and can be prevented by immunization. While immunization program promotes higher vaccine coverage, there are still challenges with implementing vaccination programs particularly in low-income countries. Economic barriers can increase inequality in vaccination, which highlights the importance of distributing cost-effective varicella vaccines. Varicella vaccines have been developed with two main Varicella-Zoster Virus (VZV) strains globally: MAV/06 and Oka strains. Most of the vaccines are based on the Oka strain, while MAV/06 strain vaccines were exclusively developed by GC Biopharma. Although more than 30 million doses of MAV/06 vaccines as cost-effective vaccines have been distributed internationally, there is no comprehensive review on safety, immunogenicity, and effectiveness of MAV/06 vaccines in the literature. This paper aims to summarize and present more than 30 years of accumulated evidence from research on safety, immunogenicity, and effectiveness of MAV/06 vaccines. We expect that MAV/06 vaccines as cost-effective varicella vaccines make a significant contribution to improving global public health and health equality in children.
Keywords: 
Subject: Medicine and Pharmacology  -   Pediatrics, Perinatology and Child Health

1. Introduction

Varicella-Zoster virus (VZV) is a type of herpesvirus with high infectivity, typically causing chickenpox in childhood and generally shingles in adulthood [1,2,3,4,5,6]. VZV belongs to the Herpesviridae family and is a double-stranded DNA virus, with only one serotype but divided into five major genotypes (clade 1 to 5). Clades 1 and 3 are usually found in Europe and America, clade 2 in Asia, clade 4, 5 in Africa [4,5,7,8,9].
The virus spreads through direct contact between individuals or inhalation of aerosol droplets from respiratory secretions of chickenpox patients, entering host cells via the upper respiratory tract or conjunctiva. After primary infection with VZV, the virus remains dormant in sensory ganglia and can later trigger shingles [4,5,6,10].
Infection with varicella leads to fever and typically manifests as vesicular rash on the trunk or head, with an incubation period of 14-16 days and a duration of around 6 days post-onset [5,10]. Healthy children generally develop around 250 to 500 skin vesicles. While severity and complications of chickenpox can increase among immunocompromised individuals, even healthy children or adults can experience rare but severe complications, including death [5,6].
VZV is globally distributed, and in countries without national immunization programs (NIP), most individuals become infected by adolescence, with the highest incidence observed in preschool or early elementary school children. Chickenpox also exhibits a strong seasonal pattern in temperate and some tropical climates, with the highest incidence occurring between winter and spring. Outbreaks can occur periodically in schools or daycare centers [4,5,6,11,12,13]. Globally, chickenpox affects over 140 million individuals annually, resulting in serious complications requiring hospitalization in over 4 million cases and causing over 4,000 deaths [5,6,14]. Prior to vaccination in the United States, approximately 4 million cases of chickenpox occurred annually, leading to over 10,000 hospitalizations and over 100 deaths each year [6,14]. Chickenpox significantly contributes to the burden of disease from secondary infections (e.g., group A streptococcal infections) among children [15]. Most hospitalizations due to chickenpox occur in children, resulting in significant absenteeism from school and work for parents caring for sick children. Therefore, some countries have implemented vaccination programs during childhood to control or eliminate chickenpox [5].
The United States was the first country to introduce the one-dose varicella vaccine into its NIP program in 1995. Since then, several countries have been introducing the varicella vaccine as a universal vaccination program, with its effectiveness being demonstrated through various studies. In the United States, a two-dose program was introduced in 2006. During twenty-five years after the introduction of the varicella NIP in the United States, the incidence of chickenpox has decreased by over 97% in all age groups, and particularly in individuals under 20 years of age [5,16,17,18]. In most countries where the varicella vaccine has been introduced into national vaccination programs, incidence and hospitalization rates have decreased by over 80%, indicating that vaccination is an effective method for preventing chickenpox. Therefore, the introduction of a varicella NIP has been recommended from a public health and economic perspective [5,14,19,20].
However, there are still many countries that have not introduced the varicella vaccine as a NIP [17,19,20,21,22,23,24,25,26,27,28]. In particular, most low-income countries in Africa lack a varicella NIP [17,19,29]. And within low- and middle-income countries, generally, vaccination coverage is lower in the children with low socioeconomic background (household wealth and mother’s education level) [30]. Cost-effective varicella vaccines are an essential prerequisite for increasing vaccine coverage and reducing vaccination inequality particularly among the children in low- and middle-income countries.
The objective of this study is to provide a comprehensive review of the characteristics, safety, immunogenicity, and effectiveness of the MAV/06 varicella vaccine developed by GC Biopharma Corp., and qualified by the World Health Organization (WHO) for routine childhood immunization in many countries.

2. Varicella Vaccines

The currently licensed vaccines for preventing chickenpox are the live attenuated vaccines, which include the Oka strain and the MAV/06 strain. Both strains belong to Clade 2 and are genetically very similar [31,32,33,34].
The majority of varicella vaccines used worldwide are derived from the wild-type pOka virus, which has been attenuated to create the vOka strain, known as the Oka-derived varicella vaccine. Vaccines derived from this attenuated virus are produced by Biken, MSD, GSK, and other manufacturers in China, among others [5,17,35,36].
In addition, varicella vaccines produced by GC Biopharma Corp. in South Korea are manufactured using the attenuated MAV/06 virus, which they have developed internally [37,38] (Table 1).
Among these, varicella vaccines from MSD, SK Bioscience, Sinovac, and GC Biopharma corp. are prequalified by the World Health Organization (WHO). These vaccines have met the criteria set by the WHO and are eligible for bidding at WHO and UN agencies [39] (Table 1).

3. MAV/06 Varicella Vaccines

3.1. Development History

3.1.1. Isolation of MAV Strain

According to research conducted by the Mogam Biotechnology Research Institute [37,38], varicella viruses were isolated from vesicles of seven patients who presented with chickenpox symptoms at a pediatric clinic in Seoul, South Korea, in 1989 (Table 2).

3.1.2. Attenuation of MAV/06 Strain

To attenuate the obtained varicella viruses, several passages were carried out in normal human embryonic lung diploid cells (LuMa, normal human embryonic Lung diploid MogAm) and normal guinea pig lung diploid cells (GEL) through multiple cultivation steps (Table 3). To confirm the degree of attenuation, temperature sensitivity tests and cell susceptibility tests, which were previously used in the attenuation of the Oka virus strain [40] were employed. Among the varicella viruses tested, the sixth virus (designated MAV/06 virus) exhibited the highest cell susceptibility and the lowest temperature sensitivity. Therefore, it was selected as the attenuated varicella virus strain for GC Biopharma Corp.'s varicella vaccine [37].
Subsequent sequencing studies of varicella vaccines revealed 42 known single nucleotide polymorphisms (SNPs) occurring during the attenuation process from wild type to attenuated varicella viruses [31,33,41,42]. To confirm whether the MAV/06 vaccine was well attenuated, sequencing comparison studies were conducted with Oka-derived varicella vaccines. The results showed that levels of nucleotide sequence variations at the 42 SNP positions were similar between the MAV/06 vaccine and to vOka-derived varicella vaccines such as VARILRIX and VARIVAX. Based on these findings, it was confirmed that the MAV/06 vaccine was well attenuated [31,43].

3.1.3. Genomic characteristics of MAV/06 Strain

  • Genotyping
To date, there are multiple VZV strains whose whole genome sequence has been identified, and their nature can be divided into the pathogenic wild-type (Dumas and pOka, Table 4), which induces disease in humans, and the vaccine-type, which induces defensive immunity. The Oka strain (vOka, VARILRIX, and VARIVAX) and the MAV/06 strain (BARYCELA inj. and Varicella Vaccine-GCC inj. (Suduvax), Table 4).
As a result, the whole genome sequence length of the MAV/06 strain was 124,758 bp, and the structure of VZV consisting of TRL, UL, IRL, IRS, US, and TRS was identified. This confirms that the MAV/06 virus does not exhibit significant differences compared to other representative wild-type viruses and vOka-derived viruses [34] (Table 4).
Table 4. Genome structure of VZV strain [34].
Table 4. Genome structure of VZV strain [34].
Strain Accession Number Full Length (bp) Length (bp)
TRL1 UL2 IRL3 IRS4 US5 TRS6
Dumas NC001348 124,884 88 104,836 88 7,320 5,232 7,320
pOka* AB097933 125,125 88 104,798 88 7,463 5,225 7,463
vOka* AB097932 125,078 88 104,822 88 7,427 5,232 7,421
VARILRIX DQ008354 124,821 88 104,761 88 7,326 5,231 7,327
VARIVAX DQ008355 124,815 88 104,758 88 7,324 5,232 7,325
MAV/06* JF306641 124,758 88 104,798 88 7,276 5,232 7,276
1TRL (Terminal long repeat); 2UL (Unique long region); 3IRL (Internal long repeat); 4IRS (Internal short repeat); 5US (Unique short region); 6TRS (Terminal short repeat); *pOka (parental Oka), *vOka (vaccine Oka), *MAV/06 (BARYCELA inj. & Varicella Vaccine-GCC inj.).
  • Clade analysis
The MAV/06 vaccine underwent whole-genome sequencing in three studies, allowing for the confirmation of its genetic characteristics. The results of the whole-genome sequencing revealed that the MAV/06 vaccine belongs genetically to the same clade (Clade 2) as the well-known Oka-derived vaccines (VARIVAX, VARILRIX and Biken) [31,34,43] (Figure 1).

3.2. Product Information

There are two varicella vaccines that are derived from the MAV/06 strain: BARYCELA inj. and Varicella Vaccine-GCC inj. (Suduvax).
Varicella Vaccine-GCC inj. was developed by GC Biopharma Corp. using MAV/06 strain and LuMA cell line, which became the world’s second licensed varicella vaccine in 1993 [34,43,44].
The second generations MAV/06 varicella vaccine, BARYCELA inj., was developed by GC Biopharma Corp. using MAV/06 strain and MRC-5 cell line and licensed in 2020 [45,46]. BARYCELA inj. features an enhanced manufacturing process and greater stability compared to Varicella Vaccine-GCC inj. Antibiotic additives are generally used to prevent contamination of cells during a manufacturing process of vaccines. There are possibilities that these antibiotics may cause adverse drug reactions such as anaphylaxis in some people after administration. BARYCELA inj. is the world’s first and only antibiotic-free varicella vaccine that eliminates the risk of adverse reactions and assures improved safety [47,48,49,50,51].
  • Varicella Vaccine-GCC inj. (Suduvax) [44,52,53]
For each vial of Varicella Vaccine-GCC inj., not less than 1,400 PFU of live attenuated VZVs are supplied in lyophilized powder. In addition to the active ingredient, each vial contains the following ingredients: sucrose (as a stabilizer), glycine (as a stabilizer), sodium L-glutamate hydrate (as a stabilizer), gelatin (as a stabilizer), L-cysteine (as a stabilizer), edetate disodium (as a stabilizer), Na₂HPO₄.12H₂O (as a buffer) and NaH₂PO₄.2H₂O (as a buffer). For each annexed vial of diluent, a volume of 0.7mL sterile water for injection is included in a kit. Varicella Vaccine-GCC inj. becomes a transparent colorless or yellowish solution when reconstituted with the diluent supplied and is stored at 2-8℃ with a shelf life of 2 years.
For each vial of BARYCELA inj., not less than 3,800 PFU of live attenuated VZVs are supplied in lyophilized powder. In addition to the active ingredient, each vial contains the following ingredients: Sucrose (as a stabilizer), Glycine (as a stabilizer), Sodium L-glutamate hydrate (as a stabilizer), Gelatin (as a stabilizer), L-cysteine (as a stabilizer), Disodium edetate hydrate (as a stabilizer), Urea (as a stabilizer); Dibasic sodium phosphate hydrate (as a buffer), Potassium dihydrogen phosphate (as a buffer). For each enclosed vial of diluent, a volume of 0.7 mL sterile water for injection is included in a kit. BARYCELA inj. becomes a transparent colorless or pale-yellow solution when reconstituted with the diluent supplied and is stored at 2-8℃ with a shelf life of 2 years.

3.3. Registration and Distribution

3.3.1. Registration

  • Varicella Vaccine-GCC inj. (Suduvax) [44]
Varicella Vaccine-GCC inj. was first approved in 1993 in South Korea and later approved in other Asian and South American countries (Table 5).
BARYCELA inj. was first approved in 2020 and launched in 2021 in South Korea. It was included in the list of prequalified varicella vaccines by the World Health Organization (WHO) in 2023 (Table 5). In the same year, this vaccine was approved in Pakistan. As of 2024, regulatory approval processes are underway in about 10 countries, including Turkiye, Saudi Arabia, Vietnam in Asia, and countries in South America such as Brazil and Argentina.
Table 5. Worldwide market authorization status (as of March 2024) [44,45,46,47,54].
Table 5. Worldwide market authorization status (as of March 2024) [44,45,46,47,54].
Vaccine Country Approved date Trade Name
Varicella Vaccine-GCC inj. S.Korea June, 1993 Suduvax inj.
Peru March, 2000 Varicella vaccine KGCC
Dominica December, 2000 VACUNA DE VARICELA GCC, 1,400 PFU/0.7mL
Indonesia September, 2001 Varicella vaccine KGCC
Philippines June, 2005 V-z vax
Egypt August, 2006 Varicella vaccine GCC
Thailand March, 2007 Varicella vaccine-GCC inj.
Vietnam October, 2008 Varicella vaccine-GCC inj.
Colombia September, 2011 Vacuna contra la varicella GCC inyeccion
Guatemala April, 2019 Vacuna contra la Varicela
BARYCELA inj. S.Korea March, 2020 BARYCELA inj.
WHO February, 2023 BARYCELA inj.
Pakistan June, 2023 BARYCELA inj.

3.3.2. Distribution

  • Varicella Vaccine-GCC inj. (Suduvax)[44]
Varicella Vaccine-GCC inj. has been shipped and exported to 26 countries, totaling over 29 million doses (Total 26 countries; Aruba, Anguilla, Antigua and Barbuda, Barbados, Bahamas, Bermuda, Brazil, British Virgin Islands, Cayman Islands, Chile, Colombia, Costa Rica, Ecuador, Grenada, Guatemala, Nepal, Panama, Paraguay, Philippines, S.Korea, Saint Lucia, Saudi Arabia, Thailand, Trinidad and Tobago, Turkiye, Vietnam).
  • BARYCELA inj.[55]
BARYCELA inj. has been shipped and exported to 6 countries, totaling over 520,000 doses (Total 6 countries; Aruba, Antigua and Barbuda, Guatemala, S.Korea, Saint Lucia, Trinidad and Tobago).
  • Over the past 30 years, MAV/06 varicella vaccines have been distributed to over 20 countries worldwide, totaling approximately 30 million doses. Through the Pan American Health Organization (PAHO) bidding, the vaccines have been stably supplied to countries in Central and South America. Throughout this process, MAV/06 varicella vaccines have been confirmed as the most cost-effective option, offering the most rational pricing in terms of cost [56,57,58] (Table 6). On average, the price of the MAV/06 vaccine supplied to the PAHO was 20% lower than that of the Oka vaccines during 2021-2023 according to the PAHO.

3.4. Safety, Immunogenicity and Effectiveness

3.4.1. Safety

The evidence of the safety of MAV/06 vaccines has been accumulated and demonstrated through several clinical trials and 30 years of real-world use. The secured safety data is as follows:
  • Evidence from clinical trials
The safety of the MAV/06 vaccine has been confirmed through various clinical trials. When summarizing the safety results obtained from these trials, the following points emerge:
MAV/06 vaccine has demonstrated satisfactory safety profiles across different age groups, including infants, children, adolescents, and adults.
Safety assessments conducted in both healthy individuals and those with compromised immune function (such as immunocompromised infants) have shown satisfactory outcomes.
No significant differences in safety profiles were observed between MAV/06 vaccine and comparator vaccine (such as VARIVAX) in randomized controlled trials.
The vaccine exhibited satisfactory safety outcomes at different dosage levels, ranging from 300 PFU to 25,000 PFU.
Safety assessments conducted in various countries, including S.Korea, Thailand, the Philippines, and Vietnam, have consistently confirmed the safety of MAV/06 vaccine across diverse populations.
Overall, the comprehensive safety data obtained from multiple clinical trials support the conclusion that the MAV/06 vaccine is safe for use in the prevention of varicella infection (Table 7).
1.
Safety and immunogenicity of live attenuated varicella vaccine (MAV/06 strain) in adults and children (1994) [59]
In Korea, safety was confirmed by administering MAV/06 vaccines ranging from 300 PFU to 2,000 PFU to a total of 62 healthy adults and children (30 adults, 32 infants). Safety issues were not observed, and no serious adverse events were reported. Additionally, no significant adverse effects were identified.
2.
Immunogenicity and safety of live attenuated vaccine (MAV/06 strain) on healthy children and immunocompromised children (1995) [60]
In Korea, safety was confirmed by administering the MAV/06 vaccine to a total of 177 healthy infants, children, and adolescents (aged 12 months to 19 years), as well as 22 immunocompromised infants (who had undergone medical treatment for conditions such as 6 leukemia, 10 solid tumors, and 6 nephrotic syndromes). No unusual adverse events were observed.
3.
Immunogenicity and safety of a new live attenuated varicella vaccine (MAV/06 strain) among healthy Filipino children of ages 9 months to 17 years (2001) [61]
In the Philippines, the MAV/06 vaccine was administered to a total of 375 healthy infants and children (aged 9 months to 17 years). Safety was assessed by dividing the participants into age-specific groups, and the vaccine was well tolerated with no serious or unusual adverse events were reported.
4.
A single-center, dose block-randomized, single-blind, active-controlled, dose-escalation phase I clinical trial to evaluate the safety and efficacy of MG1111 in healthy adults (2015) [62,63]
In Korea, a total of 39 healthy adults were recruited, with the WHO pre-qualified vaccine VARIVAX serving as the control vaccine. The BARYCELA inj. vaccine was administered at different doses (2,000 PFU, 8,000 PFU, 25,000 PFU) to assess safety. No significant safety issue was observed in the overall trends and no serious adverse event was reported (ClinicalTrials.gov ID; NCT02367638).
5.
A Phase II, single-blind, randomized, multi-center, active-controlled, dose-escalation study to evaluate safety and efficacy of MG1111 in healthy children (2017) [64,65]
In Thailand, a total of 299 healthy infants and children (aged 12 months to 12 years) were recruited. The WHO pre-qualified vaccine VARIVAX served as the control vaccine. The BARYCELA inj. vaccine was administered at different doses (2,000 PFU, 8,000 PFU, 25,000 PFU) to assess safety. Vaccination with all groups was safe and well-tolerated in subjects aged 12 months to 12 years (ClinicalTrials.gov ID; NCT03375502).
6.
Immunogenicity and safety profiles of a new MAV/06 strain varicella vaccine in healthy children: A multinational, multicenter, randomized, double-blinded, active-controlled phase III study (2018) [64,65,66]
In both Korea and Thailand, a total of 515 healthy infants and children (aged 12 months to 12 years) were recruited. The WHO pre-qualified vaccine VARIVAX served as the control vaccine. The subjects were randomly assigned in a 1:1 ratio, with 258 subjects receiving BARYCELA and 257 subjects receiving VARIVAX. Safety was assessed, and it was confirmed that there were no significant differences compared to the control group (ClinicalTrials.gov ID; NCT03375502).
7.
An open-label, bridging study to assess the safety and immunogenicity of BARYCELA inj. in healthy Vietnamese children aged between 12 months to 12 years (2024) [67,68]
In Vietnam, a total of 250 healthy infants and children were vaccinated with BARYCELA vaccine. Safety was assessed by dividing the participants into age-specific groups, and safety findings continue to support good safety profile in healthy children aged 12 months to 12 years. Satisfactory safety was confirmed in all groups (ClinicalTrials.gov ID; NCT05664152).
  • Evidence from post-marketing real world uses
Once a medicine receives regulatory approval and is marketed, periodic benefit-risk evaluation reports (PBRER), previously known as Periodic Safety Update Reports (PSUR), are prepared according to the ICH E2C (R2) guideline [69].
As of March 2024, four reports have been compiled for Varicella Vaccine-GCC inj., while six reports have been prepared for BARYCELA inj. These reports include information on the quantities of vaccines supplied during a specific period and adverse reaction cases reported in the field during that period.
Varicella Vaccine-GCC inj. was distributed a total of 29,224,770 doses from 2005 to June 2022. Among these, there were 120 reports about adverse drug reactions. BARYCELA inj. has been distributed 528,360 doses since 2020 and 3 voluntary adverse reaction reports have been accumulated [44,46,55,70,71,72,73,74,75,76] (Table 8).
Table 8. Summary of PBRER(PSUR) for Varicella Vaccine-GCC inj. and BARYCELA inj. [44,46,55,70,71,72,73,74,75,76].
Table 8. Summary of PBRER(PSUR) for Varicella Vaccine-GCC inj. and BARYCELA inj. [44,46,55,70,71,72,73,74,75,76].
Vaccine Report version Reporting Period Distribution (vials) Overall reported ADRs1 cases Conclusion
Varicella Vaccine-GCC inj. PSUR v1.0 January 2005-June 2013 6,512,915 3 There were no new safety issues associated with Varicella Vaccine-GCC inj. during this PSUR reporting period
PSUR v2.1 June 2013- June 2016 5,070,608 30 There were no new safety issues associated with Varicella Vaccine-GCC inj. during this PSUR reporting period
PBRER v3.0 June 2016-June 2019 11,475,897 77 No new relevant safety findings which would necessitate an analysis and a change in the current reference safety information
PBRER v4.0 June 2019-June 2022 6,165,350 10 No new relevant safety findings which would necessitate an analysis and a change in the current reference safety information
Total 29,224,770 120 -
BARYCELA inj. PBRER v1.0 March 2020-September 2020 - * - No new relevant safety findings which would necessitate an analysis and a change in the current reference safety information
PBRER v2.0 September 2020 -March 2021 - * - No new relevant safety findings which would necessitate an analysis and a change in the current reference safety information
PBRER v3.0 March 2021-September 2021 - * - No new relevant safety findings which would necessitate an analysis and a change in the current reference safety information
PBRER v4.0 September 2021 -March 2022 52,070 - No new relevant safety findings which would necessitate an analysis and a change in the current reference safety information
PBRER v5.0 March 2022-March 2023 182,980 1 No new relevant safety findings which would necessitate an analysis and a change in the current reference safety information
PBRER v6.0 March 2023-March 2024 293,310 2 No new relevant safety findings which would necessitate an analysis and a change in the current reference safety information
Total 528,360 3 -
1ADRs: Adverse Drug Reactions, *No launch.
Although direct comparison may be limited due to differences in pharmacovigilance reporting systems among manufacturers and countries, as well as variations in reporting practices across nations, it can be observed that MAV/06 vaccine demonstrates a lower incidence of adverse reactions compared to other varicella vaccines. This suggests favorable safety outcomes post-market approval (Table 9) [77,78,79].
  • Strain Interchangeability
Some countries have incorporated a two-dose regimen of varicella vaccine into their NIP, and the WHO also recommends a two-dose vaccination to further reduce the incidence of varicella cases and to decrease outbreaks in the community [6].
In line with this, a study was conducted to assess the safety of cross-vaccination with MAV/06 and vOka-derived vaccines when administered in a two-dose regimen [80].
The study involved a total of 406 Korean infants, who received the first and second doses of vaccination with MAV/06-vOka, vOka-MAV/06, MAV/06-MAV/06 and vOka-vOka, respectively. The study confirmed that there were no safety concerns associated with this cross-strain vaccination regimen.
  • Antibiotic-Free
Antibiotics (e.g., Kanamycin, Neomycin, and Erythromycin) are generally used to prevent contamination of cells during a manufacturing process of vaccines. There are possibilities that these antibiotics may cause adverse drug reactions such as anaphylaxis in some people after administration [81]. However, BARYCELA inj. is a varicella vaccine that does not contain antibiotics, thus eliminating the risk of adverse reactions associated with antibiotics [47,49,50,51].

3.4.2. Immunogenicity

The gold standard test for measuring VZV antibodies is the Fluorescent Antibody to Membrane Antigen (FAMA) assay, developed in the 1970s. Additionally, the glycoprotein enzyme-linked immunosorbent assay (gpELISA) is commonly used. Generally, an FAMA antibody titer of 1:4 or higher is considered seropositive, indicating protection against varicella [5,82,83].
The immunogenicity of MAV/06 vaccines have been investigated tested through several clinical trials and studies.
  • Results of clinical trials
Through various clinical trials, high post-vaccination antibody titers and very high seroconversion rates (SCRs) have been confirmed.
In South Korea, the SCR of MAV/06 vaccines (BARYCELA inj. and Varicella Vaccine-GCC inj.) were close to 100% in healthy infants and children aged 12 months to 19 years, and immunocompromised children.
In the Philippines, healthy infants and children aged 9 months to 17 years, the SCR of Varicella Vaccine-GCC inj. was close to 100% at both 6 weeks and 5 years after vaccination.
In Thailand, the SCR of BARYCELA inj. was close to 100% in healthy infants and children aged 12 months to 12 years.
In Vietnam, healthy infants and children, high antibody titers of 69.9 and 126.5 were observed after vaccination with BARYCELA inj. (Table 10).
  • Safety and immunogenicity of live attenuated varicella vaccine (MAV/06 strain) in children (1994) [59]
In South Korea, a total of 32 healthy children with negative FAMA antibodies before vaccination were vaccinated with MAV/06 vaccine doses ranging from 300 PFU to 1,000 PFU to confirm immunogenicity. The results showed that regardless of the vaccine dose, children had a 100% SCR and high antibody levels 4 weeks after vaccination.
2.
Immunogenicity and safety of live attenuated vaccine (MAV/06 strain) on healthy children and immunocompromised children (1995) [60]
In South Korea, a total of 161 healthy children and adolescents (aged 12 months to 19 years) and 18 immunocompromised children (who had undergone medical treatment for conditions such as 6 leukemia, 10 solid tumors, and 6 nephrotic syndromes) were vaccinated with MAV/06 vaccine to confirm immunogenicity. After 4 weeks, both healthy children and immunocompromised children showed a 100% SCR.
3.
Immunogenicity and safety of a new live attenuated varicella vaccine (MAV/06 strain) among healthy Filipino children of ages 9 months to 17 years (2001) [61]
In the Philippines, a total of 299 healthy infants and children (aged 9 months to 17 years) were vaccinated with MAV/06 vaccine, and immunogenicity was assessed by age group. The average SCR was confirmed to be 99.7% six weeks after vaccination.
4.
A 5-year follow-up immunogenicity of a new live attenuated varicella vaccine (MAV/06 strain) among healthy Filipino children of ages 9 months to 17 years (2006) [74,84]
In 2001, a clinical study was conducted in the Philippines to assess the immunogenicity and safety of the vaccine [61]. Five years later, long-term immunogenicity and protective efficacy were evaluated. Among the 299 healthy children enrolled in the study, 163 were followed up, and 162 of them were confirmed to be seropositive (99.4%).
5.
A single-center, dose block-randomized, single-blind, active-controlled, dose-escalation phase I clinical trial to evaluate the safety and efficacy of MG1111 in healthy adults (2015) [62,63]
In a study conducted in Korea, a total of 39 healthy adults were vaccinated with BARYCELA inj. at different doses (2,000 PFU, 8,000 PFU, 25,000 PFU) with WHO pre-qualified vaccine VARIVAX as the control vaccine. After 6 weeks, the FAMA GMT results for each dose were found to be 78.8, 90.5, and 68.6, respectively (ClinicalTrials.gov ID; NCT02367638).
6.
A Phase II, single-blind, randomized, multi-center, active-controlled, dose-escalation study to evaluate immunogenicity and safety of MG1111 in healthy children (2017) [64,65]
In a study conducted in Thailand, a total of 193 healthy infants and children (12 months to 12 years) were vaccinated with BARYCELA inj. at different doses (2,000 PFU, 8,000 PFU, 25,000 PFU) with WHO pre-qualified vaccine VARIVAX as the control vaccine. After 6 weeks, the results showed a 100% SCR for each dose, with geometric mean titer (GMT) results of 85.5, 109.9, and 65.6, respectively (ClinicalTrials.gov ID; NCT03375502).
7.
Immunogenicity and safety profiles of a new MAV/06 strain varicella vaccine in healthy children: A multinational, multicenter, randomized, double-blinded, active-controlled phase III study (2018) [64,65,66]
In both Korea and Thailand, a total of 478 healthy infants and children (aged 12 months to 12 years) were enrolled in a randomized, 1:1 controlled trial, with WHO pre-qualified vaccine VARIVAX as the control vaccine and BARYCELA as the test vaccine (239 subjects in each group). After 6 weeks, the test group showed non-inferiority compared to the control group in terms of immunogenicity. The SCR results were 97.9% and 99.2% for the test and control groups, respectively. The GMT results were 74.2 and 112.7, respectively (ClinicalTrials.gov ID; NCT03375502).
8.
An open-label, bridging study to assess the safety and immunogenicity of BARYCELA inj. in healthy Vietnamese children aged between 12 months to 12 years (2024) [67,68]
In Vietnam, a total of 246 healthy infants and children were vaccinated with the BARYCELA vaccine. They were divided into age-specific groups to assess immunogenicity. After 6 weeks, the GMT results for each age group were 69.9 and 126.5, respectively (ClinicalTrials.gov ID; NCT05664152).
  • Results of seroprevalence study
In 2016, a study conducted in South Korea examined the seropositivity rate among total 715 children who received the varicella vaccines distributed in Korea. In the study, the seropositivity of the MAV/06 vaccine using the FAMA test was 74%, while the seropositivity of a vOka derived vaccine (Vari-L) was 63% [85]. This result is similar to the findings from previous studies conducted in the United States in 2006 (76%) [5,86] and in Korea in 2010 (83.6%) [82] (Table 11).
Furthermore, in a Korean study [85], there was a tendency that antibody levels (assessed with gpELISA tests) decreased as age of children increased from 1 to 4 years. However, there was no significant difference in the tendency between the MAV/06 vaccine group and the Oka vaccine group, indicating a long-term persistence of antibodies of the MAV/06 vaccines would be similar to that of the Oka vaccine [85].
  • Cell-Mediated Immunity (CMI)
CMI is known to play a crucial role in regulating VZV and providing protection against additional VZV infections. Therefore, it was investigated whether CMI is induced after MAV/06 vaccination using a non-clinical animal model, and the results confirmed the induction of CMI through a Th1 cell-mediated response [87].
  • Cross-reactive humoral immunity
VZV exhibits genetic variation regionally, but currently licensed varicella vaccines are all developed based on clade 2 strains [4,7,88]. Studies have investigated whether antibodies generated from Oka varicella vaccines elicit immune responses against different genotypes of varicella viruses [89]. Similarly, research has been conducted to assess cross-reactivity of antibodies generated after MAV/06 vaccination with varicella viruses of different clades, using both animal and human sera [87,90]. The findings indicate that antibodies generated after MAV/06 vaccination show effective immune responses against varicella viruses of different clades (clade 1, 3, and 5), including wild-type clade 2 viruses, demonstrating high and similar FAMA antibody titers across different clades [90].

3.4.3. Effectiveness

After conducting clinical trial on immunogenicity and safety of MAV/06 vaccine in the Philippines in 2001, a follow-up effectiveness study was conducted for 5 years. Out of 299 healthy children enrolled in the previous clinical trial, 163 were able to be observed up to 5 years after the clinical trial. None of them contracted chickenpox during the follow-up period, indicating 100% protection over the follow-up period [74,84].
In addition, two separate groups of Korean researchers investigated changes in the varicella epidemiology in Korean populations before and after the introduction of a one-dose universal varicella vaccination program in 2005. They reported that varicella incidence significantly decreased by 60-67%, and the peak age of varicella occurrence also shifted towards older ages [91,92,93]. Furthermore, according to a recent study [94], the incidence rate of complicated varicella cases among Korean children significantly (96%) decreased from 137 per 100,000 persons in 2010 to 6 per 100,000 persons in 2021. Considering that MAV/06 vaccine was predominantly distributed in Korea during this period, all of the above results indirectly support the effectiveness of the MAV/06 vaccine in Korean populations.
In a retrospective birth cohort study in 2011 in Korea where the vaccine coverage was higher than 95%, the incidence rate of break-through varicella cases in the cohort that received a single dose of MAV/06 vaccine was 27.1 per 1,000 person-years during a follow-up period of six years [95,96]. This rate was similar to the results of other studies conducted in the United States using the vOka-derived vaccine, which reported a range of 21.7-28.3 cases per 1,000 person-years [97,98,99,100].
GC Biopharma Corp. is currently conducting an effectiveness study with a follow-up period of six years in 1,000 Korean children who received the BARYCELA vaccine [55]. We expect that the on-going study will provide another good evidence of the effectiveness of the MAV/06 vaccines.

4. Conclusions

MAV/06 varicella vaccines, which are developed by GC Biopharma Corp., have been distributed worldwide with more than 30 million doses over the past 30 years, ensuring stable vaccine supply to numerous countries. Through various clinical trials and post-marketing experiences, their safety, including strain-interchangeability, has been confirmed. Especially, the recently developed BARYCELA inj. is antibiotic-free, addressing safety concerns associated with antibiotics. Outstanding humoral (utilizing the FAMA assay and cross-reactivity test) and cell-mediated immunogenicity of the MAV/06 vaccines has been demonstrated through diverse clinical trials and research. Moreover, several studies have supported the effectiveness of MAV/06 vaccines, although on-going and future studies will add more evidence. Overall, we think that safety, immunogenicity, and effectiveness of MAV/06 varicella vaccines are at least comparable to vOka vaccines, while MAV/06 vaccines have been more cost-effective for low-and middle-income countries than vOka vaccines.
Varicella vaccine administration is the most effective method for preventing chickenpox. We expect that MAV/06 vaccines as cost-effective varicella vaccines make a significant contribution to improving global public health and health equality in children.

Author Contributions

Conceptualization, Shin, Y.; Ryu, H.; Kim, G.; Yang, S.; and Choi, B. K.; writing—original draft preparation, Shin, Y.; Ryu, H.; writing—review and editing, Kim, G.; Yang, S.; Lee, J.; and Choi, B. K.; visualization, Shin, Y.; Ryu, H.; supervision, Choi, B. K.; project administration, Lee, J. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Acknowledgments

We thank Mina Lee from Sunchon National University for support with analysis of the data including figures and tables.

Conflicts of Interest

All authors are employees of GC Biopharma Corp. Involvement of GC Biopharma Corp. employee did not compromise the scientific integrity of this work.

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  98. Clements, D.A.; Moreira, S.P.; Coplan, P.M.; Bland, C.L.; Walter, E.B. Postlicensure Study of Varicella Vaccine Effectiveness in a Day-Care Setting. Pediatric Infectious Disease Journal 1999, 18. [CrossRef]
  99. Black, S.; Ray, P.; Shinefield, H.; Saddier, P.; Nikas, A. Lack of Association between Age at Varicella Vaccination and Risk of Breakthrough Varicella, within the Northern California Kaiser Permanente Medical Care Program. In Proceedings of the Journal of Infectious Diseases; 2008; Vol. 197.
  100. Choi, B.K.; Cho, H.; Shin, Y.; Lee, E.K. Letter to the Editor: Effectiveness of the Varicella Vaccine Among Korean Children: Suggestions for Future Research. J Korean Med Sci 2022, 37. [CrossRef]
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Figure 1. Phylogenetic tree showing five major varicella-zoster virus (VZV) clades include Oka & MAV/06 [5,31,34].
Figure 1. Phylogenetic tree showing five major varicella-zoster virus (VZV) clades include Oka & MAV/06 [5,31,34].
Preprints 105151 g001
Table 1. Examples of marketed varicella vaccines [5,17,35,36,39].
Table 1. Examples of marketed varicella vaccines [5,17,35,36,39].
Strain Trade Name Manufacturer Country WHO
prequalification
Oka/Biken OKAVAX Biken Japan -
Oka/Merck VARIVAX MSD USA Yes
Oka/RIT VARILRIX GSK Belgium -
Oka VARI-L Changchun Keygen Biological Products China -
Oka Varicella Vaccine, Live Sinovac China Yes
Oka/SK SKYVaricella SK Bioscience S.Korea Yes
MAV/06 Varicella Vaccine-GCC inj. (Suduvax) GC Biopharma Corp. S.Korea -
MAV/06 BARYCELA GC Biopharma Corp. S.Korea Yes
Table 2. Isolation of Varicella-Zoster Virus from vesicle fluid of varicella patients [38].
Table 2. Isolation of Varicella-Zoster Virus from vesicle fluid of varicella patients [38].
Isolate Clinical Symptom Ages(months)/Sex
MAV 1/1 Varicella 22/Male
MAV/2 Varicella 16/Male
MAV/3 Varicella 20/Male
MAV/4 Varicella 45/Female
MAV/5 Varicella 28/Female
MAV/6 Varicella 33/Male
MAV/7 Varicella 23/Male
1 MAV (MogAm Virus).
Table 3. Number of passage levels in the MAV/06 strain for attenuation [37].
Table 3. Number of passage levels in the MAV/06 strain for attenuation [37].
Cell Passage Number Remark
HEL1 11 LuMa2 cell
GEL3 13 -
HEL 8 LuMa cell
HEL 4 MRC-54 cell
HEL 24 LuMa cell
1 HEL (Human Embryonic Lung diploid cell), 2LuMa (normal human embryonic Lung diploid MogAm), 3 GEL (Guinea-pig Embryonic Lung diploid cell), 4 MRC-5 (Medical Research Council cell strain 5).
Table 6. Varicella vaccine prices disclosed on PAHO (US$ per dose) [56–58.]
Table 6. Varicella vaccine prices disclosed on PAHO (US$ per dose) [56–58.]
Strain 2021 2022 2023 Average
Oka 16.93 16.19 16.93 16.68
MAV/06 13.80 12.50 13.80 13.37
Table 7. Safety information of MAV/06 vaccines confirmed through clinical trials.
Table 7. Safety information of MAV/06 vaccines confirmed through clinical trials.
Clinical trial (year) Cohort Number of subjects by cohort Country
1994* [59] 300 PFU1
500 PFU
1,000 PFU
1,500 PFU
2,000 PFU		 6 children
7 children
19 adults, 13 children
6 children
11 adults		 S.Korea
1995* [60] Healthy children
Immunocompromised children		 177 children
22 children (6 leukemia, 10 solid tumors, 6 nephrotic syndromes)		 S.Korea
2001* [61] 9-12 months
1-12 years
13-17 years		 102 children
172 children
101 children		 Philippines
2015** [62,63] 2,000 PFU
8,000 PFU
25,000 PFU		 10 adults
10 adults
10 adults		 S.Korea
2017** [64,65] 2,000 PFU
8,000 PFU
25,000 PFU		 75 children
75 children
76 children		 Thailand
2018** [64,65,66] MG11112 258 children S.Korea/Thailand
2024** [67,68] 12-24 months
2-12 years		 124 children
126 children		 Vietnam
1PFU: Plaque Forming Unit, 2MG1111: project code of BARYCELA, * Varicella Vaccine-GCC inj., **BARYCELA inj.
Table 9. Comparison of the incidence of reported adverse events between MAV/06 and Oka vaccines during post-approval use periods [44,46,55,70,71,72,73,74,75,76,77,78,79].
Table 9. Comparison of the incidence of reported adverse events between MAV/06 and Oka vaccines during post-approval use periods [44,46,55,70,71,72,73,74,75,76,77,78,79].
Strain Oka MAV/06
Vaccine VARIVAX1 VARIVAX2 OKAVAX3 Varicella Vaccine-GCC inj. BARYCELA inj.
Total number of vials distributed 16,100,000 55,700,000 9,467,000 29,224,770 528,360
Number of reported adverse events 7,963 16,683 351 120 3
Estimated incidence rates (/100,000 doses) 49.46 29.95 3.71 0.41 0.57
1 R.G. Sharrar et al. [79], 2 S.A. Galea et al. [78], 3 Yosikawa et al. [77].
Table 10. Immunogenicity of MAV/06 vaccines in clinical trials.
Table 10. Immunogenicity of MAV/06 vaccines in clinical trials.
Clinical trial (year) Cohort SCR1 No, of subjects achieved/ No. of total subjects (%) FAMA GMT2 (95% CI)
1994* [59] 300 PFU3
500 PFU
1,000 PFU
1,500 PFU		 6/6(100)
7/7(100)
13/13(100)
6/6(100)		 72.0
116.2
83.3
160.9
1995* [60] Healthy children
Immunocompromised children		 161/161(100)
18/18(100)		 173.7
111.4
2001* [61] 9-12 months
1-12 years
13-17 years		 100/100(100)
99/100(99)
99/99(100)		 741.7
227.6
500.9
2006* [74,84] 9-12 months
1-12 years
13-17 years		 49/49(100)
62/62(100)
51/52(98.1)		 20.6 (15.3, 25.8)
26.4 (19.2, 33.7)
27.0 (18.7, 35.3)
2015** [62,63] 2,000 PFU
8,000 PFU
25,000 PFU		 -
-
-		 78.8 (44.3, 140.0)
90.5 (53.0, 154.6)
68.6 (41.9, 112.3)
2017** [64,65] 2,000 PFU
8,000 PFU
25,000 PFU		 43/43(100)
41/41(100)
57/57(100)		 85.5 (63.7, 114.9)
109.9 (88.6, 136,5)
65.6 (51.4, 83.6)
2018** [64,65,66] BARYCELA
VARIVAX		 234/239(97.9)
237/239(99.2)		 74.2 (65.0, 84.8)
112.7 (99.1, 128.1)
2024** [67,68] 12-24 months
2-12 years		 -
-		 69.9 (63.7, 76.7)***
126.5 (95.0, 168.5)***
1SCR: Sero Conversion Rate (≥1:4), 2GMT: Geometric Mean Titer, 3PFU: Plaque Forming Unit, * Varicella Vaccine-GCC inj., **BARYCELA inj., ***gpELISA GMT.
Table 11. Comparison of seropositivity between MAV/06 & Oka vaccines by FAMA test.
Table 11. Comparison of seropositivity between MAV/06 & Oka vaccines by FAMA test.
Choi UI et al.[85] Choi UI et al.[85] Michalik D. E. et al.[86] Kim SH et al.[82]
N* 26/35 22/35 113/148 56/67
Vaccine type MAV/06 Oka Oka Oka, MAV/06
Seroprevalence 74% 63% 76% 84%
*Number of seropositive/total.
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