ABSTRACT
Background
During the period of immunization with a single-dose measles-mumps-rubella (MMR) vaccine, which has been available since 2008in China, the incidence of mumps in children aged 2–5 years has been high. The aim of this study was to determine the immunity profile of mumps in children aged 2–5 years as part of the assessment of the MMR vaccination strategy.
Methods
A cross-sectional survey of IgG antibodies against mumps virus in children aged 2–5 years was performed. Analysis by enzyme-linked immune sorbent assay(ELISA)was performed to measure IgG antibodies against mumps virus in the sera of 2-to5-year-old children who had been vaccinated with at least one dose of MMR vaccine.
Results
Mumps outbreaks mainly occurred in kindergarten and primary schools and primarily involved children in kindergarten from 2015-2016 in Jiangsu Province. In total, 4,033 children were surveyed. The overall seroprevalence of mumps antibodies was 79.0% (95% CI:78.4–79.6), and the geometric mean concentration (GMC) was 323.6 mIU/ml (309.0–338.8). Both univariate and multivariate survival analysis of seroprevalence showed that several factors contributed to having significant seroprevalence among the 2-to-5-year-old group (P < .05). The seroprevalence of children with a single-dose MMR vaccine regimen (78.4%, 95% CI: 77.8–80.4) was significantly lower than that of children with a two-dose MMR vaccine regimen (96.5%, 95% CI: 88.6%-96.1%). The seroprevalence rate was negatively correlated with time since inoculation (P < .01).
Conclusion
Children who received a single dose of MMR vaccine in kindergarten, particularly the 2-year-old group in the northern region of Jiangsu Province, China, are at high risk of mumps infection. Our study demonstrates thata single-dose MMR vaccine regimen has a limited effect on controlling mumps, which highlights the benefit of introducing a two-dose MMR vaccine schedule.
1. Introduction
Mumps is an acute infectious disease caused by an enveloped single-stranded RNA virus belonging to the Paramyxoviridae family. Epidemics mainly occur among children aged 5–9 years and mostly occur in kindergarten and primary schools. The clinical symptoms of mumps include an acute febrile disease with nonspecific prodromal symptoms followed by painful swelling of one or both parotid salivary glands. Complications of mumps include deafness, aseptic meningitis, mastitis, encephalitis, orchitis and oophoritis.Citation1 Vaccination with a live attenuated mumps-containing vaccine (MuV) is the most effective way to prevent mumps, and the incidence of mumps has significantly decreased in countries where large-scale MuV vaccination has been carried out.
In recent years, however, many studies have found that a single-dose measles-mumps-rubella (MMR) vaccine regimen cannot effectively control the incidence of mumps. The underlying reasons are complex and include low vaccination coverage, imported cases from abroad, gaps in eligibility for vaccination among certain cohorts, waning immunity, and the age for vaccination. The World Health Organization (WHO) has recommended introducing a second dose of MMR vaccine to the vaccination program to ensure long-lasting immunity against mumps. A two-dose MMR vaccine schedule has been introduced to the national immunization programs (NIPs) of many developed countries: the first dose is usually administered at 12–18 months of age, and the second dose is usually administered at 4–6 years of age.
In China, vaccination with the monovalent mumps vaccine, the mumps-rubella vaccine used before 2008, or a routine single-dose MMR vaccine used since 2008 is offered to children aged 18–24 months. The coverage rate for MMR vaccination remains high, and more than 95% of children have been inoculated since 2008 in Jiangsu Province. According to the mumps vaccine position paper by the WHO, the spread of mumps can be prevented if the coverage rate for two-dose MMR vaccine regimens reaches 95%.However, surveillance data in Jiangsu Province show that the incidence decreased from 2009–2010 and significantly increased in subsequent years.Citation2 In the last two years, there were two peak incidences: one for children aged 6 years and the other for children aged 10–15 years. Therefore, it appears necessary to introduce a second dose of the MMR vaccine to better control mumps.
The aim of this study was to understand the immunity profile of mumps in children under the age of 5 years with a single-dose MMR vaccine regimen, which may help determine the optimal age of inoculation with the second dose of the vaccine. Although previous studies showed that vaccine-induced mumps immunity wanes with age, data on the immunity of children aged 2–5 years are still scarce; such data could provide data for use in confirming the optimal age for receiving the second dose of MMR vaccine. Serological surveillance plays an important role in assessing the immunity profile of the population. Therefore, a serological survey of mumps among children under the age of 5 years who received at least one dose of MMR vaccine was conducted.
2 Materials and methods
2.1 Study design
A cross-sectional serological survey of IgG antibodies against mumps virus in children aged 2–5 years was performed in Jiangsu Province in December 2015. A multistage stratified cluster sampling method was used to recruit participants based on the geographic characteristics of this province, which can roughly be divided into three regions: south, central and north. Two counties in the south region, 1 county in the central region and 3 counties in the north region were chosen using a random number table. In each county, 3–5 kindergartens were randomly selected. In each kindergarten, all children aged 2–5 years were recruited. The inclusion criteria were as follows: (1) children aged 2 to 5 years; (2)local residence for at least 3 months; (3) good physical health with a temperature <37.5°C; and (4) at least one dose of MuV (MMR, monovalent mumps vaccine, measles-mumps vaccine, or mumps-rubella vaccine). The exclusion criteria were as follows: (1) lack of MuV vaccine; (2) refusal of venous blood collection; (3) had mumps infection; or(4) serious illnesses or other reasons for exclusion after
The clinical evaluation. In total, 4033 serum samples from 4033 participants were collected.
2.1.1. Ethical clearance
This study was approved by the Medical Ethics Committee of Jiangsu of the Jiangsu Provincial Center for Disease Control and Prevention (CDC) (NO: SL2015-B015-02). Before blood collection, the parent(s) of each child signed written informed consent forms. Each participant was asked to fill out an anonymous questionnaire including information on sex, age, date of birth, vaccination and sampling date. The study has been registered at www.cliniclatrials.gov (NO. NCT02901990)
2.2. Laboratory assays
For each participant, 0.5–2 ml of blood was drawn from the median cubital vein, immediately centrifuged, transferred to a polypropylene tube and stored at −70°C for further use. The serum samples were then sent to the laboratory of the Department of Expanded Program on Immunization of Jiangsu CDC for detection of IgG antibodies. ELISA kits were utilized to measure the levels of specific IgG antibodies against mumps according to the manufacturer’s instructions (Virion/Serion GmbH, Germany). All serum samples were tested using the same batch of kits. All samples were rigorously measured according to the manufacturer’s instructions, and the results were expressed quantitatively. The antibody concentration (mIU/ml) was classified as negative, equivocal and positive according to a fixed cutoff value. An IgG concentration ≥ 108mIU/ml was considered positive, whereas values below 90mIU/ml and 90–107mIU/ml were considered negative and equivocal, respectively. Samples with equivocal results were retested and reclassified as negative or positive.
2.3 Statistical analysis
The incidence data were obtained from the National Notifiable Disease Reporting System (NNDRS) of China. Pearson chi-square analysis was used to assess differences in seroprevalence (seronegative or seropositive) among regions, sexes and ages. The Student-Newman-Keuls q test was used to compare the geometric mean concentrations (GMCs) of the different groups. The Cochran-Mantel-Haenszel χ2 test was used to analyze the differences between groups. Bonferroni correction methods were used for multiple comparisons of seroprevalence if significant differences were observed across regions and ages. Univariate regression variables with statistical significance were incorporated into the multivariate regression model for adjusting. SPSS version 22.0 (SPSS Inc., Chicago, IL, USA) was used for data analysis. P < .05 indicated statistical significance.
3 Results
3.1 Mumps incidence among children aged 2–5 years
The incidence of mumps among children aged 2, 3, 4 and 5 years was high, with a tendency to increase with age (). shows the number of outbreaks and cases of mumps in 2015.
Table 1. Outbreaks and cases of mumps in Jiangsu Province from 2014 to 2016.
Figure 1. Mumps incidence in children aged 2–5years.
3.2 Seroprevalence and gmcs of mumps antibodies stratified by sex, region, age and vaccine status
In total, 4,033 healthy children were enrolled in this study. The overall seroprevalence and GMCs of mumps antibodies among children aged 2–5 years were 79.0% (95% CI: 78.4–79.6%) and 323.6 mIU/ml (95% CI: 309.0–338.8 mIU/ml), respectively (). Significant differences between sexes, regions, age groups, and different immunization histories were observed across the entire province. The multivariate analyses showed that all factors contributed significantly to seroprevalence in the 2–5-year age group (P < .05) (). The seroprevalence of children living in the southern region was significantly higher than that of children living in the northern and central regions. The value among children aged 4 years was 86.2%, which was significantly higher than that among children aged 2 and 3 years. The seroprevalence among girls was significantly higher than that among boys (80.5% vs. 77.8%, P < .001). The seroprevalence among children with a single-dose MMR vaccine regimen was lower than that among children with a two-dose MMR vaccine regimen (78.4% and 96.5%, respectively).
Table 2. Seroprevalence and GMCs of mumps antibodies by sex,region,age groups and vaccine statusin Jiangsu province.
Table 3. Logistic regression analysis of influencing factors on seroprevalence of mumps antibodies.
3.3 Region-specific seroprevalence of mumps in different age groups in 2015
As shown in , except for the seroprevalence in the central region, the seroprevalence of each region exhibited an upward trend with age, and the seroprevalence of northern region was lower than 70% in 2-year-old children.
Figure 2. Region-specific seroprevalence of mumps among different age groups.
3.4 Trend of mumps seroprevalence since the last MuV
As shown in , the participants with a single-dose MuV regimen were included in the waning immunity analysis since the last vaccination. The seroprevalence (from 82.2% to 61.4%) was negatively correlated with time since inoculation.
Table 4. Relationship between times since vaccination and seroprevalence in children administered one MMR dose.
4. Discussion
Mumps has become a public health issue due to the many outbreaks that have occurred among school children in recent years. In particular, the incidence of mumps increased after a short decrease during the first 3 years after 2008, when a single-dose MMR vaccine was offered to children in China. A total of 250,000 cases of mumps were reported in China in 2013, with an incidence rate of 24.2/100,000.Citation3 The incidence of mumps among children aged 3–9 years is high, and most cases occur in childcare settings and primary schools.Citation4–Citation7 The efficacy of a single-dose MMR vaccine for mumps prevention remains controversial. A post-license study conducted from 1973–1989 showed that the efficacy of a single-dose regimen was between 75% and 91%.Citation8 However, the results of this study showed that the overall seroprevalence of antibodies against the mumps in children aged 2–5 years was only 79.0% (95% CI: 78.4%-79.6%),which was significantly lower than that needed to maintain herd immunity against mumps (88%-92%), which is the threshold for interrupting mumps transmission.Citation9 This finding indicated that children in kindergartens are at high risk of infection with mumps. According to the NNDRS of our country, the coverage rates of single-dose MMR vaccine in these areas are all above 95%, and the incidence of mumps in these areas is between 4.92/100,000–6.60/100,000. In 2015, a total of 7 outbreaks occurred, including in one selected site in central Jiangsu Province and one selected site in northern Jiangsu Province; there were no outbreaks in other selected areas. Under the current vaccination program, most of these children only received a single dose of MMR vaccine. Thus, a single-dose MMR vaccine schedule is insufficient to control the transmission of mumps, which is consistent with the experiences of other countries.Citation10 A study on the mumps outbreak in the central United States has attracted attention; the number of patients reached 6,000, and most of them were university students. Additionally, 70% of patients received 2 doses of MMR vaccine.Citation11 There were 17 outbreaks of mumps involving 532 cases from 2014 to 2016 in Jiangsu Province. Waning immunity to mumps was an important reason for the outbreaks. There is no case in our survey thus far, but the children are still at risk of being infected. Once the infection spreads in kindergartens, outbreaks of mumps cannot be avoided. In addition, our results showed that the seroprevalence of the single-dose MMR vaccine regimen was significantly lower than that of the two-dose MMR vaccine regimen(78.4% vs. 96.5%). Our results showed that the seroprevalence of mumps was 78.4%(95% CI:77.7–79.1) with the single-dose MMR vaccine regimen and 96.5%(95% CI: 95.1–97.9) with the two-dose MMR vaccine regimen, indicating that the efficacy of the single-dose MMR vaccine regimen is still limited.Citation12 Therefore, the two-dose MMR vaccine regimen is urgently needed for children aged 3–5 years, although the optimal age for the second dose of the two-dose MMR vaccine regimen is not clear. In the United States, the second dose is usually administered at4–6 years of age,Citation13 and in Britain and the Netherlands, the second dose is given at the ages of 3 and 9 years, respectively. However, the administration of the second dose of the MMR vaccineCitation14 before the age of 3 years may result in a high prevalence of mumps in adolescents and young adults due to waning immunity. For example, there are reports of mumps outbreaks in the Netherlands.Citation15,Citation16
Our results also showed higher seroprevalence and GMC values for girls, so we should pay more attention to boys in this age group. Similar studies have also shown that higher proportions of cases involving males have been observed in mumps outbreaks. These findings may be interpreted as more exposure between boys, especially face-to-face contact with high exposure, and exposures overcome vaccine-induced protection.Citation17–Citation21 Furthermore, the seroprevalence and GMCs among children aged 2 to 3 years in the northern region were lower than those among children in the southern and central regions. The reasons may be complex, such as the economic level of the region, MuV coverage, and different contact rates. Further action in closing the immunization gap is urgently needed due to the high risk of mumps infection.
Our study also shows that the seroprevalence (from 82.2% to 61.4%) was negatively correlated with the time since inoculation, which is consistent with the findings of previous studies.Citation22,Citation23Some studies have also indicated that a two-dose MMR vaccine regimen is essential to induce a humoral response,Citation24–Citation26 which may be related to waning immunity.Citation26,Citation27 As presented in , the seroprevalence showed a slight increase with time, especially at the age of 4 years, where the seroprevalence peaked, though the reasons for such immune system changes are complicated. According to our results, the seroprevalence with a single-dose MMR vaccine regimen was 78.4%, while the seroprevalence was 96.5% with a two-dose regimen. Overall, the seroprevalence of mumps in the population showed a decreasing trend with increasing time since vaccination, especially at 3 years after MMR vaccination (). The immunity profiles of the children aged 2–5 years in this study suggested that the second dose of a two-dose MMR vaccine regimen should be offered at 3–5 years of age because the vaccination strategies utilizing a two-dose regimen result in higher seroprevalence than those utilizing a single-dose regimen, and it will help us control mumps more effectively in the future.
Although this study involved a relatively large sample size, there are some limitations. Because we found no case of mumps in the study, we could not evaluate the efficacy of a single-dose MMR vaccine regimen. Thus, further follow-up and study of these vaccinated children are needed. In particular, stricter surveillance of future mumps cases will provide more compelling evidence of the waning immunity status associated with a single-dose MMR vaccine regimen.
In summary, both the seroprevalence and GMCs among children were low. A single-dose MMR vaccine regimen is not highly effective in preventing mumps in school settings in Jiangsu Province, China. Children with a single-dose MMR vaccine regimen in kindergarten, particularly the 2-year-old group in the northern region in Jiangsu Province of China, are still at high risk of mumps infection, and we should introduce a two-dose MMR vaccine schedule.
Disclosure of potential conflicts of interest
The authors declare that they have no competing interests.
Acknowledgments
We would like to thank all of the municipal (Wujin, Gaogang, Tongshan, Ganyu, Lianshui, Danyang) CDCs in Jangsu Province for their field work.
Additional information
Funding
References
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