ABSTRACT
We evaluated the safety and immunogenicity of different time intervals for a second dose of varicella vaccine in children in Zhejiang Province, China. Participants had all received a first dose of varicella vaccine and were assigned to 4 groups according to age (2–7 years). A second dose of live attenuated varicella vaccine was administered 1 month, 1 year, 3 years, or 5 years after the first. A serology assay was conducted and fluorescent-antibody-to-membrane-antigen test performed to measure the antibody titers against varicella before and approximately 30 days after the second dose. Of 1,078 participants, most tolerated the second dose well. Age at first dose did not affect the response to vaccination. Geometric mean titers (GMTs) significantly differed between group 1 and all other groups, both before and after the second vaccination. The GMT for group 1 was higher than those for the other 3 groups prior to the second vaccination (GMT = 20.52, 14.68, 12.49, 12.29, respectively, p < 0.001 for all), while the opposite was true after the second vaccination (GMT = 51.14, 83.37, 85.01, 81.83, respectively, p < 0.001 for all). There was no significant difference in seropositive rate among the 4 groups prior to the second vaccination (p = 0.093), and these rates were all 100% after the second vaccination. The vaccine was well tolerated in healthy children, regardless of the timing of the second dose. GMTs showed a particularly high boost after the second dose when the interval between doses was more than 1 year.
Introduction
Varicella (chickenpox) is a highly contagious disease caused by varicella zoster virus (VZV), and is characterized by various rashes, including pruritic, maculopapules, vesicles, and crusted lesions.Citation1 Transmission occurs via airborne droplets and vertical transmission. People are generally susceptible to it, especially children younger than 15 years.Citation2 Serious complications, such as viral pneumonia, viral encephalitis, and septicemia, can occur and result in long hospitalization periods and potential death. The virus may reactivate after patients have recovered and may develop into the more serious condition herpes zoster. Varicella has the highest incidence of all the vaccine-preventable diseases, and varicella outbreaks have become the main public health emergency in nurseries and primary schools in China.
To estimate the disease burden, the Chinese Center for Disease Control and Prevention conducted a retrospective survey in Shangdong, Gansu, and Hunan Provinces. The survey revealed that 95% of all the varicella cases were individuals less than 15 years old, that the incidence rate for individuals aged 1–14 years was 3424.14 cases/105 people, and that incidence peaked in children aged 5–9 years.Citation3 Varicella cases and outbreaks have been monitored through the National Infectious Disease Reporting System since 2006. These data show that recent incidence in China exceeds 20 cases/105 people and that varicella cases constitute 30% of all infectious disease events that cause a public health emergency and mainly occur in kindergartens and primary schools.Citation4 Although the medical expense per case is low, the burden of disease from varicella is huge because of the high incidence rate.
Live attenuated vaccine (varicella Oka/GSK vaccine, Varilrix; GlaxoSmithKline Biologicals), first developed from the virus of an infected child in Japan, was approved for use in Zhejiang Province in 1998. The use of the vaccine was associated with fewer outbreaks. However, breakthrough cases still occurred after a single dose of varicella vaccine.Citation5-6 Therefore, a 2-dose varicella immunization strategy is recommended for children aged ≥ 12 months to reduce outbreaks and improve immunity level.
To date, there was no official recommended time interval between the 2 doses. It is important for China to establish an immunization schedule for varicella that considers the disease burden, vaccine effectiveness, and vaccine cost. The present study was aimed at determining whether a 2-dose regimen of varicella vaccine can better prevent varicella, and at developing the optimal time interval between the doses, considering both safety and immunogenicity aspects.
Results
Study population
From June to December 2013, a total of 1,214 participants were enrolled in our study, including 377 children who were not more than 2 years old (group 1), 280 children aged 3 years (group 2), 277 children aged 5 years (group 3), and 280 children aged 7 years (group 4) (). During the study, 136 individuals (11.20%) dropped out due to refusal to participate in blood draws or failure to maintain contact with researchers. The dropout rates were 17.24%, 11.07%, 10.11%, and 4.29% for groups 1–4, respectively. The remaining 1,078 valid cases included 312, 249, 249, and 268 children in groups 1–4, respectively, with no significant differences among the 4 groups regarding gender ratio (p = 0.094).
Table 1. Characteristics of the four groups of study participants in Zhejiang province, China.
Immunogenicity
The seropositivity rate (SR, %) and geometric mean titers (GMTs) to the anti-varicella antibodies before and after the second vaccination are presented in .
The GMTs were 20.52, 14.68, 12.49, and 12.29 for groups 1–4, respectively, before the second vaccination, and 51.14, 83.37, 85.01, and 81.83 after the second vaccination. Wilcoxon signed-ranks test showed that the GMTs after the second vaccination were all significantly higher than the relevant GMTs in the 4 groups prior to this dose (p < 0.001 for all groups). According to the Kruskal-Wallis test for GMTs, significant differences were detected among all 4 groups both before and after the second vaccination (P1 < 0.001, χ2 = 71.243; P2 < 0.001, χ2 = 96.065, respectively). Furthermore, multiple comparisons between groups revealed a significant difference in GMTs between group 1 and any other group both before (P < 0.001 for all) and after the second vaccination (P < 0.001 for all). The GMT for group 1 was higher than that of the other 3 groups before the second vaccination, whereas the opposite was true after the second dose. No significant differences were detected in GMT after the second dose between any 2 groups from group 2 to group 4 (P1 = 0.622 for group 2 and 3; P2 = 0.438 for group 2 and 4; P3 = 0.201 for group 3 and 4 respectively).
Table 2. Comparison of immunization effects of the second dose of varicella vaccine among the four groups.
No significant difference in SR was detected among the 4 groups prior to the second vaccination (p = 0.093), and the rate for all groups was 100% after the second dose.
The seroconversion rate (SCR, %) was significantly lower in group 1 than in the other 3 groups (p < 0.001, χ2 = 134.809 for group 2; p < 0.001, χ2 = 100.720 for group 3; p < 0.001, χ2 = 121.067 for group 4).
Safety
In general, participants tolerated the second dose well. Few adverse effects occurred, and the majority of them were mild. Among the 1,078 cases, only one child from group 3 presented an outbreak of rash all over the body 24 hours after the second dose, an overall incidence of 0.09%, and the rash soon faded. In addition, there were 2 cases of redness and swelling in group 1, an overall incidence rate of 0.19%. The most frequent adverse effect was fever, in most cases mild. In one case from group 2, the fever reached 39°C. There were significant differences among the 4 groups in fever rate (p < 0.001, χ2 = 20.760). Group 2 had a higher incidence of fever (10.04%) than did the other 3 groups (p < 0.001, χ2 = 15.650 for group 1; p = 0.002, χ2 = 9.379 for group 3; p = 0.014, χ2 = 6.011 for group 4).
Breakthrough cases
No breakthrough cases (defined as wild-type varicella occurring >42 days after immunization) occurred in any of the groups.
Discussion
This study evaluated the safety and immunogenicity of a 2-dose varicella vaccination with different schedules in 1,078 children. There was one case of a serious adverse event that was deemed related to vaccination, the outbreak of systemic skin rash in group 3. Fever, thought to be the consequence of replication of the live-attenuated vaccine virus strain, was the most frequently reported side reaction, with an overall incidence rate of 4.82%. Our data showed that all time intervals between doses, ranging from 1 month to 5 years, were safe for healthy children.
A 10-year safety profileCitation7 for varicella vaccine concluded that the overall rate of adverse events was 3.4‰, including rash within 42 days post-vaccination, fever, swelling, and breakthrough cases. Prymula et al.Citation8 also confirmed that when varicella did occur in vaccinated children, it was milder and was associated less often with fever, regardless of whether they had received one or 2 doses. The two-dose schedule is widely applied in the United States, Canada, and Germany.Citation1
Although no breakthrough cases occurred in our study, many previous studiesCitation9-13 reported that a single dose of varicella vaccine was not sufficient to protect children from developing varicella and that an increased time interval between the first and second doses of vaccine increased the risk of breakthrough cases. A matched case-control study carried out in Tai'an prefecture, China,Citation9 demonstrated that single-dose varicella vaccine-induced immunity appears to decrease 5 years after vaccination. KuterCitation14 considered that the use of a 2-dose regimen could provide an increased rate of protection through the follow-up study in Oakland. ShapiroCitation11 conducted a case-control study in southern Connecticut and found that odds of developing varicella were 95% higher for children who received single dose compared with 2-dose regimen. However, different levels of vaccine coverage and different classifications of case status might account for the different opinions on the incremental second dose. When the surrounding population was highly vaccinated, viral outbreaks were less common. Moreover, the sensitivity of the clinical diagnosis of varicella also affects the incidence rate, so misclassification of cases may occur in the absence of laboratory confirmation. Better diagnostics are needed for varicella in vaccinated individuals.
In the present study, the GMTs of all groups after the second vaccination were significantly higher than the GMTs for every group before the second vaccination, indicating that the additional dose significantly strengthened resistance to VZV. Watson et al.Citation15 also found a sharp increase in the GMT of an antibody to VZV after the second dose. Ngai et al.Citation16 compared the immunogenicity of vaccine regimens in children aged 1–12 years and reported that the GMTs 6 weeks after vaccination were 19.5 after one dose and 31.2 after 2 doses.
Many studiesCitation17-23 showed that the 2-dose recommendation for varicella vaccine significantly decreased varicella incidence, and Kuter et al.Citation14 reported that the second dose improved the humoral and cellular immune responses that promote protection against VZV. Their post-licensure clinical trial also found that the risk for breakthrough cases was 3.3-fold higher in the one-dose group than in the 2-dose group.Citation14 According to Zhou et al.,Citation24 after the adjustment to 2 doses in the United States, varicella incidence in 2 sentinel sites (Antelope Valley, CA, and West Philadelphia, PA) in the Varicella Active Surveillance Project was reduced by 76% and 67%, respectively, and the number of outbreaks decreased by 90%. Their study found that the societal cost–benefit ratio was 1:4.37 for the one-dose regimen and 1:2.73 for the 2-dose program. Although 2-dose vaccination was not more cost-effective than 1-dose vaccination in the US, it is more cost-effective than no vaccination and the incremental second dose increased the level of protection and limited the risk of breakthrough cases. A study in GermanyCitation25 showed that 2 doses of MMRV (measles-mumps-rubella-varicella) vaccine was cost-effective from a societal perspective compared with an adolescent immunization strategy with one dose of varicella vaccine (BCR = 2.56).
In the present study, the GMTs for varicella antibody after the second vaccination were significantly higher in groups 2–4 than in group 1. This finding indicates that the dose interval may influence the antibody level. Recent studiesCitation26-27 demonstrated that increasing the time interval between each dose of vaccine did not reduce the vaccine's effectiveness, and decreasing the time interval may interfere in the antibody response as well as affecting protection. In other words, the immune response generated by longer intervals between doses may be superior to the response generated by short intervals, especially for vaccines containing an adsorbent. However, the risk of exposure clearly increased if the time interval between doses was too long.
We recommend that individuals receive the first immunization by the time they have reached 2 years of age. In most countries that have introduced a 2-dose regimen for varicella vaccine, the first dose is administered at 12–15 months of age (both for monovalent vaccine and MMRV) and the second dose may be administered either during the second year of life, at least 1 month after the first dose (Germany), or at 4–6 years of age (United States and most other countries).Citation1
In China, the varicella vaccine is available for private purchase, but it has not been included in national routine immunization programs, and relevant laws on communicable diseases have not included varicella as a notifiable disease. As vaccination is voluntary and proceeds at families' own expense, the vaccination coverage of varicella is relatively low compared with that of vaccines that are free, and an immune barrier in the population has not been established. We recommend that policy makers in China consider listing varicella as a notifiable disease and that a universal 2-dose regimen be implemented. The potential for a varicella epidemic is not limited to children; adolescents and adults are more prone to developing severe complications from infection and should also receive 2 doses of vaccine.Citation5,28-29 In order to strengthen the prevention and control of varicella, Zhejiang Province recommended a 2-dose regimen for varicella vaccine, the first dose to be provided at 12–18 months, ideally 15 months, and the second to be provided at 3–4 years old, ideally before kindergarten enrollment in order to provide proof of a complete course of vaccination prior to enrollment. Our study also supports 3 years as a good time interval between 2 doses, as this interval offered a high GMT and low rates of adverse effects.
Our study has several limitations. We did not collect the GMTs before and 1 month after the first dose, so we were not able to determine whether participants had the same foundation level. In addition, we were unable to obtain data on the incidence of adverse effects after the first dose in the 4 groups. The safety evaluation in our study was not comprehensive. Future efforts should collect more follow-up data, and more specific information on adverse effects and disease severity should be recorded. Some patients with mild breakthrough varicella may not have reported their symptoms to us, which would lead us to overestimate the efficacy of the vaccine. The drop-out rate of patients also can affect results and should be minimized.
In summary, we evaluated the safety and immunogenicity of a 2-dose varicella vaccine in children in Zhejiang Province and determined that there is good justification for introducing a 2-dose varicella vaccination schedule in China. The vaccine was well tolerated in healthy children, regardless of the timing of the second dose. A significant boost in GMT was observed in all groups after the second dose. Therefore, our study strongly supports the introduction of a 2-dose varicella vaccination program that provides the first dose at 12–18 months and the second at 3–4 years of age.
Materials and methods
Subjects
Our study group included healthy children, aged 1–7 years, who had received a single injection of varicella vaccine in Zhejiang Province, China. The second dose was provided 1 month, 1 year, 3 years, and 5 years after the first one in groups 1–4, respectively, so participants in the groups were not more than 2, 3, 5, and 7 years old, respectively. No significant difference regarding the age of the first dose (approximately 15 months) was detected among the 4 groups. Considering the different seropositive rates for 2 doses (SR after the first dose was 95.0% and after the second dose was 99.5%) and the statistical parameters (α = 0.05, β = 0.90, drop-out rate = 20%), the sample size for each group was at least 107 children. Subjects were excluded if they had lived in the location of the investigation for less than 1 year; if they had a history of varicella, other immunodeficiency diseases, neurological diseases, or seizures; if they had previously received immunoglobulin or blood products; or if they had shown an allergic reaction to any vaccine or vaccine-related component in the past.
Written informed consent was obtained from the legal guardians of all the subjects prior to any study-related actions. The study was approved by the ethics committee of Zhejiang Provincial Center for Disease Control and Prevention and was conducted in accordance with Good Clinical Practice guidelines and the Helsinki Declaration of 1975. The study was registered in the China Food and Drug Administration (Registration No.: ChiCTR-PNRC-13003527).
Vaccine
The Shanghai Institute of Biological Products Company (Shanghai, China) provided us with the live attenuated varicella vaccine, which was cultured from the Oka strain of the varicella zoster virusCitation6 and contained more than 3.3 Lg PFU live virus per dose (0.5 mL). All vaccine was refrigerated and supplied as lyophilized powder for injection in monodose vials. Subjects were vaccinated subcutaneously in the deltoid region of the arm and monitored for 30 minutes in case of anaphylactic reactions.
Immunogenicity assessment
To assess immunogenicity, a blood sample (3 mL) was collected before vaccination (on the same day as vaccination) and another was collected approximately 30 days after vaccination (range, 30–35 days) and kept at −20°0 before testing. Serology assay with a fluorescent-antibody-to-membrane antigen test was performed by a third-party detection institution (Jilin Provincial Center for Disease Control and Prevention) to measure the antibody titers of specific IgG against varicella with a cut-off value of 4-dilution.
Safety evaluation
Active surveillance visits were conducted to follow up the physical condition of participants. The children's guardians were instructed to record any adverse reactions, including fever (axillary temperature ≥ 37.3°7), redness, rash, swelling, anaphylactic reaction, and neurological symptoms. Our staff visited the participants at 24 h, 48 h, 72 h, 7 d, 14 d, and 30 d post-vaccination. Experts on adverse effects following immunization evaluated any reported side effects to determine whether they were related to vaccination.
Statistical analysis
SRs and GMTs were the main statistical indicators to evaluate the immunogenicity of the varicella vaccine, while the rate of adverse reactions was used to assess the safety. Antibody titers were natural log–transformed prior to calculations and the cut-off value of seropositivity was 4. Seroconversion was defined as any positive antibody response after vaccination for seronegative participants or at least a fourfold increase in antibody titers for seropositive participants.Citation30 The comparison of rates between different groups was performed using a Pearson chi-square test or Fisher's test. Kruskal-Wallis H test or Wilcoxon rank sum test was used to compare the GMTs among the 4 groups. Statistical significance was achieved at p < 0.05. All data were handled using EpiData 3.1, and statistical operations were performed using SPSS 17.0 (SPSS, Inc., Chicago, IL).
Abbreviations
| GMT | = | geometric mean titer |
| MMRV | = | measles-mumps-rubella-varicella vaccine |
| SCR | = | seroconversion rate |
| SR | = | seropositivity rate |
| VZV | = | varicella zoster virus |
Disclosure of potential conflicts of interest
No potential conflicts of interest were disclosed.
Acknowledgments
We greatly appreciate the careful attention of the staff of the department of immunization program in Zhejiang CDC and the scientific suggestions from Dr. Jinren Pan. We are also grateful to the participants in the study and their guardians. We sincerely thank the staff members from the Center for Disease Control and Prevention of Ninghai, Yuyao, Shangyu, Liandu, Kaihua, and Jiangshan in Zhejiang Province for all their assistance with this research.
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