A review of testing used in seroprevalence studies on measles and rubella

Seroprevalence studies are an essential tool to monitor the efficacy of vaccination programmes, to understand population immunity and to identify populations at higher risk of infection. An overarching review of all aspects of seroprevalence studies for measles and rubella published between 1998 and June 2014 was undertaken and the findings reported elsewhere. This paper details the considerable variation in the testing formats identified in the review. Apart from serum/plasma samples, testing of oral fluid, breast milk, dry blood spots and capillary whole blood were reported. Numerous different commercial assays were employed, including microtitre plate assays, automated immunoassays and classical haemagglutination inhibition and neutralisation assays. A total of 29 of the 68 (43%) measles and 14 of the 58 (24%) rubella studies reported qualitative test results. Very little information on the testing environment, including quality assurance mechanisms used, was provided. Due to the large numbers of testing systems, the diversity of sample types used and the difficulties in accurate quantification of antibody levels, the results reported in individual studies were not necessarily comparable. Further efforts to standardise seroprevalence studies may overcome this deficiency.     

Seroprevalence of measles and rubella antibodies in pregnant women Haiti, 2012

Background

Haiti had set a national goal to eliminate measles and rubella, as well as congenital rubella syndrome (CRS) by 2010. A 2007–2008 nationwide measles and rubella vaccination campaign targeting 1–19 years, however, reached only 79% of the target population. To assess whether population immunity was adequate to support elimination, we conducted a national serosurvey.

Methods

We systematically selected 740 serum specimens collected from pregnant women in a 2012 national antenatal HIV sentinel serosurvey across four age strata: 15–19, 20–24, 25–29 and 30–39 years. Sera were tested for measles and rubella specific immunoglobulin G antibodies (IgG) using commercial immunoassays. We classified sera as seropositive, seronegative or indeterminate per manufacturer's instructions, and analyzed seroprevalence according to age strata, and rural or urban residence. We assessed immunity by estimating antibody concentrations in international units per milliliter (IU/mL) for seropositive and indeterminate sera. Measles IgG concentrations >0.12 IU/mL and rubella IgG concentrations >10 IU/mL were considered clinically protective.

Results

Of 740 sera, 696 (94.1%) were seropositive and 20 (2.7%) were indeterminate for measles IgG; overall 716 (96.8%) sera had IgG concentrations >0.12 IU/mL. For rubella IgG, 691 (93.4%) sera were seropositive and 1 (0.1%) was indeterminate; a total of 687 (92.8%) had IgG concentrations >10 IU/mL. Measles seropositivity varied across age strata (p = 0.003); seropositivity increased from 88.6% among 15–19 year olds to 98.4% among 30–39 year olds (Cochran–Armitage trend test ≤ 0.0001). Rubella seropositivity did not differ across age strata. There were no statistically significant differences in measles or rubella seropositivity by urban versus rural residence.

Conclusion

Despite previous low vaccination coverage for measles, results from this serosurvey indicate high levels of measles and rubella seropositivity in pregnant women, and contribute to the evidence for measles, rubella and CRS elimination from Haiti by the target date.     

Measles and rubella IgG seroprevalence in persons 6 month-35 years of age,Mongolia, 2016

BackgroundIn 2015–2016, Mongolia experienced an unexpected large measles outbreak affecting mostly young children and adults. After two nationwide vaccination campaigns, measles transmission declined. To determine if there were any remaining immunity gaps to measles or rubella in the population, a nationally representative serosurvey for measles and rubella antibodies was conducted after the outbreak was over.MethodsA nationwide, cross-sectional, stratified, three-stage cluster serosurvey was conducted in November-December 2016. A priori, four regional strata (Ulaanbaatar, Western, Central, and Gobi-Eastern) and five age strata (6 months-23 months, 2–7 years, 8–17 years, 18–30 years, and 31–35 years) were created. Households were visited, members interviewed, and blood specimens were collected from age-appropriate members. Blood specimens were tested for measles immunoglobulin G (IgG) and rubella IgG (Enzygnost® Anti-measles Virus/IgG and Anti-rubella Virus/IgG, Siemens, Healthcare Diagnostics Products, GmbH Marburg, Germany). Factors associated with seropositivity were evaluated.ResultsAmong 4598 persons aged 6 months to 35 years participating in the serosurvey, 94% were measles IgG positive and 95% were rubella IgG positive. Measles IgG seropositivity was associated with increasing age and higher education. Rubella IgG seropositivity was associated with increasing age, higher education, smaller household size, receipt of MMR in routine immunization, residence outside the Western Region, non-Muslim religious affiliation, and non-Kazakh ethnicity. Muslim Kazakhs living in Western Region had the lowest rubella seroprevalence of all survey participants.ConclusionsNationally, high immunity to both measles and rubella has been achieved among persons 1–35 years of age, which should be sufficient to eliminate both measles and rubella if future birth cohorts have ≥ 95% two dose vaccination coverage. Catch-up vaccination is needed to close immunity gaps found among some subpopulations, particularly Muslim Kazakhs living in Western Region.     

Age-stratified seroprevalence of measles, mumps and rubella (MMR) virus infections in Switzerland after the introduction of MMR mass vaccination

We have performed age-stratified seroprevalence studies for MMR to evaluate these vaccinations. Serum samples submitted for diagnostic testing were randomly selected for unlinked anonymous panels. IgG antibodies were tested by ELISA and indirect immunofluorescence. In the vaccination cohort (age 1.5 to 6.5 years), seroprevalence attained 80%. For measles and mumps it continued to increase to 95%, while for rubella it declined transiently to 60% between 7 and 12 years of age. We observed no differences according to gender in any age group in 1991--1992. (Semi)quantitative values of the IgG antibodies against all three viruses increased during adolescence, suggesting wild virus circulation. In 1992, MMR vaccination has reached < 80% of the children during their second year of age. Due to previous monovalent measles and mumps vaccinations in pre-school children and due to endemic and epidemic activity, particularly of mumps virus, a trough of the seroprevalence in adolescents was evident only for rubella. MMR vaccination campaigns performed at school since 1987 have increased seroprevalence in this population segment and have probably over-compensated for the expected shift to the right of the seroprevalence curves. A more compulsive implementation of the recommended childhood vaccination schedule and continued efforts at catchup vaccinations during school age especially for rubella are necessary to avoid the accumulation of susceptible young adults during the forthcoming decades.     

Measles and rubella immunity in the population of Bhutan, 2017

BackgroundIn 2017, measles elimination was verified in Bhutan, and the country appears to have sufficiently high vaccination coverage to achieve rubella elimination. However, a measles and rubella serosurvey was conducted to find if any hidden immunity gaps existed that could threaten Bhutan’s elimination status.MethodsA nationwide, three-stage, cluster seroprevalence survey was conducted among individuals aged 1–4, 5–17, and >20 years in 2017. Demographic information and children’s vaccination history were collected, and a blood specimen was drawn. Serum was tested for measles and rubella immunoglobulin G (IgG). Frequencies, weighted proportions, and prevalence ratios for measles and rubella seropositivity were calculated by demographic and vaccination history, taking into account the study design.ResultsOf the 1325 individuals tested, 1045 (81%, 95% CI 78%–85%) were measles IgG seropositive, and 1290 (97%, 95% CI 95%–99%) were rubella IgG seropositive. Rubella IgG seropositivity was high in all three age strata, but only 47% of those aged 5–17 years were measles IgG seropositive. Additionally, only 41% of those aged 5–17 years who had documented receipt of two doses of measles– or measles-rubella–containing vaccine were seropositive for measles IgG, but almost all these children were rubella IgG seropositive.ConclusionsAn unexpected measles immunity gap was identified among children 5–17 years of age. It is unclear why this immunity gap exists; however, it could have led to a large outbreak and threatened sustaining of measles elimination in Bhutan. Based on this finding, a mass vaccination campaign was conducted to close the immunity gap.     

Global landscape of measles and rubella surveillance

BackgroundAll six World Health Organization (WHO) regions have committed to eliminate measles, and three WHO regions have committed to eliminate rubella. One of the key tenets of measles and rubella elimination is to have a strong surveillance system in place. The presence of a case-based measles and rubella surveillance system that is national, population-based, provides laboratory confirmation, and directs action, is one of the requirements for elimination-standard surveillance.MethodsIn order to understand the global landscape for measles and rubella surveillance, a questionnaire was sent to all 194 WHO member states (herein referred to as countries) requesting information on how surveillance was conducted for measles, rubella, and congenital rubella syndrome. Data were supplemented with information provided to WHO through other reporting mechanisms and by national policy documents available to the public. Frequencies and percentages were calculated.ResultsData were available to review from 164 (85%) countries, although not every country responded to every question. Case-based, population-based, national surveillance with laboratory confirmation was reported to be conducted in 136 (86%) of 158 countries for measles and 122 (77%) of 158 countries for rubella. Congenital rubella syndrome surveillance was reported to be conducted by 126 (77%) of 163 countries. Gaps were noted in the quality of measles-rubella surveillance conducted, and 26 (16%) of 158 countries reported not including all healthcare providers as mandatory reporters.ConclusionsMany countries reported having some of the essential components in place to conduct elimination-standard surveillance for measles and rubella; however, in order to achieve elimination, the quality of surveillance needs to improve to detect all cases. In those countries without these essential components of elimination-standard surveillance, the first step is to implement these components.     

Measles and rubella eradication

This article discusses concepts of eradication, some issues relating to vertical and horizontal public health programs, some current issues relating to measles and rubella, and what we need to do about them. It concludes that measles and rubella/CRS can and should be eradicated. A target date should be established in 2020 (or before). Eradication can only be accomplished in the context of strengthening ongoing immunization services and strengthening surveillance so it can guide activities. Additional resources will be required to achieve the goal.     

A systematic review of rubella vaccination strategies implemented in the Americas: impact on the incidence and seroprevalence rates of rubella and congenital rubella syndrome

Objective

To evaluate the impact of rubella vaccination strategies on the rates of acquired rubella and congenital rubella syndrome in the Americas.

Methods

We conducted a systematic review of the literature (MEDLINE, PubMed, EMBASE, Cochrane Library, Artemisa Database, LILACS Database, Evidence Portal, VHL-PAHO Portal, Scielo, and Grey-Literature sources) that was published from 1969–2010. We included studies on rubella incidence and seroprevalence rates that were associated with rubella vaccination. The quality of the studies was evaluated according to international guidelines.

Results

A total of 14 studies were identified: 2 clinical trials, 2 cohort studies, 3 transversal studies, 5 ecological studies, and 2 mathematical models. Childhood vaccination reduced the incidence of rubella by 23.6% to 99.6%, increased the occurrence of epidemic cycles in Argentina and in the United States, and shifted the illness to susceptible adults. Vaccination strategies that focused on women and children in Brazil were associated with a 5.5-fold greater incidence of rubella in men leading to new outbreaks and CRS. A combined vaccination strategy with a universal approach that included routine vaccination for boys, girls, women, and men in Mexico and in Costa Rica reduced the incidence of rubella by more than 98% and led to absence of CRS since 2008. A medium and a low risk of bias were found in 3 and 4 articles, respectively.

Conclusion

The results of this review demonstrate that the combined vaccination strategy with a universal approach was the most effective strategy as evidenced by a drastic reduction in the number of cases and the interruption of endemic transmission of rubella in the Americas.     

Fully vaccinated children are rare: immunization coverage and seroprevalence in Austrian school children

Vaccination coverage for vaccine-preventable diseases in Austria as well as in many Central European countries has been reported to be too low to eradicate such diseases and prevent further outbreaks. Austria lacks an adequate surveillance system to monitor prevalence of the diseases, the vaccination coverage and seroconversion. School children aged 10–14 years (n = 1077) were recruited in all four schools in the city of Schwaz, Austria, to present their vaccination documents and to give blood for serological testing (diphtheria, pertussis, measles, mumps, rubella, varicella). All participants received a report with a personal guideline for (re-) vaccination. Overall vaccination coverage was 86.4% for measles, 85.5% for mumps and 35.0% for rubella. Tetanus vaccination coverage was 98.4% for the first, 97.8% for the second and 96.7% for the third dose, while 55.4% of the study subjects received the recommended two booster injections. For diphtheria the corresponding vaccination coverage was found to be almost identical. Pertussis coverage was lower in general (first dose: 90.9%; second dose: 89.0%; third dose: 86.5%). Oral poliomyelitis vaccination showed a coverage of 98.6, 96.5, 95.3%, with 78.7% receiving the fourth dose. Overall 38.7% were classified as fully vaccinated. Seropositivity for measles was found in 90.4%, for mumps in 61.8%, for rubella in 82.3%, for diphtheria in 65.8%, for pertussis in 35.6% and for varicella in 95.0%. In summary, fully vaccinated children are rare and intensive public health efforts will be necessary to reach higher levels of immunity and prevent further outbreaks.     

Feasibility assessment of measles and rubella eradication

This report addresses the epidemiological aspects and feasibility of measles and rubella eradication and the potential resource requirements in response to the request of the Director-General at the Seventieth World Health Assembly held on May 31, 2017. A guiding principle is that the path toward measles and rubella eradication should serve to strengthen primary health care, promote universal health coverage, and be a pathfinder for new vision and strategy for immunization over the next decade as laid out in the Immunization Agenda 2030. Specifically, this report: 1) highlights the importance of measles and rubella as global health priorities; 2) reviews the current global measles and rubella situation; 3) summarizes prior assessments of the feasibility of measles and rubella eradication; 4) assesses the progress and challenges in achieving regional measles and rubella elimination; 5) assesses additional considerations for measles and rubella eradication, including the results of modelling and economic analyses; 6) assesses the implications of establishing a measles and rubella eradication goal and the process for setting an eradication target date; 7) proposes a framework for determining preconditions for setting a target date for measles and rubella eradication and how these preconditions should be understood and used; and 8) concludes with recommendations endorsed by SAGE.     

Differential loss of humoral immunity against measles,mumps, rubella and varicella-zoster virus in children treated for cancer

BackgroundIntensive chemotherapy in children with cancer results in long-term impairment of humoral immunity. Whereas most studies to date focused on children with acute lymphoblastic leukemia (ALL), little data have been published on patients suffering from Hodgkin disease or from solid tumors. We therefore analyzed the loss of protective immunity (defined as immunity at the time of diagnosis and lack of immunity after completion of therapy) against vaccine-preventable diseases in children treated for various malignancies.MethodsChildren and adolescents <21 years of age at diagnosis and treated between 2001 and 2010 for various malignancies in the Department of Pediatric Hematology and Oncology, University of Frankfurt, were included in the retrospective chart review. Antibody levels against measles, mumps, rubella and varicella-zoster-virus (VZV) were routinely assessed at the time of diagnosis and within 12 months after completion of therapy.ResultsThe study population consisted of 195 children (122 male); 80 patients had ALL, 15 acute myelogenous leukemia (AML), 18 non-Hodgkin lymphoma (NHL), 22 Hodgkin disease, and 60 various solid tumors. Overall, 27%, 47%, 19%, and 17% of the patients lost their humoral immunity against measles, mumps, rubella, and VZV, respectively. The risk of losing protective antibody titers depended on age with a higher risk in younger children. The loss of protective humoral immunity occurred significantly more often in patients with ALL compared to patients with any other underlying malignant disease (hematological malignancies such AML and NHL, Hodgkin disease or solid tumors).ConclusionsOur data demonstrate that a significant number of children lose pre-existing humoral immunity against measles, mumps, rubella, and VZV after completion of chemotherapy. This loss occurs more often in children with ALL than in children with AML, solid tumors and Hodgkin disease. Our results underline the need for post-chemotherapy revaccination of childhood cancer survivors.     

The strategy for prevention of measles and rubella prevalence with measles–rubella (MR) vaccine in Japan

To eliminate the indigenous measles and rubella virus by 2012 in Japan, the strategy for prevention of measles and rubella prevalence with measles-rubella (MR) vaccine was proposed. Since the vast majority of 1-year old infants are susceptible to measles and rubella, the first MR vaccine should be administered at 1-year old to sustain the herd immunity. Since significant elevation of measles and rubella antibody titers was estimated in a half of children after the second dose, the second dose of MR vaccine within 1 year before elementary school entry is the effective maneuver. Moreover, supplement MR vaccination to the teenage group and 20–29 years’ group might be necessary, because the mean measles antibody titers in this group were significantly lower compared with those in the older individuals’ groups.     

2014年新疆克拉玛依市健康人群麻疹、风疹抗体水平监测分析

目的 了解克拉玛依市人群麻疹、风疹抗体水平,有针对性地开展麻疹、风疹免疫预防工作,有效控制麻疹、风疹的发生和流行,实现消除麻疹的目标。方法 按照分层随机抽样方法,采集0～60岁健康人群1 056人份血样,采用ELISA方法,定量检测麻疹抗体、风疹抗体。结果 人群麻疹抗体阳性率97.54%、风疹抗体阳性率87.22%,抗体几何平均浓度(Geometric Mean Concentration,GMC) 麻疹、风疹分别为:1 220.10 mIU/ml、68.23 IU/ml,不同人群麻疹、风疹抗体阳性率差异均有统计学意义（麻疹χ2＝20.170,风疹χ2＝17.090,P均＜0.05）;不同地区麻疹抗体阳性率在95%以上、保护率在65%～75%之间,风疹抗体阳性率在75%～94%之间,不同地区风疹抗体阳性率差异有统计学意义（χ2 = 31.106;P＜0.001）;不同免疫史风疹抗体阳性水平差异有统计学意义（χ2＝30.254,P＜0.001）。结论 克拉玛依市麻疹人群抗体阳性率总体保持在较高水平,风疹抗体阳性率水平略低,乌尔禾区和部分年龄组风疹阳性率较低。应重点加强地区及重点人群疫苗预防接种管理,必要时开展人群查漏补种免疫。     

Seroprevalence of rubella in school girls and pregnant women

Many studies have been assigned to investigate the surveillance of congenital rubella syndrome, acquired rubella and seroprevalence in different countries to determine the new vaccination program and national vaccination schedules. Seroprevalence of rubella in Turkey is still insufficient and national immunization schedules do not include routine rubella vaccination. In this study we aimed to investigate the seroprevalence of rubella at child bearing age in an unvaccinated population in Adana, southern Turkey, to help determine whether routine rubella vaccination is necessary, if so when it should be administered. Ninety-four school girls aged 12–18 years living in Adana were selected for the study and stratified according to the socioeconomic status of their parents and evaluated for rubella antibodies. One hundred pregnant women aged 18–25 years and 100 pregnant women aged 26–35 years were sampled rubella antibodies. Rubella specific IgG antibody was measured qualitatively and quantitatively by using microparticule enzyme immune assay technology. Rubella specific IgG antibody was positive in 87–94 school girls (92.5%). The geometric mean rubella specific IgG antibody value was found be 148.14 IU/ml. No correlation was found between socioeconomic status and rubella seropositivity (p = 0.6521). In all pregnant women rubella specific IgG antibody was found to be positive. In conclusion rubella vaccination should be considered carefully in developing countries. Because of the high seropositivity to rubella in our region we do not recommend rubella vaccination in early childhood. Yet this is a preliminary study and further studies with larger population size are needed to determine the national immunization policy for rubella.     

昌平区2006年麻疹和风疹疑似病例血清学检测结果分析

目的:了解昌平区麻疹、风疹疑似病例的血清学实验室诊断符合率和血清流行病学特征,为进一步提高麻疹、风疹的病例诊断提供依据。方法:应用酶联免疫吸附试验检测血清标本中麻疹或风疹IgM抗体。结果:2006年共检测麻疹疑似病例血清175例,检出麻疹IgM抗体阳性55例,实验室诊断符合率为31.4%,在其余麻疹IgM抗体阴性的120例病例中检出风疹IgM抗体阳性34例,检出率为28.3%。检测风疹疑似病例血清172例,检出风疹IgM抗体阳性75例,实验室诊断符合率为43.6%,在其余风疹IgM抗体阴性的97例病例中检出麻疹IgM抗体阳性3例,检出率为3.1%。麻疹、风疹疑似病例与实验室诊断病例的发病时间均集中在3~6月份;年龄均以20~24岁组最多;外地户籍和无疫苗接种史或接种史不详的麻疹和风疹病例占80%以上。结论:我区麻疹疑似病例实验室诊断阳性符合率为31.4%,低于国内相关报道[1]。风疹实验室诊断阳性符合率为43.6%,与国内相关报道相同[2],存在误诊漏诊现象;外地户籍和无疫苗接种史或接种史不详的麻疹和风疹病例占80%以上。     

大连市2010年麻疹风疹疑似病例IgM抗体检测结果分析

目的:通过实验室麻疹、风疹IgM抗体检测结果,了解大连市2010年麻疹、风疹的流行特征,为促进免疫规划工作提供科学依据。方法:采用ELISA对2010年麻疹、风疹疑似病例血清标本进行IgM抗体检测;结果:全年共检测麻疹、风疹IgM抗体69份,麻疹IgM抗体阳性率为28.99%;风疹IgM抗体阳性率为43.48%;发病地区主要集中在流动人口频繁的城乡结合部,麻疹发病以5岁以内儿童为主,风疹以青少年居多;流行季节均主要为春季。结论:加强流动人口管理仍是今后防控的重点,同时继续加强计划免疫管理,开展查漏补种,做好疫情监测,预防暴发。     

Research priorities for global measles and rubella control and eradication

In 2010, an expert advisory panel convened by the World Health Organization to assess the feasibility of measles eradication concluded that (1) measles can and should be eradicated, (2) eradication by 2020 is feasible if measurable progress is made toward existing 2015 measles mortality reduction targets, (3) measles eradication activities should occur in the context of strengthening routine immunization services, and (4) measles eradication activities should be used to accelerate control and elimination of rubella and congenital rubella syndrome (CRS). The expert advisory panel also emphasized the critical role of research and innovation in any disease control or eradication program. In May 2011, a meeting was held to identify and prioritize research priorities to support measles and rubella/CRS control and potential eradication activities. This summary presents the questions identified by the meeting participants and their relative priority within the following categories: (1) measles epidemiology, (2) vaccine development and alternative vaccine delivery, (3) surveillance and laboratory methods, (4) immunization strategies, (5) mathematical modeling and economic analyses, and (6) rubella/CRS control and elimination.     

Humoral immunogenicity to measles,rubella, and varicella-zoster vaccines in biliary atresia children

To investigate the humoral immune response to measles, rubella, and varicella-zoster virus (VZV) vaccines in biliary atresia (BA) children before liver transplantation, we conducted the cross-sectional designed study. Fifty BA children (age, 3.6 ± 0.2 years; 24 girls) who had not yet received liver transplantation, and another 150 healthy controls (age, 4.0 ± 0.1 years; 78 girls) were recruited into this study to evaluate their primary humoral immune response to measles, rubella, and VZV vaccines. All of these BA children (n = 50) and controls (n = 150) received one dose of measles, one dose of measles–mumps–rubella (MMR), and one dose of VZV vaccine before our assessment. Serum samples were collected at least 1 month after the vaccination and serum immunoglobulin G (IgG) antibody to measles, rubella, and VZV were then determined by qualitative enzyme-linked immune-sorbent assay. The prevalence of seropositive rate of measles IgG antibody (84% vs. 96.7%; P = 0.002), rubella (82.0% vs. 98.7%; P < 0.001), and VZV (74% vs. 95.3%; P < 0.001) were significantly different between BA children and the controls after regular measles, MMR, and VZV vaccination before 2 years of age. In those BA children with seronegative VZV antibody after vaccination, two had VZV infection after the liver transplantation. This study indicated that humoral immunity to rubella, measles and VZV vaccines are significantly lower in BA children than the normal population by standard vaccine schedule.     

上海市麻疹、流行性腮腺炎、风疹抗体水平调查分析

[目的 ]　了解本市健康人群麻疹、腮腺炎、风疹的抗体水平。　 [方法 ]　采集 0～ 5 0岁健康人群血标本 5 43份 ,检测麻疹、腮腺炎、风疹抗体。　 [结果 ]　小于 8月龄组麻疹抗体GMT最低 ,接种麻疹疫苗后抗体GMT显著升高 (P<0 .0 0 1) ;小于 8月龄组及 8月龄组风疹抗体水平最低 ,1岁接种疫苗后风疹抗体显著升高 (P <0 .0 0 1) ,但随着年龄的增长抗体水平有所下降 ,抗体阳性率维持在 85 %以上 ;小于 8月龄组及 8月龄组流行性腮腺炎抗体水平最低 ,1岁以上各年龄组抗体水平显著上升 (P <0 .0 0 1)。　 [结论 ]　上海市现阶段实行麻疹疫苗、MMR疫苗的接种程序比较合理和有效 ,但应该进一步开展上海市育龄期妇女风疹抗体水平调查和MMR疫苗免疫持久性观察 ,研究预防未及龄儿童麻疹疫苗免疫策略、育龄期妇女接种风疹疫苗免疫策略 ,预防先天性风疹综合征