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BACKGROUND: Measles can lead to serious complications and remains an important cause of morbidity and mortality worldwide. In this study we aimed to assess the etiological diagnosis of discarded measles cases in the context of an outbreak among a highly immunized population. METHODS: We conducted a retrospective observational study of discarded measles cases from an outbreak that occurred from October 2006 to July 2007 in Catalonia. A confirmed case was defined as having a positive measles serum IgM result and/or a positive result by RT-PCR in urine and/or nasopharyngeal swab; or an epidemiological link to a confirmed case. Serum specimens were tested by a commercially available indirect-format and by an in-house capture-format measles IgM enzyme immunoassays. RESULTS: Testing of 89 samples discarded for measles determined the etiologies for 10 (11.2%), including one rubella, three human herpes virus 6, and six measles infections. Of 381 confirmed cases in the outbreak, 10% had received at least one dose of the measles-mumps-rubella vaccine versus 54% of the discarded for measles (OR: 0.09; 95% CI: 0.06, 0.14; p < 0.001). CONCLUSIONS: Highly sensitive surveillance systems are critical to identifying cases, responding to outbreaks and verifying progress towards measles elimination. Molecular tools for measles detection and differential diagnosis, and collection of appropriate specimens for molecular and serological testing are essential to correctly diagnose suspected measles infection.
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Sarampo , Rubéola (Sarampo Alemão) , Humanos , Sarampo/diagnóstico , Sarampo/epidemiologia , Sarampo/prevenção & controle , Rubéola (Sarampo Alemão)/epidemiologia , Vírus do Sarampo/genética , Surtos de Doenças , Imunoglobulina M , Anticorpos AntiviraisRESUMO
Laboratory confirmation of infection is an essential component of measles surveillance. Detection of measles-specific IgM in serum by enzyme-linked immunosorbent assay (ELISA) is the most common method used to confirm measles infection. ELISA formats vary, as does the sensitivity and specificity of each assay. Specimens collected within 3 days of rash onset can yield a false-negative result, which can delay confirmation of measles cases. Interfering substances can yield a false-positive result, leading to unnecessary public health interventions. The IgM capture assay developed at the Centers for Disease Control (CDC) was compared against five commercially available ELISA kits for the ability to detect measles virus-specific IgM in a panel of 90 well-characterized specimens. Serum samples were tested in triplicate using each commercial kit as recommended by the manufacturer. Using the CDC measles IgM capture assay as the reference test; the sensitivity and specificity for each commercial kit ranged from 50 to 83% and 86.9 to 98%, respectively. Discrepant results were observed for samples tested with all five commercial kits and ranged from 13.8 to 28.8% of the specimens tested. False-positive results occurred in 2.0 to 13.1% of sera, while negative results were observed in 16.7 to 50% of sera that were positive by the CDC measles IgM capture assay. Evaluation and interpretation of measles IgM serologic results can be complex, particularly in measles elimination settings. The performance characteristics of a measles IgM assay should be carefully considered when selecting an assay to achieve high-quality measles surveillance.
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Sarampo , Humanos , Imunoglobulina M , Ensaio de Imunoadsorção Enzimática/métodos , Sarampo/diagnóstico , Sarampo/epidemiologia , Vírus do Sarampo , Sensibilidade e Especificidade , Anticorpos AntiviraisRESUMO
Serosurveys are important tools for estimating population immunity and providing immunization activity guidance. The measles and rubella multiplex bead assay (MBA) offers multiple advantages over standard serological assays and was validated by comparison with the enzyme-linked immunosorbent assay (ELISA) and the measles plaque reduction neutralization (PRN) assay. Results from a laboratory-produced purified measles virus whole-virus antigen MBA (MeV WVAL) correlated better with ELISA and PRN than results from the baculovirus-expressed measles nucleoprotein (N) MBA. Therefore, a commercially produced whole-virus antigen (MeV WVAC) was evaluated. Serum IgG antibody concentrations correlated significantly with a strong linear relationship between the MeV WVAC and MeV WVAL MBAs (R = 0.962 and R2 = 0.926). IgG concentrations from the MeV WVAC MBA showed strong correlation with PRN titers (R = 0.846), with a linear relationship comparable to values obtained with the MeV WVAL MBA and PRN assay (R2 = 0.716 and R2 = 0.768, respectively). Receiver operating characteristic (ROC) curve analysis of the MeV WVAC using PRN titer as the comparator resulted in a seroprotection cutoff of 153 mIU/ml, similar to the established correlate of protection of 120 mIU/ml, with a sensitivity of 98% and a specificity of 83%. IgG concentrations correlated strongly between the rubella WVA MBA and ELISA (R = 0.959 and R2 = 0.919). ROC analysis of the rubella MBA using ELISA as the comparator yielded a cutoff of 9.36 IU/ml, similar to the accepted cutoff of 10 IU/ml for seroprotection, with a sensitivity of 99% and a specificity of 100%. These results support use of the MBA for multiantigen serosurveys assessing measles and rubella population immunity.
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Sarampo , Rubéola (Sarampo Alemão) , Anticorpos Antivirais , Ensaio de Imunoadsorção Enzimática , Humanos , Imunoglobulina G , Sarampo/diagnóstico , Vírus do Sarampo , Rubéola (Sarampo Alemão)/diagnósticoRESUMO
Measurement of measles virus-specific IgG is used to assess presumptive evidence of immunity among immunocompetent individuals with uncertain immune or vaccination status. False-negative test results may lead to unnecessary quarantine and exclusion from activities such as employment, education, and travel or result in unnecessary revaccination. In contrast, false-positive results may fail to identify susceptible individuals and promote spread of disease by those who are exposed and unprotected. To better understand the performance characteristics of tests to detect measles IgG, we compared five widely used, commercially available measles IgG test platforms using a set of 223 well-characterized serum samples. Measles virus neutralizing antibodies were also measured by in vitro plaque reduction neutralization, the gold standard method, and compared to IgG test results. Discrepant results were observed for samples in the low-positive ranges of the most sensitive tests, but there was good agreement across platforms for IgG-negative sera and for samples with intermediate to high levels of IgG. False-negative test results occurred in approximately 11% of sera, which had low levels of neutralizing antibody.
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Vírus do Sarampo , Sarampo , Anticorpos Antivirais , Ensaio de Imunoadsorção Enzimática , Humanos , Imunoensaio , Imunoglobulina G , Sarampo/diagnóstico , Testes de Neutralização , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: We describe a measles outbreak and control measures implemented at a privately operated detention facility housing US Immigration and Customs Enforcement detainees in 2016. METHODS: Case-patients reported fever and rash and were either laboratory-confirmed or had an epidemiological link to a laboratory-confirmed case-patient. Immunoglobulin G (IgG) avidity and plaque reduction neutralization tests distinguished between primary acute and reinfection case-patients. Measles-specific IgG was measured to assess detainee immunity levels. We compared attack rates (ARs) among detainees and staff, between IgG-negative and IgG-positive detainees, and by detainee housing units and sexes. RESULTS: We identified 32 measles case-patients (23 detainees, 9 staff); rash onsets were during 6 May-26 June 2016. High IgG avidity and neutralizing-antibody titers >40000 to measles (indicating reinfection) were identified in 18 (95%) and 15 (84%) of 19 tested case-patients, respectively. Among 205 unit A detainees tested for presumptive immunity, 186 (91%) had detectable IgG. Overall, the AR was 1.65%. ARs were significantly higher among detainees in unit A (7.05%) compared with units B-F (0.59%), and among male (2.33%) compared with female detainees (0.38%); however, ARs were not significantly different between detainees and staff or between IgG-negative and IgG-positive detainees. Control measures included the vaccination of 1424 of 1425 detainees and 190 of 510 staff, immunity verification for 445 staff, case-patient isolation, and quarantine of affected units. CONCLUSIONS: Although ARs were low, measles outbreaks can occur in intense-exposure settings, despite a high population immunity, underscoring the importance of high vaccination coverage and containment in limiting measles transmission.
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Surtos de Doenças , Sarampo/epidemiologia , Prisões , Adulto , Arizona/epidemiologia , Feminino , História do Século XXI , Humanos , Técnicas Imunoenzimáticas , Imunoglobulina G , Imunoglobulina M , Masculino , Sarampo/diagnóstico , Sarampo/história , Sarampo/prevenção & controle , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Vigilância em Saúde Pública , Testes Sorológicos , Adulto JovemRESUMO
BACKGROUND: Measles was eliminated in the United States through high vaccination coverage and a public health system able to rapidly respond to measles. Measles may occur among vaccinated individuals, but secondary transmission from such individuals has not been documented. METHODS: Suspected patients and contacts exposed during a measles outbreak in New York City in 2011 were investigated. Medical histories and immunization records were obtained. Cases were confirmed by detection of measles-specific immunoglobulin M and/or RNA. Tests for measles immunoglobulin G (IgG), IgG avidity, measurement of measles neutralizing antibody titers, and genotyping were performed to characterize the cases. RESULTS: The index patient had 2 doses of measles-containing vaccine; of 88 contacts, 4 secondary patients were confirmed who had either 2 doses of measles-containing vaccine or a past positive measles IgG antibody. All patients had laboratory confirmation of measles infection, clinical symptoms consistent with measles, and high-avidity IgG antibody characteristic of a secondary immune response. Neutralizing antibody titers of secondary patients reached >80 000 mIU/mL 3-4 days after rash onset and that of the index was <500 mIU/mL 9 days after rash onset. No additional cases of measles occurred among 231 contacts of secondary patients. CONCLUSIONS: This is the first report of measles transmission from a twice-vaccinated individual with documented secondary vaccine failure. The clinical presentation and laboratory data of the index patient were typical of measles in a naive individual. Secondary patients had robust anamnestic antibody responses. No tertiary cases occurred despite numerous contacts. This outbreak underscores the need for thorough epidemiologic and laboratory investigation of suspected cases of measles regardless of vaccination status.
Assuntos
Sarampo/transmissão , Vacinação , Adulto , Idoso , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Afinidade de Anticorpos , Surtos de Doenças , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Sarampo/epidemiologia , Sarampo/imunologia , Vacina contra Sarampo/administração & dosagem , Vacina contra Sarampo/uso terapêutico , Pessoa de Meia-Idade , Cidade de Nova IorqueRESUMO
Background: In 2017, a mumps outbreak occurred in a US military barracks. Serum collected at service entry was used to compare pre-exposure with presumptive vaccine-induced antibody levels from persons who developed mumps (cases) and potentially exposed persons who did not develop mumps (non-cases). Sufficient information to determine levels of exposure during the outbreak was not available. Methods: Pre-outbreak serum samples from the Department of Defense Serum Repository were available from 254 potentially exposed service members. Twelve developed clinical symptoms and had post-outbreak serum collected. All sera were tested with a mumps-specific enzyme immunoassay for immunoglobulin M, immunoglobulin G (IgG), and IgG avidity. The neutralizing antibodies to vaccine strain (Jeryl Lynn [JL], genotype A) and wildtype virus (genotype G) was assessed by a plaque reduction neutralization test. A Fisher exact test and receiver operator characteristic curve were used to analyze the antibody response for non-cases and mumps cases. Results: Eight mumps cases were laboratory confirmed. Pre-outbreak neutralizing antibody titers to JL and genotype G mumps virus and pre-outbreak IgG index values were proportionately lower for most cases as compared with exposed non-cases. When compared with potentially exposed non-cases, cases with clinical symptoms had greater odds of having a pre-outbreak JL titer <41 and a genotype G titer <16. Conclusions: We identified potential correlates of protection for mumps neutralizing antibody titers against JL and genotype G mumps viruses.
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Mongolia experienced a nationwide measles outbreak during 1 March 2015-31 December 2016, with 49,077 cases reported to the WHO; many were among vaccinated young adults, suggesting a possible role of vaccine failure. Advanced laboratory methods, coupled with detailed epidemiological investigations, can help classify cases as vaccine failure, failure to vaccinate, or both. In this report, we conducted a study of cases to identify risk factors for breakthrough infection for a subset of laboratory-confirmed measles cases. Of the 193 cases analyzed, only 19 (9.8%) reported measles vaccination history, and 170 (88%) were uncertain. Measles-specific IgG avidity testing classified 120 (62%) cases as low IgG avidity, indicating no prior exposure to measles. Ten of these cases with low IgG avidity had a history of measles vaccination, indicating primary vaccine failure. Overall, sixty cases (31%) had high IgG avidity, indicating breakthrough infection after prior exposure to measles antigen through vaccination or natural infection, but the IgG avidity results were highly age-dependent. This study found that among young children aged 9 months-5 years, breakthrough infection was rare (4/82, 5%); however, among young adults aged 15-25 years, breakthrough infection due to secondary vaccine failure (SVF) occurred on a large scale during this outbreak, accounting for the majority of cases (42/69 cases, 61%). The study found that large-scale secondary vaccine failure occurred in Mongolia, which highlights the potential for sustained outbreaks in post-elimination settings due to "hidden" cohorts of young adults who may have experienced waning immunity. This phenomenon may have implications for the sustainability of measles elimination in countries that remain vulnerable to the importation of the virus from areas where it is still endemic. Until global measles elimination is achieved, enhanced surveillance and preparedness for future outbreaks in post- or peri-elimination countries may be required.
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Background: A third dose of measles-mumps-rubella vaccine (MMR) may be administered for various reasons, but data on long-term immunity are limited. We assessed neutralizing antibody levels against measles and rubella among adults up to 11 years after receipt of a third MMR dose. Methods: In this longitudinal study, healthy adults who received a third MMR dose as young adults (ages 18-28 years) were recalled around 5 years and 9-11 years after the third dose. Measles and rubella antibody levels were assessed by plaque-reduction and immunocolorimetric neutralization assays, respectively. Antibody concentrations <120â mIU/mL and <10â U/mL were considered potentially susceptible to measles and rubella, respectively. Geometric mean concentrations (GMCs) and 95% confidence intervals (CIs) over time were estimated from generalized estimating equation models. Results: Approximately 5 and 9-11 years after receipt of the third dose, 405 and 304 adults were assessed, respectively. Measles GMC was 428â mIU/mL (95% CI, 392-468â mIU/mL) 5 years postvaccination, declining to 381â mIU/mL (95% CI, 339-428â mIU/mL) 11 years postvaccination. At the last follow-up visit (9-11 years postvaccination), 10% of participants were potentially susceptible to measles infection. Rubella GMCs were stable throughout the follow-up period (63â U/mL to 65â U/mL); none of the participants was susceptible to rubella at the last follow-up visit. Conclusions: Eleven years after receiving a third MMR dose, measles and rubella neutralizing antibody levels remained high in adults. However, on the basis of waning antibody levels, some adults may become susceptible to measles infection over time despite receipt of 3 vaccine doses.
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Waning mumps IgG antibody and incomplete IgG avidity maturation may increase susceptibility to mumps virus infection in some vaccinees. To measure mumps IgG avidity, serum specimens serially diluted to the endpoint were incubated on a commercial mumps-specific IgG enzyme immunoassay and treated with the protein denaturant diethylamine (60 mM, pH 10). End titer avidity indices (etAIs [percent ratio of detected diethylamine-resistant IgG at endpoint]) were calculated. Unpaired serum specimens (n = 108) from 15-month-old children living in a low-incidence setting were collected 1 month and 2 years after the first measles, mumps, and rubella vaccine dose (MMR1) and tested for mumps avidity. Per the receiver operating characteristic curve, the avidity assay is accurate (area under the curve, 0.994; 95% confidence interval [CI], 0.956 to 1.000), 96.5% sensitive (95% CI, 87.9 to 99.6%), and 92.2% specific (95% CI, 81.1 to 97.8%) at an etAI of 30%. When 9 sets of paired serum specimens collected 1 to 60 months post-MMR1 were tested for mumps and measles IgG avidity using comparable methods, the mumps etAI increased from 11% to 40 to 60% in 6 months. From 6 to 60 months, avidity was sustained at a mean etAI of 50% (95% CI, 46 to 54%), significantly lower (P < 0.0001) than the mean measles etAI of 80% (95% CI, 74 to 86%). Mean etAIs in children 2 years post-MMR1 (n = 51), unvaccinated adults with distant mumps disease (n = 29), and confirmed mumps cases (n = 23) were 54, 62, and 57%, respectively. A mumps-specific endpoint avidity assay was developed and validated, and mumps avidity was determined to be generally sustained at etAIs of 40 to 60%, reaching etAIs of >80% in some individuals.IMPORTANCE Numerous outbreaks of mumps have occurred in the United States among two-dose measles-mumps-rubella (MMR)-vaccinated populations since 2006. The avidity of mumps-specific IgG antibodies may affect susceptibility to mumps virus infection in some vaccinated individuals. To accurately measure mumps avidity, we developed and validated a mumps-specific IgG avidity assay that determines avidity at the endpoint titer of serially diluted serum specimens, providing results that are independent of IgG concentration. At low antibody titers, endpoint methods are considered more accurate than methods that determine avidity at a single dilution. We determined that 6 months after the first MMR dose, mumps IgG avidity is high and generally sustained at avidity indices of 40 to 60%, reaching values of >80% in some individuals. Additionally, 4% (4/103) of individuals had avidity indices of ≤30% (low avidity) 2 years after vaccination. Inadequate mumps avidity maturation may be one factor influencing susceptibility to mumps virus infection among previously vaccinated or naturally infected individuals.
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Anticorpos Antivirais/sangue , Imunoglobulina G/sangue , Vacina contra Sarampo-Caxumba-Rubéola/administração & dosagem , Vírus da Caxumba/imunologia , Afinidade de Anticorpos , Estudos de Casos e Controles , Feminino , Humanos , Esquemas de Imunização , Lactente , Masculino , Caxumba/prevenção & controle , Estados UnidosRESUMO
In the United States, approximately 9% of the measles cases reported from 2012 to 2014 occurred in vaccinated individuals. Laboratory confirmation of measles in vaccinated individuals is challenging since IgM assays can give inconclusive results. Although a positive reverse transcription (RT)-PCR assay result from an appropriately timed specimen can provide confirmation, negative results may not rule out a highly suspicious case. Detection of high-avidity measles IgG in serum samples provides laboratory evidence of a past immunologic response to measles from natural infection or immunization. High concentrations of measles neutralizing antibody have been observed by plaque reduction neutralization (PRN) assays among confirmed measles cases with high-avidity IgG, referred to here as reinfection cases (RICs). In this study, we evaluated the utility of measuring levels of measles neutralizing antibody to distinguish RICs from noncases by receiver operating characteristic curve analysis. Single and paired serum samples with high-avidity measles IgG from suspected measles cases submitted to the CDC for routine surveillance were used for the analysis. The RICs were confirmed by a 4-fold rise in PRN titer or by RT-quantitative PCR (RT-qPCR) assay, while the noncases were negative by both assays. Discrimination accuracy was high with serum samples collected ≥3 days after rash onset (area under the curve, 0.953; 95% confidence interval [CI], 0.854 to 0.993). Measles neutralizing antibody concentrations of ≥40,000 mIU/ml identified RICs with 90% sensitivity (95% CI, 74 to 98%) and 100% specificity (95% CI, 82 to 100%). Therefore, when serological or RT-qPCR results are unavailable or inconclusive, suspected measles cases with high-avidity measles IgG can be confirmed as RICs by measles neutralizing antibody concentrations of ≥40,000 mIU/ml.
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Anticorpos Neutralizantes/sangue , Afinidade de Anticorpos , Testes Diagnósticos de Rotina/métodos , Imunoglobulina G/sangue , Vírus do Sarampo/imunologia , Sarampo/diagnóstico , Testes de Neutralização/métodos , Adolescente , Adulto , Idoso , Anticorpos Antivirais/sangue , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Sarampo/imunologia , Pessoa de Meia-Idade , Recidiva , Sensibilidade e Especificidade , Estados Unidos , Adulto JovemRESUMO
Neutralizing antibodies are assumed to be essential for protection against mumps virus infection, but their measurement is labor- and time-intensive. For this reason, enzyme-linked immunosorbent assays (ELISAs) are typically used to measure mumps-specific IgG levels. However, since there is poor correlation between mumps neutralization titers and ELISAs that measure the presence of mumps-specific IgG levels, ELISAs that better correlate with neutralization are needed. To address this issue, we measured mumps antibody levels by plaque reduction neutralization, by a commercial ELISA (whole-virus antigen), and by ELISAs specific for the mumps nucleoprotein and hemagglutinin. The results indicate that differences in the antibody response to the individual mumps proteins could partially explain the lack of correlation among various serologic tests. Furthermore, the data indicate that some seropositive individuals have low levels of neutralizing antibody. If neutralizing antibody is important for protection, this suggests that previous estimates of immunity based on whole-virus ELISAs may be overstated.