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The potential benefits of varicella post-exposure prophylaxis at more than 5 days after exposure during an outbreak were investigated.
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Vaccination is still recommended even it has been more than 5 days since exposure, in order to control varicella outbreaks.
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The administration of a second dose of varicella vaccine as post-exposure prophylaxis may be worthwhile for persons who have previously received one dose of the vaccine.
Abstract
Objectives
Varicella vaccine (VarV) is recommended as effective post-exposure prophylaxis (PEP) within 3–5 days to control outbreaks. However, the effectiveness of PEP at >5 days after exposure and the administration of a second dose to those with a history of one dose prior to exposure have not been fully examined. This study evaluated the vaccine effectiveness (VE) of PEP in preventing disease during a varicella outbreak in Shanghai, China in 2013.
Methods
Self-administered questionnaires were used to obtain the students’ varicella history, vaccination status, and willingness to receive PEP. One dose of VarV was provided free of charge to eligible students. The VE of PEP was calculated as [1 − relative risk (RR)] × 100%. Analyses were restricted to grade 8 students, as no students from the other grades or teachers developed varicella during the outbreak.
Results
Twenty-seven varicella cases were identified, 16 (59%) of which were infected after the PEP campaign. Sixty-five students received one dose of VarV on day 13 or 19 after the index case. Attack rates were 28% (9/32), 16% (15/94), 0% (0/10), and 6% (3/55) among unvaccinated, one-dose Pre-PEP, first dose as PEP, and second dose as PEP recipients, respectively. Cases among second dose as PEP recipients tended to have less fever compared with unvaccinated or one-dose Pre-PEP recipients. Compared with unvaccinated students, the VE of first dose as PEP recipients was 100% and of the second dose as PEP recipients was 60% (95% confidence interval −72% to 91%).
Conclusions
Post-exposure vaccination should be given as soon as possible after exposure. Nevertheless, vaccination is still recommended even at more than 5 days post-exposure to control varicella outbreaks.
). Varicella vaccine (VarV) is widely available and is the most effective prevention and control measure against varicella. Since 1998, VarV has been licensed for use as a single dose for children aged 1–12 years in China. In 2012, it was reported that 78% of students aged 3–17 years in Shanghai, China, had received one dose of VarV, even though the vaccine was not included in the China National Immunization Program (
). A meta-analysis that included vaccine effectiveness (VE) calculated from 42 studies published between 1995 and 2014, reported that a single dose of VarV was moderately effective at preventing all varicella (81%) and highly effective at preventing moderate and severe varicella combined (98%) (
Despite successful global varicella vaccination programs, varicella outbreaks in the school setting continue to occur, even with high one-dose VarV coverage (
). According to infectious disease surveillance data for the years 2005–2007, more than 80% of varicella infections in China occurred among children younger than 14 years old, and varicella outbreaks were most likely to occur in the school setting (97%) (
Previous studies from Japan, the USA, and Israel on varicella household exposure in children have indicated that VarV is highly effective in preventing moderate or severe varicella disease (79–100%) if given within 3–5 days post-exposure (
). In addition, the potential benefits of PEP at more than 5 days after exposure and the administration of a second dose of VarV after exposure to persons who have previously received one dose have not been fully examined.
During the 2013 varicella outbreak in a middle school in Shanghai, China, one dose of VarV was recommended as PEP even for students exposed more than 12 days previously in order to reduce disease transmission. In this study, an epidemiological investigation was conducted to assess the effectiveness of PEP given as first-dose VarV to unvaccinated students or as second-dose VarV to students who had received one dose of VarV.
Materials and methods
Outbreak setting
A varicella outbreak occurred in a middle school located in Xuhui District, Shanghai, China from October to December 2013. The school had a total of 707 students in grades 6–9. All grades were located in a four-story building, which included 16 classrooms. Each grade had four classes that were all located on the same floor.
Study definitions
A case of varicella was defined as an acute maculopapular vesicular rash without any other explanation in a middle school student, occurring between October 24 and December 25, 2013. In this study, students were classified as unvaccinated, one-dose Pre-PEP, first dose as PEP, and second dose as PEP recipients based on their varicella vaccination status. One-dose Pre-PEP was defined as students who had received only one-dose of VarV before the outbreak and refused PEP. First dose as PEP was defined as students with no VarV immunization history before the outbreak who received one dose of VarV as PEP during the outbreak. Second dose as PEP was defined as students who had received one dose of Pre-PEP and then received a second dose of VarV as PEP.
Data collection
Xuhui Center for Disease Control and Prevention conducted the outbreak investigation to identify varicella cases. Self-administered questionnaires and informed consent forms were distributed to the students’ parents to obtain the students’ varicella history, vaccination status, and willingness to receive PEP. The VarV status of these students was further verified through the school immunization records. Information on clinical manifestations and duration of isolation was collected by telephone interview with the parents. The severity of varicella was classified based on the number of skin lesions as follows: mild (<50 lesions), moderate (50–500 lesions), and severe (>500 lesions, or the presence of complications or hospitalization).
Outbreak control measures
Students with varicella were excluded from school until their lesions had crusted over. Their classmates were isolated from other students by time-shifting the school dismiss, using specific stairwells, and prohibiting the use of public rooms. Moreover, school activities were suspended and classrooms, indoor play areas, and public rooms were disinfected daily during the outbreak.
According to the Shanghai Varicella Emergency Vaccination Program, which was started in 2013, one dose of VarV should be offered immediately to immunize all unvaccinated classmates with no varicella history once two varicella cases are detected in the same school class. All unvaccinated students at the school should be vaccinated when the varicella outbreak evolves into a public health emergency event (≥10 varicella cases within 7 days during an outbreak). A second dose of VarV is recommended for post-exposure administration for students with a history of one dose of VarV more than 5 years before the outbreak. One dose of VarV was provided as PEP at no cost to the students willing to receive the vaccination. Students with any acute illness or whose parents refused to allow them to be vaccinated were excluded from vaccination.
On November 6, 2013, six students in class 2 of grade 8 were vaccinated with VarV on day 13 of exposure. On November 9, 2013, the outbreak developed into a public health emergency event, as 15 students were infected from November 2 to November 8. On November 11, 2013, another 281 middle school students (59 from grade 8) were offered PEP vaccination on day 19 after the occurrence of the index case.
Statistical methods
Data were entered into EpiData 3.1 (The EpiData Association, Odense, Denmark). Statistical analyses were performed using SPSS for Windows version 12.0 (IBM Corp., Armonk, NY, USA). Varicella severity was compared between unvaccinated, one-dose Pre-PEP, first dose as PEP, and second dose as PEP recipients using Pearson’s Chi-square test, Fisher’s exact test, or the Wilcoxon rank-sum test, as appropriate. A p-value of <0.05 was considered statistically significant.
VE was calculated using the following formula: [1 − relative risk (RR)] × 100% (
), where RR was the incidence ratio calculated from this outbreak investigation. VE of PEP was analyzed after stratifying students according to VarV immunization status, and the unvaccinated students were the control group. To calculate the VE of PEP, the at-risk period for each uninfected student who refused PEP began on the day of PEP (November 6, 2013 for students in class 2 of grade 8; November 11, 2013 for students in the other three classes). The theoretical basis for PEP relates to the ability of the vaccine to result in a rapid immune response within 4–7 days (
). It was assumed that it takes at least 4 days after vaccination to induce sufficient antibodies against varicella-zoster virus infection. Therefore, first dose PEP recipients and second dose PEP recipients within 4 days after varicella exposure were grouped as unvaccinated and one-dose Pre-PEP, respectively, during the outbreak. To calculate the at-risk period for students who received one dose of VarV as PEP, this began at 5 days after the day of PEP (November 11, 2013 for students in class 2 of grade 8; November 16, 2013 for students in the other three classes). Each PEP ended on December 26, 2013 (21 days after the date of rash onset for the last infected student, as 21 days is the maximum incubation period of varicella) or the date of rash onset for students who developed varicella. In addition, the additional reduction in varicella disease experienced by second dose as PEP recipients relative to one-dose Pre-PEP was assessed. A 95% confidence interval (CI) of VE excluding 0 was considered as statistically significant.
Results
Outbreak epidemiology
During the varicella outbreak from October 24, 2013 to December 4, 2013, 27 cases were reported. The mean age of the cases was 13.6 ± 0.3 years and 18 of them (67%) were male. The index case was a 14-year-old boy from class 2 of grade 8 who had previously received one-dose VarV. He developed a rash on the evening of October 24, 2013, approximately 10.5 years after varicella vaccination on March 5, 2002. The next day, he attended school and participated in the school Olympic day before he was sent home and clinically diagnosed with varicella. He had a generalized rash with <50 lesions and reported a fever of 38 °C. One case report peak occurred during this outbreak at approximately 2 weeks after the index case (Figure 1).
Figure 1Distribution of cases by date of rash onset, and immunization and PEP status.
The outbreak was restricted to the four classes of grade 8 in the middle school, with 5–10 cases per class. All students in the four classes of grade 8 stayed on the third floor and performed a gymnastic show on the school Olympic day on October 25, 2013. All analyses were restricted to students in grade 8, as no varicella was reported in students in the other grades or their teachers. There were 191 students in grade 8 and none of them had had varicella before the outbreak. The mean age of the 191 students was 13.7 ± 0.3 years (range 12.9–14.7 years) and 50% were male. Among the 191 students, 42 (22%) were unvaccinated and 149 (78%) had previously received one dose of VarV before the outbreak according to their immunization records (Figure 2). Among one-dose recipients (n = 149), the mean time since vaccination before the outbreak was 11.8 ± 1.2 years (range 7.4–12.9 years).
Figure 2Varicella vaccination, case, and PEP status in students of grade 8 during a varicella outbreak in Shanghai, China.
Before the PEP campaign, five unvaccinated students and six one-dose Pre-PEP recipients were diagnosed with varicella (2–3 cases per class). Among the 180 students from grade 8 who were eligible for one dose of VarV as PEP, a total of 65 received one dose of VarV on day 13 or 19 after the index case (Figure 2). The rate of PEP was 27% (10/37) among unvaccinated students and 39% (55/143) among one-dose recipients before the outbreak, which was not statistically significant (p = 0.20). After PEP, attack rates were 28% (9/32), 16% (15/94), 0% (0/10), and 6% (3/55) among unvaccinated, one-dose Pre-PEP, first dose as PEP, and second dose as PEP recipients, respectively.
Disease characteristics
All cases had mild varicella. Among second-dose as PEP recipients, one out of three cases (33%) had fever. In contrast, fever was reported in 67% (6/9) of unvaccinated subjects and 53% (8/15) of one-dose Pre-PEP recipients (Table 1). There was no difference between one-dose Pre-PEP and second dose as PEP recipients with breakthrough varicella with regard to rash severity (p = 1.0), fever (p = 1.0), duration of rash (p = 0.53), or duration of isolation (p = 1.0) (Table 1).
Table 1Disease severity of varicella according to varicella vaccine status.
Among the 27 varicella cases, 11 (41%) were infected before the PEP campaign and 16 (59%) were infected after the campaign (Figure 2). After PEP, the incidence rate was 3.6 cases/1000 person-days, 2.3 cases/1000 person-days, 0 cases/1000 person-days, and 1.4 cases/1000 person-days among unvaccinated, one-dose Pre-PEP, first dose as PEP, and second dose as PEP recipients, respectively (Table 2). Compared to unvaccinated students, the effectiveness of the first dose as PEP was 100% and of the second dose as PEP was 60% (95% CI −72% to 91%) (Table 2). The incremental VE (second dose as PEP vs. one-dose Pre-PEP) was 38% (95% CI −127% to 83%).
Table 2Effectiveness of PEP during a varicella outbreak in a middle school in Shanghai, China.
This study appears to be the first to present the potential benefit of administering a second dose of VarV as PEP to those who have received one dose during an outbreak in China. In this study, the VE of the second dose as PEP was 60% and the incremental effectiveness was 38% compared with unvaccinated students and one-dose Pre-PEP recipients, respectively. However, the difference in effectiveness between groups was not statistically significant, although this may be the result of the small sample size and the late start of the PEP campaign (>12 days after exposure). Moreover, cases among second dose as PEP recipients tended to have less fever. The results of this study add to the limited data regarding the potential benefit of administering a second dose of VarV after exposure to persons who have previously received one dose of VarV. Additional data are needed to better understand the benefit of administering a second dose of VarV to one-dose recipients after exposure, as varicella outbreaks in the school setting have become an increasing challenge even with high one-dose VarV coverage.
The incremental effectiveness calculated in this study differs from one report showing a high efficacy of second-dose vaccination for outbreak control (
reported an incremental effectiveness of 76% during an outbreak in a Philadelphia elementary school. The discrepancy between the results of the two studies may be explained by different reference groups and methods for calculating the at-risk period. The start date began in the infectious period of the first case in the study by
, whereas it began on the day of PEP in the present study. Therefore, cases from one-dose recipients who were infected before the PEP campaign were also included when calculating the incremental effectiveness in the Philadelphia outbreak, which likely overestimated the incremental VE of PEP. Moreover, the one-dose VarV coverage rate was higher (97%) in the Philadelphia outbreak compared with that in the present study (78%), and the rate of second-dose VarV as PEP was higher than that in the present study (65% versus 38%). The effectiveness of the second dose of VarV as PEP might vary among populations with lower one-dose vaccine coverage or PEP uptake, or outbreaks with later PEP implementation.
As no varicella was identified in 10 unvaccinated students who received the first dose of VarV as PEP during this outbreak, the VE of PEP in first-dose students was 100%. The time from exposure to vaccination in this study was more than 12 days, and 91% of students received one dose of VarV as PEP at 19 days after exposure, which is longer than reported in other published studies (within 3–5 days) (
Protective effect of immediate inoculation of a live varicella vaccine in household contacts in relation to the viral dose and interval between exposure and vaccination.
), and the mean age in the present study was 13.7 years. This study provides support for the recommendation of the Advisory Committee on Immunization Practices to administer VarV during varicella outbreaks as PEP, even if more than 5 days have passed since exposure (
). However, the sample size of unvaccinated students was small in this study and thus the VE of PEP may have been overestimated. These findings support the need for additional evaluations in which people receive VarV as PEP more than 5 days after exposure during an outbreak.
Several limitations of this study should be considered when evaluating the VE of PEP. First, a clinical case definition that did not require laboratory confirmation was employed. Moreover, it could not be determined whether rashes in PEP students were caused by wild virus or VarV. In this study, any rash after one dose of VarV as PEP was considered to have been caused by wild virus, which may have led to an underestimation, not an overestimation of the VE of PEP. Second, the number of days of transition from unvaccinated to first dose as PEP, or from one-dose VarV to second dose as PEP vaccine immunity was inferred and not confirmed by antibody immune response testing. It was assumed that vaccine-induced immunity could develop as early as 5 days after PEP. This is the shortest period given the rapid immune response identified in previous studies (4–7 days), and thus may have led to an underestimation of the VE of PEP. Third, it was assumed that all students were exposed to varicella during the outbreak. Although the calculation was restricted to students in grade 8, it is possible that not all students had the same exposure to the index case. However, 11 students were identified as varicella-positive before the PEP campaign, with 2–3 cases per class in grade 8. Therefore, the other cases may have been exposed to these students from the other three classes of grade 8 before PEP.
In conclusion, VarV was effective in preventing a varicella outbreak in a middle school in China, even when administered more than 5 days after exposure to varicella. Before the implementation of a two-dose VarV schedule, the administration of a second dose of VarV may be worthwhile for persons who have previously received one dose, even if it does not offer sufficient protection as PEP. Future studies on administering first-dose or second-dose VarV as PEP during varicella outbreaks are warranted.
Conflict of interest/funding
None.
References
Arbeter A.M.
Starr S.E.
Plotkin S.A.
Varicella vaccine studies in healthy children and adults.
Protective effect of immediate inoculation of a live varicella vaccine in household contacts in relation to the viral dose and interval between exposure and vaccination.
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