PLoS One. 2014; 9(2): e89361.
Published online 2014 Feb 20. doi: 10.1371/journal.pone.0089361
PMCID: PMC3930734
Difficulties in Eliminating Measles and Controlling Rubella and Mumps: A Cross-Sectional Study of a First Measles and Rubella Vaccination and a Second Measles, Mumps, and Rubella Vaccination
Martyn Kirk, Editor
Abstract
Background
The
reported coverage of the measles–rubella (MR) or measles–mumps–rubella
(MMR) vaccine is greater than 99.0% in Zhejiang province. However, the
incidence of measles, mumps, and rubella remains high. In this study, we
assessed MMR seropositivity and disease distribution by age on the
basis of the current vaccination program, wherein the first dose of MR
is administered at 8 months and the second dose of MMR is administered
at 18–24 months.
Methods
Cross-sectional
serological surveys of MMR antibodies were conducted by collecting
epidemiological data in Zhejiang province, China in 2011. In total, 1015
participants were randomly selected from two surveillance sites. Serum
MMR-specific immunoglobulin G levels were tested by enzyme-linked
immunosorbent assay. The geometric mean titers and seroprevalence with
95% confidence intervals (CIs) were calculated by age and gender.
Proportions of different dose of vaccine by age by vaccine were also
identified. Statistically significant differences between categories
were assessed by the Chi-square test.
Results
Over
95% seroprevalence rates of measles were seen in all age groups except
<7 months infants. Children aged 5–9 years were shown lower
seropositivity rates of mumps while elder adolescences and young adults
were presented lower rubella seroprevalence. Especially, rubella
seropositivity was significantly lower in female adults than in male.
Nine measles cases were unvaccinated or unknown vaccination history.
Among them, 66.67% (6/9) patients were aged 20–29 years while 33.33%
(3/9) were infants aged 8–12 months. In addition, 57.75% (648/1122)
patients with mumps were children aged 5–9 years, and 50.54% (94/186)
rubella cases were aged 15–39 years.
Conclusions
A
timely two-dose MMR vaccination schedule is recommended, with the first
dose at 8 months and the second dose at 18–24 months. An MR vaccination
speed-up campaign may be necessary for elder adolescents and young
adults, particularly young females.
Introduction
Measles,
mumps, and rubella are viral infections that are preventable through
vaccination programs. Under a national Expanded Program on Immunization
(EPI), a one-dose, single-antigen, live attenuated measles vaccine (MV)
was used in a limited population aged 8 months for a short period in
Zhejiang province, China between the late 1970s and early 1980s. In
1985, the MV program was amended so that an additional dose could be
administered at 7 years of age. This schedule was modified again in
2007, with the MV being replaced by a routine measles-containing
vaccination providing a measles–rubella vaccine (MRV) at 8 months of
age, followed by a measles–mumps–rubella (MMR) vaccine at 18–24 months
of age. Since 2008, revaccination policy has been implemented with MRV
for the secondary school students. In 2010, Supplementary Immunization
Activity (SIA) was achieved throughout the whole country. This
large-scale measles vaccination campaign was held on September, 2010,
with providing a measles-mumps vaccine (MMV) to children aged from 8
months to 4 years old in the province. However, despite the safe, free,
and high uptake rate of the two doses of measles-containing vaccine
(MCV) and rubella-containing vaccine (RCV) and one dose of
mumps-containing vaccine (MuCV), measles, mumps, and rubella remain
common diseases throughout Zhejiang province. Measles outbreaks
continued in 2008, with 12782 cases reported, which translated to 252.61
per million of the population. From 2009 to 2011, the incidence of
measles remained high at 3.14–17.2 per million of the population.
Similarly, the incidence of mumps increased from 394.32 to 558.26 per
million of the population in 2007 and 2008, respectively. Finally, the
reported cases of rubella increased from 3284 to 4284 in 2007 and 2011,
respectively, representing a 30.45% increase or an increase from 65.94
to 78.71 per million of the population. Therefore, the elimination of
measles and control of mumps and rubella are urgent public health
priorities in local regions. Serological surveillance can be effective
in achieving these goals [1], [2].
In
our study, we determined the incidence, seroprevalence and vaccination
history of MMR in Zhejiang Province in 2011 to clarify the population
immunity characteristics and aid in the development of improved
vaccination strategies.
Methods
Study subjects
A
population-based cross-sectional surveillance study was conducted at
two surveillance sites (Sanmen county and Cixi city) in healthy
population in Zhejiang Province between June and December 2011. The
total of 16 towns within Sanmen county and 20 within Cixi city were
stratified into 5 regions (east, west, north, south, and center),
respectively. The 5 towns in each site were sampled from each region at
random. At least 60 individuals within each selected towns were
systematically sampled from the inhabitants register to be
representative by age and gender.
According to the
policies and conventions on routine obligatory vaccination provided by
the Ministry of Health of China in 2005, the sample size required to
determine population immunity should be 30–50 per age group per
surveillance site. Our study assessed 10 age groups: 0–7 months, 8–12
months, 2–4 years, 5–9 years, 10–14 years, 15–19 years, 20–29 years,
30–39 years, 40–49 years, and ≥50 years. In total, at least 300 study
subjects were randomly chosen from each surveillance site, with
approximately 30 participants randomly selected from each age group of
each site.
Eligible subjects were selected from the two
sites where they had consistently lived for at least 6 months.
Participants were excluded if they had any acute disease or
immunodeficiency, or had a history of disease of immune system, or had a
history of using immunosuppressive agents. Study subjects were also
ineligible if they had a previously received blood products or
immunoglobulin during the recent 3 months.
Vaccination
status was determined by checking immunization record book for those
subjects aged younger than 15 years old and by recalling for others who
don't have immunization card. Disease status was confirmed by laboratory
diagnosis or physician clinical diagnosis. The ethics committee of
Zhejiang provincial center for disease control and prevention approved
all study materials, including the study protocol and written materials
provided to the subjects, parents, or legal guardians. Written informed
consent was obtained from all participants, parents, or legal guardians.
Antibody assay
A
3–5-ml blood sample was obtained via the median cubital vein,
immediately centrifuged, and transferred into polypropylene tubes for
storage at −20°C. Serological tests were performed at the measles
laboratory of the Department of Expanded Program on Immunization,
Zhejiang Provincial Center for Disease Control and Prevention. This
Laboratory meets the accreditation criteria for WHO National Measles
Laboratories. Immunoglobulin G (IgG) antibodies against measles, mumps,
and rubella were measured in the sera by enzyme-linked immunosorbent
assay (ELISA) using specific commercially available kits (Virion/Serion
GmbH, Germany). All samples were determined with the kits of the same
lot number. The control and standard sera were ready to use without
further dilution. For each test run, control and standard sera were
included independent of the number of microtest strips used. The
standard sera were set up in duplicate. All samples were rigorously
measured according to the manufacturer's instructions and the results
were expressed quantitatively.
A
measles IgG antibody concentration of >200 mIU/ml was considered
positive, a concentration of <150 was negative while a concentration
of between 150 and 200 was equivocal. Mumps IgG antibody concentrations
greater than 100 U/ml were detected as positivity. Mumps antibody values
less than 70 U/ml and 70–100 were negative and equivocal, respectively.
Concentration of samples between 70 and 100 was equivocal. Rubella
seropositivity was defined as a titer of >20 IU/ml, a titer of <10
was seronegative, and a titer between 10 and 20 was equivocal. Sera
with equivocal results were retested.
Source of disease information
Data
on the incidence and age distribution of measles, mumps, and rubella
were obtained from the National Electronic Disease Surveillance System
(NEDSS) of China.
Statistical analysis
The
geometric mean titers (GMTs) and antibody seroprevalence were
calculated with 95% confidence intervals (CIs). GMTs were calculated
using log-transformed individual concentrations and were reported as
back-transformed titers. The seropositive prevalence among different
groups was compared using the chi-square test. Statistical significance
was considered when P was ≤0.05. Data analysis was
performed using SPSS, version13.0 (SPSS Inc., Chicago, IL). Graphs were
produced with Microsoft Office Excel 2007.
Results
Baseline demographics of subjects from the two surveillance sites
We
enrolled 1015 subjects in 2011, of which 87 (8.6%) subjects had
developed measles, 1 (0.1%) had developed rubella, and 19 (1.9%) had
developed mumps during the previous year. Table 1
shows the mean age, age range, and gender distribution by age.
Moreover, the changing MCV vaccination strategies under EPI are also
listed by age group in Table 1.
Vaccination policy was varied with years based on national
recommendation of Ministry of Health of China, the various disease
burden, health priorities and financial capacity as well.
Characteristics of subjects in the two surveillance sites.
Reported cases of measles, mumps, and rubella at the two surveillance sites in 2011
The
incidence of measles, mumps, and rubella was 10.61, 648.14, and 93.23
per one million inhabitants, corresponding to overall reported cases of
9, 1122, and 167, respectively. Figure 1 (also see Table S1, Table S2 and Table S3)
presents the reported number of cases of measles, mumps, and rubella by
age group in 2011. Of the 9 patients with measles, 3 (33.33%) were
infants aged 8–12 months who were not yet immunized, while 6 (66.67%)
were young adults aged 20–29 years who were unsure of their vaccination
histories. Of the 1122 patients with mumps, 648 (57.75%) were children
aged 5–9 years. Among the 186 patients with rubella, 94 (50.54%) were
aged 15–39 years, while 38 (20.43%) were children aged 5–9 years.
Vaccination history data was unavailable for patients with mumps and
rubella.
Reported cases number of measles, mumps and rubella by age group in 2011.
Vaccination history by age at the two surveillance sites in 2011
Figure 2 (also see Table S1, Table S2 and Table S3)
shows proportion of vaccination history of different dose of MCV, RCV,
or MuCV by age at these two surveillance points in 2011. At least one
dose of MCV were administered to 80% of infants aged 8 months–1 year,
97% of children aged 2–4 years, and 96% of those aged 5–9, respectively.
Approximately 85% of children aged 2 years–4 years and 81% of those
aged 5–9 years received two doses of MCV. About 70% of children aged 2
years–9 years were given at least one dose of RCV or at least one dose
of MuCV. Nevertheless, less than 30% of adults aged 15 years–39 years
received one dose of RCV and no more than 40% of children aged 5–9 were
immunized with two doses of MuCV.
Percentage of vaccination history with different dose by age in 2011.
Seroprevalence and GMTs of measles, mumps, and rubella antibodies in the different age groups
Seropositivities for measles, mumps, and rubella by age are shown in Table 2.
Seroprevalence by age group in two surveillance sites.
The
overall seroprevalence of measles was 93.6% in the 1015 participants,
with a GMT of 1109.21±2.77 mIU/ml. Seropositivity increased from 71.5%
among infants aged <7 months old to 98.3% among those aged 8–12
months old; the majority of children (98%) aged between 8 months and 2
years had received at least one dose of the MCV. Seropositivity levels
decreased slightly at 2–4 years of age and gradually increased to 99.0%
in the ≥10-year age group, where it remained in the range of
95.5%–99.0%.
The overall seropositivity of mumps was
86.7%, with a GMT of 342.34±2.98 U/ml. Before vaccination,
seropositivity remained low from birth to 1 year of age. At the age of 2
years, the coverage of the mumps-containing vaccine was 97%. Therefore,
seropositivity abruptly increased to 92.2% in the 2–4-year group,
decreased to 86.0% in the 5–9-year group, and fluctuated in the range of
90.1%–95.8% in the ≥10-year group.
The
overall seropositivity of rubella was 74.6%, with a GMT of 42.37±3.26
IU/ml. Seropositivity increased from 54.6% at 0–7 months to a peak of
93.8% at 2–4 years, with 90% coverage of the rubella-containing vaccine
during this period. Subsequently, it decreased to 71.7% in the
10–14-year group, increasing to 82.5% in the 20–29-year group and
decreasing to 64.1% in the ≥50-year group. The GMTs of measles, mumps,
and rubella (Table 3) followed the trend of seropositivity in each age group (Fig. 3).
GMTs and seroprevalence of measles, mumps and rubella antibodies in different age group in 2011.
GMTs by age group in two surveillance sites.
Seroprevalence and GMTs of measles, mumps, and rubella antibodies in different vaccination schedules
Measles
seropositivity was higher in the participants who had received a second
dose of MCV than in those who had received a single dose, while GMTs
followed a similar trend as that followed by the seropositive rates. The
similar results were found for seropositive rates of mumps or rubella
if more than two doses of MuCV or RCV were administered compared with
one dose (data not shown). Seropositivity rates for one-dose and
two-dose regimes were higher for measles-specific antibodies but lower
for rubella-specific antibodies.
Seroprevalence and GMTs of measles, mumps, and rubella antibodies in males and females
Gender
differences were observed for rubella and measles in the 20–29-year and
30–39-year age group, respectively. Seropositivities of measles and
rubella were significantly lower in adult females than in adult males (χ2measles 
=4.794, P=0.029; χ2rubella =5.443, P=0.020). No significant gender differences existed in the other age groups (Table 4).
=4.794, P=0.029; χ2rubella =5.443, P=0.020). No significant gender differences existed in the other age groups (Table 4).
Seropositivity rates of measles-, mumps- and rubella-IgG antibodies by age and sex in 2011.
Discussion
There
are overall five surveillance sites (which were located in Cixi city,
Haining city, Xianju county, Sanmen county, and Quzhou city as well,
respectively.) in Zhejiang province of China in 2011. IgG antibodies
against measles, mumps and rubella in the sera of healthy population in
local areas were tested in these five disease surveillance points. Only
two surveillance sites (both Ci'xi city and Sanmen county) were chosen
by our study due to the poor compliance of other three surveillance
sites. Thus, the sampling surveillance sites constitute a limitation in
our study when it was assumed to represent the whole province. However,
it should be ideal to be a representative data from these two
surveillance sites.
We conducted a vaccination coverage
and serosurvey of IgG antibodies against measles, mumps, and rubella in
Zhejiang province, China in 2011. Our results showed that the
seropositivity rate in every age group (except 0–7 months) was >95%,
even though at least one dose of MCV coverage in the age groups of 10–14
years, 15–19 years, 20–29 years, 30–39 years, 40–49 years, and ≥50
years were reported to be less than 95%, and two-dose MCV coverage was
determined to be <95% in most of the age groups except 2–4 years and
5–9 years. It indicted higher level of seroprevalence for measles
possibly has been achieved by measles campaigns. Progress toward the
goal of WHO measles elimination has been made via both routine and mass
vaccination campaigns in the local areas. In 2005, the Regional
Committee of WHO Western Pacific Region established 2012 as the target
date for regional measles elimination. In 2006, China set a goal of
accelerating the progress of eliminating measles by 2012, keeping
measles incidence below 0.1 per 100,000, and then developed a series of
vaccination strategies. For example, except strengthening two-dose
routine measles immunization schedule administered at 8 and 18 months of
age, large-scale of SIAs were also included. Likewise, province-wide
measles SIAs have been implemented annually for the secondary school
students since 2008. Until 2011, approximately 0.5 million teenage
students at school were given the MRV each year and the reported vaccine
coverage was more than 95%. In addition, to reach the measles
elimination goal, China conducted a nationwide measles SIA in September
2010, which is the largest measles campaign in the whole world. In this
activity, the target age group was children aged from 8 months to 4
years throughout the whole province and the vaccine was given by MMV.
All the children in the age groups were targeted, regardless of resident
status or vaccination or disease history. A total of 78551 children
were vaccinated through this effort in the two sites and the
administrative vaccination coverage of measles vaccine was also over
95%. The subsequent measles cases are at an historic low from 328 in
2008 to 9 in 2011 and measles incidence decreased markedly to 1.061 per
100,000 in 2011, down from 19.11 per 100,000 in 2008. All these efforts
to reach more children and teenagers with MCV have rapidly reduced
measles cases in this area between 2008 and 2011, which is promising to
achieve the goal (measles incidence <5 per million in 2015) suggested
by WHO Strategic Advisory Group of Expert (SAGE) in 2010.
Of
note, we determined that measles seropositivity was the lowest (71.5%)
in the 0–7-month age group, which is probably related to the fact that
this age group is not eligible for being vaccinated under the current
vaccination schedule and is assumed to be protected by maternal
antibody. Furthermore, this study demonstrated that the maximum cases of
measles were found in the 20–29-year age group, followed by the
8–12-month age group with no documented prior doses of MCV. These
findings have potential explanations. First, young infants are at a high
risk of infection because a proportion of them may not have received
the MCV vaccination in time. Second, the measles vaccine was introduced
free of cost in China in 1978. Although its coverage has gradually
increased with a commensurate reduction in the rate of measles, there
remains a potential for increased susceptibility in individuals in their
twenties. Further investigation of the case-based reporting system from
NEDSS of China found that, in 2011, nine measles cases were
unvaccinated or unknown vaccination history, suggesting more catch-up
vaccination need to target unvaccinated children and young adults to
fill the immunization gaps. Meanwhile, it also showed that two infants
among nine measles cases were local residents while the other seven
cases (one was infants and the left six were young adults) were all from
the other parts of China, indicating that imported measles pose threat
to eliminate disease and improving MCV coverage in child and younger
adult interprovincial migrates is essential. In developed countries, the
incidence of measles in adults became a focus following its control in
younger children [3], [4]. After extensive use of MCV in Guangzhou city [2], Jiangsu province [1], Wenzhou city [5], and Hangzhou city [6]
in China, the proportion of young adults affected by measles increased
significantly. It indicted that, with MCV coverage is enhanced, this
age-specific proportion of measles has been shifted from children in
period of “control and accelerated control” to infants of <1 year and
adults of >15 years in that of “measles elimination”. This
phenomenon could be potentially explained as an inevitable period to be
close to elimination by strengthening two-dose MCV routine immunization
and implementing SIAs. Before the introduction of the effective measles
vaccine in 1966, nearly each adult aged over 40 years probably
experienced natural measles infection in their childhood [7]. Immunity following natural infection is believed to be lifelong [8], and it is likely that this accounts for the low proportion of measles cases in the ≥40-year age group.
In our study, the overall seropositivity of mumps was lower than the herd immunity threshold of 88%–92% [9].
Even though there is a reported higher MMR coverage, the number of
patients with mumps did not significantly decrease in 2011, supporting
the view that vulnerability accumulated in those with a low
seroprevalence of the mumps antibody. The 5–9-year-old population was
primarily affected and exhibited lower seropositivity. Most of them had
received a single opportunity to receive the one-dose mumps-containing
vaccine under the current vaccination schedule. Therefore, this one-dose
immunization schedule has been insufficient in controlling the
transmission of mumps, consistent with the global experience [10], [11].
In children aged 8 months, the MMR vaccine may be a better alternative
to either the measles or the measles–rubella vaccine, allowing an
additional opportunity for every pupil to receive two MMR doses before
starting school.
We determined that rubella vaccination
coverage was lower than MCV and MuCV coverage, with rubella primarily
occurring in the 15–39-year age group. Indeed, the potential for
decreased rubella coverage caused by introduction of the MR vaccine
under the EPI in 2008 may result in an epidemiological shift of disease
incidence to this age group [12]. These results are consistent with those of previous studies conducted in China [13], [14], Germany [15], America [16], and Japan [17].
We determined that the rubella seropositive rates in older adolescents
and young adults were lower. Moreover, this rate in females aged 20–29
years was significantly lower than that in males of the same age. This
is an important finding because it potentially increases the risk of
miscarriage, fetal death, or the congenital rubella syndrome (CRS) in
future pregnancies [18], with increased social and personal burdens. Therefore, vaccination strategies on RCV are needed to fill this immunity gap.
The
vaccination strategy that utilizes a second MMR dose resulted in higher
seroprevalence compared with single-dose regimens, indicating that this
would be more effective in the elimination of measles, mumps, and
rubella in future strategies. According to the results of this research,
there is an urgent need to modify the current MCV program in order to
eliminate measles and control mumps and rubella. Specifically, we
recommend the following measures. First, the current MMR program should
be modified to a two-dose schedule, with one dose at 8 months and a
second dose at 18–24 months. Second, more efforts should be made to
ensure that 8-month-old infants receive timely MCV. Third, MR speed-up
campaigns that focus on older adolescents and young adults, particularly
females, should be introduced.
Supporting Information
Table S1
Vaccination coverage and reported number of cases for measles by age group.
(DOCX)
Click here for additional data file.(14K, docx)
Table S2
Vaccination coverage and reported number of cases for mumps by age group.
(DOCX)
Click here for additional data file.(13K, docx)
Table S3
Vaccination coverage and reported number of cases for rubella by age group.
(DOCX)
Click here for additional data file.(14K, docx)
Acknowledgments
The
authors give special thanks to the participants who offered their blood
samples for this study. We also highly appreciate all the staff
involved in this research. This manuscript was improved from the
comments received by Jinren Pan, and two anonymous reviewers.
Funding Statement
This work was supported by a grant from Zhejiang Province Project for Medical and Health Science and Technology (No.2012ZDA008). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.References
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