Immune response to co-administration of measles, mumps, and rubella (MMR), and yellow fever vaccines: a randomized non-inferiority trial among one-year-old children in Argentina.

BACKGROUND: In yellow fever (YF) endemic areas, measles, mumps, and rubella (MMR), and YF vaccines are often co-administered in childhood vaccination schedules. Because these are live vaccines, we assessed potential immune interference that could result from co-administration. METHODS: We conducted an open-label, randomized non-inferiority trial among healthy 1-year-olds in Misiones Province, Argentina. Children were randomized to one of three groups (1:1:1): Co-administration of MMR and YF vaccines (MMR1YF1), MMR followed by YF vaccine four weeks later (MMR1YF2), or YF followed by MMR vaccine four weeks later (YF1MMR2). Blood samples obtained pre-vaccination and 28 days post-vaccination were tested for immunoglobulin G antibodies against measles, mumps, and rubella, and for YF virus-specific neutralizing antibodies. Non-inferiority in seroconversion was assessed using a -5% non-inferiority margin. Antibody concentrations were compared with Kruskal-Wallis tests. RESULTS: Of 851 randomized children, 738 were correctly vaccinated, had ≥ 1 follow-up sample, and were included in the intention-to-treat population. Non-inferior seroconversion was observed for all antigens (measles seroconversion: 97.9% in the MMR1YF1 group versus 96.3% in the MMR1YF2 group, a difference of 1.6% [90% CI -1.5, 4.7]; rubella: 97.9% MMR1YF1 versus 94.7% MMR1YF2, a difference of 3.3% [-0.1, 6.7]; mumps: 96.7% MMR1YF1 versus 97.9% MMR1YF2, a difference of -1.3% [-4.1, 1.5]; and YF: 96.3% MMR1YF1 versus 97.5% YF1MMR2, a difference of -1.2% [-4.2, 1.7]). Rubella antibody concentrations and YF titers were significantly lower following co-administration; measles and mumps concentrations were not impacted. CONCLUSION: Effective seroconversion was achieved and was not impacted by the co-administration, although antibody levels for two antigens were lower. The impact of lower antibody levels needs to be weighed against missed opportunities for vaccination to determine optimal timing for MMR and YF vaccine administration. TRIAL REGISTRATION: The study was retrospectively registered in ClinicalTrials.gov (NCT03368495) on 11/12/2017.

Past as Prologue-Use of Rubella Vaccination Program Lessons to Inform COVID-19 Vaccination.

The rapid rollout of vaccines against COVID-19 as a key mitigation strategy to end the global pandemic might be informed by lessons learned from rubella vaccine implementation in response to the global rubella epidemic of 1963-1965. That rubella epidemic led to the development of a rubella vaccine that has been introduced in all but 21 countries worldwide and has led to elimination of rubella in 93 countries. Although widespread introduction and use of rubella vaccines was slower than that for COVID-19 vaccines, the process can provide valuable insights for the continued battle against COVID-19. Experiences from the rubella disease control program highlight the critical and evolving elements of a vaccination program, including clearly delineated goals and strategies, regular data-driven revisions to the program based on disease and vaccine safety surveillance, and evaluations to identify the vaccine most capable of achieving disease control targets.

Progress Toward Rubella and Congenital Rubella Syndrome Control and Elimination - Worldwide, 2012-2020.

Rubella virus is a leading cause of vaccine-preventable birth defects and can cause epidemics. Although rubella virus infection usually produces a mild febrile rash illness in children and adults, infection during pregnancy, especially during the first trimester, can result in miscarriage, fetal death, stillbirth, or an infant born with a constellation of birth defects known as congenital rubella syndrome (CRS). A single dose of rubella-containing vaccine (RCV) can provide lifelong protection against rubella (1). The Global Vaccine Action Plan 2011-2020 (GVAP) included a target to achieve elimination of rubella in at least five of the six World Health Organization (WHO) regions* by 2020 (2), and WHO recommends capitalizing on the accelerated measles elimination activities as an opportunity to introduce RCV (1). This report updates a previous report (3) and summarizes global progress toward control and elimination of rubella and CRS from 2012, when accelerated rubella control activities were initiated, through 2020. Among 194 WHO Member States, the number with RCV in their immunization schedules has increased from 132 (68%) in 2012 to 173 (89%) in 2020; 70% of the world's infants were vaccinated against rubella in 2020. Reported rubella cases declined by 48%, from 94,277 in 2012 to 49,136 in 2019, and decreased further to 10,194 in 2020. Rubella elimination has been verified in 93 (48%) of 194 countries including the entire Region of the Americas (AMR). To increase the equity of protection and make further progress to eliminate rubella, it is important that the 21 countries that have not yet done so should introduce RCV. Likewise, countries that have introduced RCV can achieve and maintain rubella elimination with high vaccination coverage and surveillance for rubella and CRS. Four of six WHO regions have established rubella elimination goals; the two WHO regions that have not yet established an elimination goal (the African [AFR] and Eastern Mediterranean [EMR] regions) have expressed a commitment to rubella elimination and should consider establishing a goal.

Natural history of pulmonary coccidioidomycosis: Further examination of the VA-Armed Forces Database.

There are still many limitations related to the understanding of the natural history of differing forms of coccidioidomycosis (CM), including characterizing the spectrum of pulmonary disease. The historical Veterans Administration-Armed Forces database, recorded primarily before the advent of antifungal therapy, presents an opportunity to characterize the natural history of pulmonary CM. We performed a retrospective cohort study of 342 armed forces service members who were diagnosed with pulmonary CM at VA facilities between 1955 to 1958, followed through 1966, who did not receive antifungal therapy. Patients were grouped by predominant pulmonary finding on chest radiographs. The all-cause mortality was low for all patients (4.6%). Cavities had a median size of 3-3.9 cm (IQR: 2-2.9-4-4.9 cm), with heterogeneous wall thickness and no fluid level, while nodules had a median size of 1-1.19 cm (Interquartile range [IQR] 1-1.9-2-2.9 cm) and sharp borders. The majority of cavities were chronic (85.6%), and just under half were found incidentally. Median complement fixation titers in both the nodular and cavitary groups were negative, with higher titers in the cavitary group overall. This retrospective cohort study of non-disseminated coccidioidomycosis, the largest to date, sheds light on the natural history, serologic markers, and radiologic characteristics of this understudied disease. These findings have implications for the evaluation and management of CM.

Coccidioidomycosis (CM), also known as San Joaquin Valley Fever, causes a variety of symptoms including pneumonia. This historical study investigates CM of the lungs in American soldiers with CM in the 1950s, prior to modern antifungals, to better understand the natural history.

Natural History of Disseminated Coccidioidomycosis: Examination of the Veterans Affairs-Armed Forces Database.

BACKGROUND: The natural history of non-central nervous system (non-CNS) disseminated coccidioidomycosis (DCM) has not been previously characterized. The historical Veterans Affairs (VA)-Armed Forces coccidioidomycosis patient group provides a unique cohort of patients not treated with standard antifungal therapy, allowing for characterization of the natural history of coccidioidomycosis. METHODS: We conducted a retrospective study of 531 VA-Armed Forces coccidioidomycosis patients diagnosed between 1955-1958 and followed to 1966. Groups were identified as non-DCM (462 patients), DCM (44 patients), and CNS (25 patients). The duration of the initial infection, fate of the primary infection, all-cause mortality, and mortality secondary to coccidioidomycosis were assessed and compared between groups. RESULTS: Mortality due to coccidioidomycosis at the last known follow-up was significantly different across the groups: 0.65% in the non-DCM group, 25% in the DCM group, and 88% in the CNS group (P < .001). The primary fate of pulmonary infection demonstrated key differences, with pulmonary nodules observed in 39.61% of the non-DCM group, 13.64% of the DCM group, and 20% of the CNS group (P < .001). There were differences in cavity formation, with 34.20% in the non-DCM group, 9.09% in the DCM group, and 8% in the CNS group (P < .001). Dissemination was the presenting manifestation or was concurrent with the initial infection in 41% and 56% of patients in the non-CNS DCM and CNS groups, respectively. CONCLUSIONS: This large, retrospective cohort study helps characterize the natural history of DCM, provides insight into the host immunologic response, and has direct clinical implications for the management and follow-up of patients.

Progress Toward Rubella Elimination - World Health Organization European Region, 2005-2019.

In 2005, the Regional Committee of the World Health Organization (WHO) European Region (EUR) passed a resolution calling for the regional elimination of measles, rubella, and congenital rubella syndrome (CRS) (1). In 2010, all 53 countries in EUR* reaffirmed their commitment to eliminating measles, rubella, and CRS (2); this goal was included in the European Vaccine Action Plan 2015-2020 (3,4). Rubella, which typically manifests as a mild febrile rash illness, is the leading vaccine-preventable cause of birth defects. Rubella infection during pregnancy can result in miscarriage, fetal death, or a constellation of malformations known as CRS, which usually includes one or more visual, auditory, or cardiac defects (5). The WHO-recommended measles and rubella elimination strategies in EUR include 1) achieving and maintaining ≥95% coverage with 2 doses of measles- and rubella-containing vaccine (MRCV) through routine immunization services; 2) providing measles and rubella vaccination opportunities, including supplementary immunization activities (SIAs), to populations susceptible to measles or rubella; 3) strengthening surveillance by conducting case investigations and confirming suspected cases and outbreaks with laboratory results; and 4) improving the availability and use of evidence to clearly communicate the benefits and risks of preventing these diseases through vaccination to health professionals and the public (6). This report updates a previous report and describes progress toward rubella and CRS elimination in EUR during 2005-2019 (7). In 2000, estimated coverage with the first dose of a rubella-containing vaccine (RCV1) in EUR was 60%, and 621,039 rubella cases were reported (incidence = 716.9 per 1 million population). During 2005-2019, estimated regional coverage with RCV1 was 93%-95%, and in 2019, 31 (58%) countries achieved ≥95% coverage with the RCV1. During 2005-2019, approximately 38 million persons received an RCV during SIAs in 20 (37%) countries. Rubella incidence declined by >99%, from 234.9 cases per 1 million population (206,359 cases) in 2005 to 0.67 cases per 1 million population (620 cases) by 2019. CRS cases declined by 50%, from 16 cases in 2005 to eight cases in 2019. For rubella and CRS elimination in EUR to be achieved and maintained, measures are needed to strengthen immunization programs by ensuring high coverage with an RCV in every district of each country, offering supplementary rubella vaccination to susceptible adults, maintaining high-quality surveillance for rapid case detection and confirmation, and ensuring effective outbreak preparedness and response.

Progress Toward Rubella Elimination - Western Pacific Region, 2000-2019.

Rubella is the leading vaccine-preventable cause of birth defects. Rubella typically manifests as a mild febrile rash illness; however, infection during pregnancy, particularly during the first trimester, can result in miscarriage, fetal death, or a constellation of malformations known as congenital rubella syndrome (CRS), commonly including one or more visual, auditory, or cardiac defects (1). In 2012, the Regional Committee of the World Health Organization (WHO) Western Pacific Region (WPR)* committed to accelerate rubella control, and in 2017, resolved that all countries or areas (countries) in WPR should aim for rubella elimination† as soon as possible (2,3). WPR countries are capitalizing on measles elimination activities, using a combined measles and rubella vaccine, case-based surveillance for febrile rash illness, and integrated diagnostic testing for measles and rubella. This report summarizes progress toward rubella elimination and CRS prevention in WPR during 2000-2019. Coverage with a first dose of rubella-containing vaccine (RCV1) increased from 11% in 2000 to 96% in 2019. During 1970-2019, approximately 84 million persons were vaccinated through 62 supplementary immunization activities (SIAs) conducted in 27 countries. Reported rubella incidence increased from 35.5 to 71.3 cases per million population among reporting countries during 2000-2008, decreased to 2.1 in 2017, and then increased to 18.4 in 2019 as a result of outbreaks in China and Japan. Strong sustainable immunization programs, closing of existing immunity gaps, and maintenance of high-quality surveillance to respond rapidly to and contain outbreaks are needed in every WPR country to achieve rubella elimination in the region.

Assessment of Economic Burden of Concurrent Measles and Rubella Outbreaks, Romania, 2011-2012.

We estimated the economic impact of concurrent measles and rubella outbreaks in Romania during 2011-2012. We collected costs from surveys of 428 case-patients and caretakers, government records, and health staff interviews. We then estimated financial and opportunity costs. During the study period, 12,427 measles cases and 24,627 rubella cases were recorded; 27 infants had congenital rubella syndrome (CRS). The cost of the outbreaks was US $9.9 million. Cost per case was US $439 for measles, US $132 for rubella, and US $44,051 for CRS. Up to 36% of households needed to borrow money to pay for illness treatment. Approximately 17% of patients continued to work while ill to pay their treatment expenses. Our key study findings were that households incurred a high economic burden compared with their incomes, the health sector bore most costs, and CRS costs were substantial and relevant to include in rubella outbreak cost studies.

Combining serological and contact data to derive target immunity levels for achieving and maintaining measles elimination.

BACKGROUND: Vaccination has reduced the global incidence of measles to the lowest rates in history. However, local interruption of measles virus transmission requires sustained high levels of population immunity that can be challenging to achieve and maintain. The herd immunity threshold for measles is typically stipulated at 90-95%. This figure does not easily translate into age-specific immunity levels required to interrupt transmission. Previous estimates of such levels were based on speculative contact patterns based on historical data from high-income countries. The aim of this study was to determine age-specific immunity levels that would ensure elimination of measles when taking into account empirically observed contact patterns. METHODS: We combined estimated immunity levels from serological data in 17 countries with studies of age-specific mixing patterns to derive contact-adjusted immunity levels. We then compared these to case data from the 10 years following the seroprevalence studies to establish a contact-adjusted immunity threshold for elimination. We lastly combined a range of hypothetical immunity profiles with contact data from a wide range of socioeconomic and demographic settings to determine whether they would be sufficient for elimination. RESULTS: We found that contact-adjusted immunity levels were able to predict whether countries would experience outbreaks in the decade following the serological studies in about 70% of countries. The corresponding threshold level of contact-adjusted immunity was found to be 93%, corresponding to an average basic reproduction number of approximately 14. Testing different scenarios of immunity with this threshold level using contact studies from around the world, we found that 95% immunity would have to be achieved by the age of five and maintained across older age groups to guarantee elimination. This reflects a greater level of immunity required in 5-9-year-olds than established previously. CONCLUSIONS: The immunity levels we found necessary for measles elimination are higher than previous guidance. The importance of achieving high immunity levels in 5-9-year-olds presents both a challenge and an opportunity. While such high levels can be difficult to achieve, school entry provides an opportunity to ensure sufficient vaccination coverage. Combined with observations of contact patterns, further national and sub-national serological studies could serve to highlight key gaps in immunity that need to be filled in order to achieve national and regional measles elimination.

Progress Toward Rubella and Congenital Rubella Syndrome Control and Elimination - Worldwide, 2000-2018.

Rubella is a leading cause of vaccine-preventable birth defects. Although rubella virus infection usually causes a mild febrile rash illness in children and adults, infection during pregnancy, especially during the first trimester, can result in miscarriage, fetal death, stillbirth, or a constellation of birth defects known as congenital rubella syndrome (CRS). A single dose of rubella-containing vaccine (RCV) can provide lifelong protection (1). In 2011, the World Health Organization (WHO) updated guidance on the use of RCV and recommended capitalizing on the accelerated measles elimination activities as an opportunity to introduce RCV (1). The Global Vaccine Action Plan 2011-2020 (GVAP) includes a target to achieve elimination of rubella in at least five of the six WHO regions by 2020 (2). This report on the progress toward rubella and CRS control and elimination updates the 2017 report (3), summarizing global progress toward the control and elimination of rubella and CRS from 2000 (the initiation of accelerated measles control activities) and 2012 (the initiation of accelerated rubella control activities) to 2018 (the most recent data) using WHO immunization and surveillance data. Among WHO Member States,* the number with RCV in their immunization schedules has increased from 99 (52% of 191) in 2000 to 168 (87% of 194) in 2018†; 69% of the world's infants were vaccinated against rubella in 2018. Rubella elimination has been verified in 81 (42%) countries. To make further progress to control and eliminate rubella, and to reduce the equity gap, introduction of RCV in all countries is important. Likewise, countries that have introduced RCV can achieve and maintain elimination with high vaccination coverage and surveillance for rubella and CRS. The two WHO regions that have not established an elimination goal (African [AFR] and Eastern Mediterranean [EMR]) should consider establishing a goal.§.

Progress Toward Rubella and Congenital Rubella Syndrome Control - South-East Asia Region, 2000-2016.

In 2013, the 66th session of the Regional Committee of the World Health Organization (WHO) South-East Asia Region (SEAR)* adopted the goal of elimination of measles and control† of rubella and congenital rubella syndrome (CRS) by 2020 (1). Rubella is the leading vaccine-preventable cause of birth defects. Although rubella typically causes a mild fever and rash in children and adults, rubella virus infection during pregnancy, especially during the first trimester, can result in miscarriage, fetal death, or a constellation of congenital malformations known as CRS, commonly including visual, auditory, and/or cardiac defects, and developmental delay (2). Rubella and CRS control capitalizes on the momentum created by pursuing measles elimination because the efforts are programmatically linked. Rubella-containing vaccine (RCV) is administered as a combined measles and rubella vaccine, and rubella cases are detected through case-based surveillance for measles or fever and rash illness (3). This report summarizes progress toward rubella and CRS control in SEAR during 2000-2016. Estimated coverage with a first RCV dose (RCV1) increased from 3% of the birth cohort in 2000 to 15% in 2016 because of RCV introduction in six countries. RCV1 coverage is expected to increase rapidly with the phased introduction of RCV in India and Indonesia beginning in 2017; these countries are home to 83% of the SEAR birth cohort. During 2000-2016, approximately 83 million persons were vaccinated through 13 supplemental immunization activities (SIAs) conducted in eight countries. During 2010-2016, reported rubella incidence decreased by 37%, from 8.6 to 5.4 cases per 1 million population, and four countries (Bangladesh, Maldives, Sri Lanka, and Thailand) reported a decrease in incidence of ≥95% since 2010. To achieve rubella and CRS control in SEAR, sustained investment to increase routine RCV coverage, periodic high-quality SIAs to close immunity gaps, and strengthened rubella and CRS surveillance are needed.

National, Regional and Global Certification Bodies for Polio Eradication: A Framework for Verifying Measles Elimination.

The Global Certification Commission (GCC), Regional Certification Commissions (RCCs), and National Certification Committees (NCCs) provide a framework of independent bodies to assist the Global Polio Eradication Initiative (GPEI) in certifying and maintaining polio eradication in a standardized, ongoing, and credible manner. Their members meet regularly to comprehensively review population immunity, surveillance, laboratory, and other data to assess polio status in the country (NCC), World Health Organization (WHO) region (RCC), or globally (GCC). These highly visible bodies provide a framework to be replicated to independently verify measles and rubella elimination in the regions and globally.

Progress in Rubella and Congenital Rubella Syndrome Control and Elimination - Worldwide, 2000-2016.

Although rubella virus infection usually causes a mild fever and rash illness in children and adults, infection during pregnancy, especially during the first trimester, can result in miscarriage, fetal death, stillbirth, or infants with a constellation of congenital malformations known as congenital rubella syndrome (CRS) (1). Rubella is a leading vaccine-preventable cause of birth defects. Preventing these adverse pregnancy outcomes is the focus of rubella vaccination programs. In 2011, the World Health Organization (WHO) updated guidance on the preferred strategy for introduction of rubella-containing vaccine (RCV) into national immunization schedules and recommended an initial vaccination campaign, usually targeting children aged 9 months-14 years (1). The Global Vaccine Action Plan 2011-2020 (GVAP), endorsed by the World Health Assembly in 2012, includes goals to eliminate rubella in at least five of the six WHO regions by 2020 (2). This report updates a previous report (3) and summarizes global progress toward rubella and CRS control and elimination from 2000 to 2016. As of December 2016, 152 (78%) of 194 countries had introduced RCV into the national immunization schedule, representing an increase of 53 countries since 2000, including 20 countries that introduced RCV after 2012.

Hospital-based surveillance of congenital rubella syndrome in Indonesia.

Congenital rubella syndrome (CRS) has serious consequences, such as miscarriage, stillbirth, and severe birth defects in infants, resulting from rubella virus infection during pregnancy. However, rubella vaccine has not yet been implemented in Indonesia. This study aimed (1) to estimate the incidence of CRS in Indonesia, (2) describe the clinical features of CRS at our referral hospital, and (3) pilot a CRS surveillance system to be extended to other hospitals. We conducted a 4-month prospective surveillance study of infants aged <1 year with suspected CRS in 2013 at an Indonesian hospital. Infants with suspected CRS were examined for rubella-specific IgM antibody or rubella IgG antibody levels. Of 47 suspected cases of CRS, 11/47 (23.4%), 9/47 (19.1%), and 27/47 (57.5%) were diagnosed as laboratory-confirmed, clinically compatible, and discarded CRS, respectively. The most common defects among laboratory-confirmed CRS cases were hearing impairment (100%), congenital cataracts (72.7%), microcephaly (72.7%), and congenital heart defects (45.5%). CONCLUSION: The number of laboratory-confirmed CRS cases among Indonesian infants is high. Furthermore, hearing impairment is the most common clinical feature of CRS in infants. Our findings indicate the importance of implementation of rubella vaccine in Indonesia. Conducting hospital-based surveillance of CRS in other hospitals in Indonesia may be appropriate. What is Known: •Congenital rubella syndrome (CRS) has serious consequences in infants resulting from rubella virus infection during pregnancy. •The incidence of CRS in most developed countries has greatly decreased since implementation of rubella vaccination. •Rubella vaccine has not yet been implemented in many developing countries. What is New: •The number of laboratory-confirmed CRS cases among Indonesian infants was high. •Implementation of rubella vaccine into immunization programs in Indonesia is important because of the high number of CRS cases. •Our study highlights the need for ongoing prospective surveillance of CRS in Indonesia.

Synthesis of Evidence to Characterize National Measles and Rubella Exposure and Immunization Histories.

Population immunity depends on the dynamic levels of immunization coverage that countries achieve over time and any transmission of viruses that occur within the population that induce immunity. In the context of developing a dynamic transmission model for measles and rubella to support analyses of future immunization policy options, we assessed the model inputs required to reproduce past behavior and to provide some confidence about model performance at the national level. We reviewed the data available from the World Health Organization (WHO) and existing measles and rubella literature for evidence of historical reported routine and supplemental immunization activities and reported cases and outbreaks. We constructed model input profiles for 180 WHO member states and three other areas to support disease transmission model development and calibration. The profiles demonstrate the significant variability in immunization strategies used historically by regions and member states and the epidemiological implications of these historical choices. The profiles provide a historical perspective on measles and rubella immunization globally at the national level, and they may help immunization program managers identify existing immunity and/or knowledge gaps.

Characterization of the Risks of Adverse Outcomes Following Rubella Infection in Pregnancy.

Although most infections with the rubella virus result in relatively minor sequelae, rubella infection in early pregnancy may lead to severe adverse outcomes for the fetus. First recognized in 1941, congenital rubella syndrome (CRS) can manifest with a diverse range of symptoms, including congenital cataracts, glaucoma, and cardiac defects, as well as hearing and intellectual disability. The gestational age of the fetus at the time of the maternal rubella infection impacts the probability and severity of outcomes, with infection in early pregnancy increasing the risks of spontaneous termination (miscarriage), fetal death (stillbirth), birth defects, and reduced survival for live-born infants. Rubella vaccination continues to change the epidemiology of rubella and CRS globally, but no models currently exist to evaluate the economic benefits of rubella management. This systematic review provides an overall assessment of the weight of the evidence for the outcomes associated with rubella infections in the first 20 weeks of pregnancy. We identified, evaluated, and graded 31 studies (all from developed countries) that reported on the pregnancy outcomes of at least 30 maternal rubella infections. We used the available evidence to estimate the increased risks of spontaneous termination, fetal death, infant death, and CRS as a function of the timing of rubella infection in pregnancy and decisions about induced termination. These data support the characterization of the disability-adjusted life years for outcomes associated with rubella infection in pregnancy. We find significant impacts associated with maternal rubella infections in early pregnancy, which economic analyses will miss if they only focus on live births of CRS cases. Our estimates of fetal loss from increased induced terminations due to maternal rubella infections provide context that may help to explain the relatively low numbers of observed CRS cases per year despite potentially large burdens of disease. Our comprehensive review of the weight of the evidence of all pregnancy outcomes demonstrates the importance of including all outcomes in models that characterize rubella-related disease burdens and costs.

Systematic Review of the Manifestations of Congenital Rubella Syndrome in Infants and Characterization of Disability-Adjusted Life Years (DALYs).

Congenital rubella syndrome (CRS) continues to cause disability among unvaccinated populations in countries with no or insufficient rubella vaccine coverage to prevent transmission. We systematically reviewed the literature on birth outcomes associated with CRS to estimate the duration, severity, and frequency of combinations of morbidities. We searched PubMed, the Science Citation Index, and references from relevant articles for studies in English with primary data on the frequency of CRS manifestations for ≥20 cases and identified 65 studies representing 66 study populations that met our inclusion criteria. We abstracted available data on CRS cases with one or more hearing, heart, and/or eye defect following maternal rubella infection during the period of 0-20 weeks since the last menstrual period. We assessed the quality and weight of the available evidence using a modified Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Most of the evidence originates from studies in developed countries of cohorts of infants identified with CRS in the 1960s and 1970s, prior to the development of standardized definitions for CRS and widespread use of vaccine. We developed estimates of undiscounted disability-adjusted life years (DALYs) lost per CRS case for countries of different income levels. The estimates ranged from approximately 19 to 39 for high-income countries assuming optimal treatment and from approximately 29 to 39 DALYs lost per CRS case in low- and lower- middle-income countries assuming minimal treatment, with the lower bound based on 2010 general global burden of disease disability weights and the upper bound based on 1990 age-specific and treatment-specific global burden of disease disability weights. Policymakers and analysts should appreciate the significant burden of disability caused by CRS as they evaluate opportunities to manage rubella.

Identification of Serologic Markers for School-Aged Children With Congenital Rubella Syndrome.

BACKGROUND: Congenital rubella syndrome (CRS) case identification is challenging in older children since laboratory markers of congenital rubella virus (RUBV) infection do not persist beyond age 12 months. METHODS: We enrolled children with CRS born between 1998 and 2003 and compared their immune responses to RUBV with those of their mothers and a group of similarly aged children without CRS. Demographic data and sera were collected. Sera were tested for anti-RUBV immunoglobulin G (IgG), IgG avidity, and IgG response to the 3 viral structural proteins (E1, E2, and C), reflected by immunoblot fluorescent signals. RESULTS: We enrolled 32 children with CRS, 31 mothers, and 62 children without CRS. The immunoblot signal strength to C and the ratio of the C signal to the RUBV-specific IgG concentration were higher (P < .029 for both) and the ratio of the E1 signal to the RUBV-specific IgG concentration lower (P = .001) in children with CRS, compared with their mothers. Compared with children without CRS, children with CRS had more RUBV-specific IgG (P < .001), a stronger C signal (P < .001), and a stronger E2 signal (P ≤ .001). Two classification rules for children with versus children without CRS gave 100% specificity with >65% sensitivity. CONCLUSIONS: This study was the first to establish classification rules for identifying CRS in school-aged children, using laboratory biomarkers. These biomarkers should allow improved burden of disease estimates and monitoring of CRS control programs.

Global Progress Toward Rubella and Congenital Rubella Syndrome Control and Elimination - 2000-2014.

Rubella virus usually causes a mild fever and rash in children and adults. However, infection during pregnancy, especially during the first trimester, can result in miscarriage, fetal death, stillbirth, or a constellation of congenital malformations known as congenital rubella syndrome (CRS). In 2011, the World Health Organization (WHO) updated guidance on the preferred strategy for introduction of rubella-containing vaccine (RCV) into national routine immunization schedules, including an initial vaccination campaign usually targeting children aged 9 months-15 years . The Global Vaccine Action Plan endorsed by the World Health Assembly in 2012 and the Global Measles and Rubella Strategic Plan (2012-2020) published by Measles and Rubella Initiative partners in 2012 both include goals to eliminate rubella and CRS in at least two WHO regions by 2015, and at least five WHO regions by 2020 (2,3). This report updates a previous report and summarizes global progress toward rubella and CRS control and elimination during 2000-2014. As of December 2014, RCV had been introduced in 140 (72%) countries, an increase from 99 (51%) countries in 2000 (for this report, WHO member states are referred to as countries). Reported rubella cases declined 95%, from 670,894 cases in 102 countries in 2000 to 33,068 cases in 162 countries in 2014, although reporting is inconsistent. To achieve the 2020 Global Vaccine Action Plan rubella and CRS elimination goals, RCV introduction needs to continue as country criteria indicating readiness are met, and rubella and CRS surveillance need to be strengthened to ensure that progress toward elimination can be measured.

The path to eradication of rubella.

Since 1969, rubella and its harmful effect on fetuses infected in utero can be prevented by rubella vaccine, usually given in combination with measles vaccine. The rubella vaccine is highly protective both in children and in adults including women intending to become pregnant. Owing to the use of combined measles and rubella vaccines, congenital rubella infection has been eliminated from the Western Hemisphere and nearly all of Europe. Such combined vaccination is now being applied throughout the world, posing the possibility of eventual rubella eradication. The existence of viruses of animals related to rubella does not appear to be a barrier to eradication of the human virus. However, persistent rubella virus in infants infected in utero and of immunosuppressed patients with granulomas may pose a problem for eradication. Nevertheless, this review posits that eradication of rubella is now feasible if routine vaccination of infants and surveillance for chronic infection are correctly applied.