Last data update: Jan 27, 2025. (Total: 48650 publications since 2009)
Records 1-30 (of 55 Records) |
Query Trace: Bellini W[original query] |
---|
Vaccine-associated varicella and rubella infections in severe combined immunodeficiency with isolated CD4 lymphocytopenia and mutations in IL7R detected by tandem whole exome sequencing and chromosomal microarray.
Bayer DK , Martinez CA , Sorte HS , Forbes LR , Demmler-Harrison GJ , Hanson IC , Pearson NM , Noroski LM , Zaki SR , Bellini WJ , Leduc MS , Yang Y , Eng CM , Patel A , Rodningen OK , Muzny DM , Gibbs RA , Campbell IM , Shaw CA , Baker MW , Zhang V , Lupski JR , Orange JS , Seeborg FO , Stray-Pedersen A . Clin Exp Immunol 2014 178 (3) 459-69 ![]() In areas without newborn screening for severe combined immunodeficiency (SCID), disease-defining infections may lead to diagnosis, and in some cases, may not be identified prior to the first year of life. We describe a female infant who presented with disseminated vaccine-acquired varicella (VZV) and vaccine-acquired rubella infections at 13 months of age. Immunological evaluations demonstrated neutropenia, isolated CD4 lymphocytopenia, the presence of CD8(+) T cells, poor lymphocyte proliferation, hypergammaglobulinaemia and poor specific antibody production to VZV infection and routine immunizations. A combination of whole exome sequencing and custom-designed chromosomal microarray with exon coverage of primary immunodeficiency genes detected compound heterozygous mutations (one single nucleotide variant and one intragenic copy number variant involving one exon) within the IL7R gene. Mosaicism for wild-type allele (20-30%) was detected in pretransplant blood and buccal DNA and maternal engraftment (5-10%) demonstrated in pretransplant blood DNA. This may be responsible for the patient's unusual immunological phenotype compared to classical interleukin (IL)-7Rα deficiency. Disseminated VZV was controlled with anti-viral and immune-based therapy, and umbilical cord blood stem cell transplantation was successful. Retrospectively performed T cell receptor excision circle (TREC) analyses completed on neonatal Guthrie cards identified absent TREC. This case emphasizes the danger of live viral vaccination in severe combined immunodeficiency (SCID) patients and the importance of newborn screening to identify patients prior to high-risk exposures. It also illustrates the value of aggressive pathogen identification and treatment, the influence newborn screening can have on morbidity and mortality and the significant impact of newer genomic diagnostic tools in identifying the underlying genetic aetiology for SCID patients. |
Etiological analysis of discarded measles in the context of a measles outbreak among a highly immunized population
Torner N , Mercader S , Dominguez A , Martinez A , Costa J , Sowers SB , Abernathy ES , Bellini WJ , Hickman CJ . Pediatr Int 2022 65 (1) e15430 BACKGROUND: Measles can lead to serious complications and remains an important cause of morbidity and mortality worldwide. 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 1 rubella, 3 human herpes virus 6, and 6 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 serologic testing are essential to correctly diagnose suspected measles infection. |
Classification of measles breakthrough cases in an elimination setting using a comprehensive algorithm of laboratory results: why highly sensitive and specific IgM assays are important
Mercader S , Dominguez A , Torner N , Costa J , Sowers S , Martinez A , Bellini WJ , Hickman CJ . Int J Infect Dis 2021 112 21-24 OBJECTIVE: In 2006, a measles outbreak occurred in Catalonia (Spain), six years after endemic measles was declared eliminated. The aim of this study was to classify 19 confirmed measles breakthrough cases (BC) using a high-performance avidity assay developed in 2010. METHODS: Serum specimens were tested by indirect IgG, indirect IgM, capture IgM enzyme immunoassay, an endpoint-titer IgG avidity assay, and a plaque reduction neutralization assay. Serology and RNA detection results were combined in an algorithm for measles confirmation and classification of breakthrough cases and analyzed with clinical and epidemiological data. RESULTS: Of 19 samples, 13 (68%) were conclusive with classification of BCs and 6 (32%) had false-positive IgM results on an indirect-format assay; they were classified as rash and fever illness of undetermined etiology. BCs were primary vaccine failures (7 or 54%), secondary vaccine failures (4 or 31%) and 2 (15%) could not be classified. CONCLUSIONS: In measles elimination settings, high-performing assays and a comprehensive algorithm of laboratory results (IgG, IgM and RNA detection) including IgG avidity and PRN results, when necessary, can assist in accurate laboratory confirmation and classification of suspected measles cases for surveillance. Highly specific IgM assays are required to minimize the number of false-positive results. |
Decreased humoral immunity to mumps in young adults immunized with MMR vaccine in childhood
Rasheed MAU , Hickman CJ , McGrew M , Sowers SB , Mercader S , Hopkins A , Grimes V , Yu T , Wrammert J , Mulligan MJ , Bellini WJ , Rota PA , Orenstein WA , Ahmed R , Edupuganti S . Proc Natl Acad Sci U S A 2019 116 (38) 19071-19076 In the past decade, multiple mumps outbreaks have occurred in the United States, primarily in close-contact, high-density settings such as colleges, with a high attack rate among young adults, many of whom had the recommended 2 doses of mumps-measles-rubella (MMR) vaccine. Waning humoral immunity and the circulation of divergent wild-type mumps strains have been proposed as contributing factors to mumps resurgence. Blood samples from 71 healthy 18- to 23-year-old college students living in a non-outbreak area were assayed for antibodies and memory B cells (MBCs) to mumps, measles, and rubella. Seroprevalence rates of mumps, measles, and rubella determined by IgG enzyme-linked immunosorbent assay (ELISA) were 93, 93, and 100%, respectively. The index standard ratio indicated that the concentration of IgG was significantly lower for mumps than rubella. High IgG avidity to mumps Enders strain was detected in sera of 59/71 participants who had sufficient IgG levels. The frequency of circulating mumps-specific MBCs was 5 to 10 times lower than measles and rubella, and 10% of the participants had no detectable MBCs to mumps. Geometric mean neutralizing antibody titers (GMTs) by plaque reduction neutralization to the predominant circulating wild-type mumps strain (genotype G) were 6-fold lower than the GMTs against the Jeryl Lynn vaccine strain (genotype A). The majority of the participants (80%) received their second MMR vaccine >/=10 years prior to study participation. Additional efforts are needed to fully characterize B and T cell immune responses to mumps vaccine and to develop strategies to improve the quality and durability of vaccine-induced immunity. |
Development and use of an endpoint titration assay to characterize mumps IgG avidity following measles, mumps, and rubella vaccination and wild-type mumps infection
Mercader S , McGrew M , Sowers SB , Williams NJ , Bellini WJ , Hickman CJ . mSphere 2018 3 (5) 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. |
Measles in the United States since the millennium: Perils and progress in the postelimination era
Schuchat A , Fiebelkorn AP , Bellini W . Microbiol Spectr 2016 4 (2) This article describes measles and measles vaccination, along with the challenges, successes, and progress in the postelimination era. |
High concentrations of measles neutralizing antibodies and high-avidity measles IgG accurately identify measles reinfection cases
Sowers SB , Rota JS , Hickman CJ , Mercader S , Redd S , McNall RJ , Williams N , McGrew M , Walls ML , Rota PA , Bellini WJ . Clin Vaccine Immunol 2016 23 (8) 707-16 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. |
Supplemental measles vaccine antibody response among HIV-infected and -uninfected children in Malawi after 1- and 2-dose primary measles vaccination schedules
Fowlkes AL , Witte D , Beeler J , Audet SA , Broadhead R , Bellini WJ , Cutts F , Helfand RF . Vaccine 2016 34 (12) 1459-64 BACKGROUND: The long-term antibody response to measles vaccine (MV) administered at age 6 months with or without subsequent doses is not well documented. METHODS: Measles serum antibody responses were evaluated after a supplemental dose of measles vaccine (sMV) administered at a median age of 20 months among Malawian children who had previously received 2 doses of measles vaccine (MV) at ages 6 and 9 months (HIV-infected and random sample of HIV-uninfected) or 1 dose at age 9 months (random sample of HIV-uninfected). We compared measles antibody seropositivity between groups by enzyme linked immunoassay and seroprotection by plaque reduction neutralization geometric mean concentrations. RESULTS: Of 1756 children enrolled, 887 (50.5%) received a sMV dose following MV at 9 months of age and had specimens available after sMV receipt, including 401 HIV-uninfected children who received one MV dose at 9 months, 464 HIV-uninfected and 22 HIV-infected children who received two doses of MV at ages 6 and 9 months. Among HIV-uninfected children, protective levels of antibody were found post sMV in 90-99% through ages 24-36 months and were not affected by MV schedule. Geometric mean concentration levels of measles antibody were significantly increased post-sMV among those HIV-uninfected children previously non-responsive to vaccination. Among HIV-infected children, the proportion seroprotected increased initially but by 9 months post-sMV was no higher than pre-sMV. CONCLUSIONS: Our findings support early 2-dose MV to provide measles immunity for young infants without risk of interference with antibody responses to subsequent MV doses administered as part of SIAs. |
Non-interference of rotavirus vaccine with measles-rubella vaccine at 9 months and improvements in anti-rotavirus immunity: a randomized trial
Zaman K , Fleming JA , Victor JC , Yunus M , Bari TI , Azim T , Rahman M , Mowla SM , Bellini WJ , McNeal M , Icenogle JP , Lopman B , Parashar U , Cortese MM , Steele AD , Neuzil KM . J Infect Dis 2016 BACKGROUND: The burden of rotavirus morbidity and mortality is high in children under 5 years in developing countries and evaluations indicate waning protection from rotavirus immunization in the second year. An additional dose of rotavirus vaccine may enhance the immune response and lengthen the period of protection against disease, however co-administration should not interfere with immune responses to concurrently given vaccines. METHODS: Enrolling 480 9-month old participants from Matlab, Bangladesh, the primary objective was to establish non-inferiority of concomitant administration of measles-rubella (MR) vaccine and a 3rd dose of human monovalent rotavirus vaccine (HRV) [MR+HRV] compared to MR vaccine given alone [MR]. Secondary objectives included non-inferiority of rubella antibody seroconversion and evaluating rotavirus IgA/IgG seroresponses in MR+HRV participants. RESULTS: Two months post-vaccination, 75.3% and 74.3% of MR+HRV and MR group infants, respectively, had seroprotective levels of measles virus antibodies. 100.0% and 99.6%, respectively, showed anti-rubella IgG seroprotection. In the MR+HRV group, pre-vaccination anti-rotavirus IgA and IgG seropositivities (52.7% and 66.3%, respectively) increased to 69.6% and 88.3% post-vaccination. CONCLUSIONS: Vaccine-induced measles and rubella antibody responses are not negatively affected by concomitant administration of HRV. The HRV dose increases anti-rotavirus serum antibody titres and the proportion of infants with detectable anti-rotavirus antibody. |
A comparison of postelimination measles epidemiology in the United States, 2009-2014 versus 2001-2008
Fiebelkorn AP , Redd SB , Gastanaduy PA , Clemmons N , Rota PA , Rota JS , Bellini WJ , Wallace GS . J Pediatric Infect Dis Soc 2015 6 (1) 40-48 BACKGROUND: Measles, a vaccine-preventable disease that can cause severe complications, was declared eliminated from the United States in 2000. The last published summary of US measles epidemiology was during 2001-2008. We summarized US measles epidemiology during 2009-2014. METHODS: We compared demographic, vaccination, and virologic data on confirmed measles cases reported to the Centers for Disease Control and Prevention during January 1, 2009-December 31, 2014 and January 1, 2001-December 31, 2008. RESULTS: During 2009-2014, 1264 confirmed measles cases were reported in the United States, including 275 importations from 58 countries and 66 outbreaks. The annual median number of cases and outbreaks during this period was 130 (range, 55-667 cases) and 10 (range, 4-23 outbreaks), respectively, compared with an annual median of 56 cases (P = .08) and 4 outbreaks during 2001-2008 (P = .04). Among US-resident case-patients during 2009-2014, children aged 12-15 months had the highest measles incidence (65 cases; 8.3 cases/million person-years), and infants aged 6-11 months had the second highest incidence (86 cases; 7.3 cases/million person-years). During 2009-2014, 865 (74%) of 1173 US-resident case-patients were unvaccinated and 188 (16%) had unknown vaccination status; of 917 vaccine-eligible US-resident case-patients, 600 (65%) were reported as having philosophical or religious objections to vaccination. CONCLUSIONS: Although the United States has maintained measles elimination since 2000, measles outbreaks continue to occur globally, resulting in imported cases and potential spread. The annual median number of cases and outbreaks more than doubled during 2009-2014 compared with the earlier postelimination years. To maintain elimination, it will be necessary to maintain high 2-dose vaccination coverage, continue case-based surveillance, and monitor the patterns and rates of vaccine exemption. |
Immunity to Measles, Mumps, and Rubella in US Children With Perinatal HIV Infection or Perinatal HIV Exposure Without Infection
Siberry GK , Patel K , Bellini WJ , Karalius B , Purswani MU , Burchett SK , Meyer WA 3rd , Sowers SB , Ellis A , Van Dyke RB . Clin Infect Dis 2015 61 (6) 988-95 BACKGROUND: Children with perinatal human immunodeficiency virus (HIV) infection (PHIV) may not be protected against measles, mumps, and rubella (MMR) because of impaired initial vaccine response or waning immunity. Our objectives were to estimate seroimmunity in PHIV-infected and perinatally HIV-exposed but uninfected (HEU) children and identify predictors of immunity in the PHIV cohort. METHODS: PHIV and HEU children were enrolled in the Pediatric HIV/AIDS Cohort Study (PHACS) at ages 7-15 years from 2007 to 2009. At annual visits, demographic, laboratory, immunization, and clinical data were abstracted and serologic specimens collected. Most recent serologic specimen was used to determine measles seroprotection by plaque reduction neutralization assay and rubella seroprotection and mumps seropositivity by enzyme immunoassay. Sustained combination antiretroviral therapy (cART) was defined as taking cART for at least 3 months. RESULTS: Among 428 PHIV and 221 HEU PHACS participants, the prevalence was significantly lower in PHIV children for measles seroprotection (57% [95% confidence interval {CI}, 52%-62%] vs 99% [95% CI, 96%-100%]), rubella seroprotection (65% [95% CI, 60%-70%] vs 98% [95% CI, 95%-100%]), and mumps seropositivity (59% [95% CI, 55%-64%] vs 97% [95% CI, 94%-99%]). On multivariable analysis, greater number of vaccine doses while receiving sustained cART and higher nadir CD4 percentage between last vaccine dose and serologic testing independently improved the cumulative prediction of measles seroprotection in PHIV. Predictors of rubella seroprotection and mumps seropositivity were similar. CONCLUSIONS: High proportions of PHIV-infected children, but not HEU children, lack serologic evidence of immunity to MMR, despite documented immunization and current cART. Effective cART before immunization is a strong predictor of current seroimmunity. |
Measles virus neutralizing antibody response, cell-mediated immunity, and IgG antibody avidity before and after a third dose of measles-mumps-rubella vaccine in young adults
Fiebelkorn AP , Coleman LA , Belongia EA , Freeman SK , York D , Bi D , Kulkarni A , Audet S , Mercader S , McGrew M , Hickman CJ , Bellini WJ , Shivakoti R , Griffin DE , Beeler J . J Infect Dis 2015 213 (7) 1115-23 BACKGROUND: Two doses of measles-mumps-rubella (MMR) vaccine are 97% effective against measles, but waning antibody immunity and two-dose vaccine failures occur. We administered a third MMR dose (MMR3) to young adults and assessed immunogenicity over 1 year. METHODS: Measles virus (MeV) neutralizing antibody concentrations, cell-mediated immunity (CMI), and IgG antibody avidity were assessed at baseline, 1-month, and 1-year after MMR3. RESULTS: Of 662 subjects at baseline, 1 (0.2%) was seronegative (<8 mIU/mL) and 23 (3.5%) had low (8-120 mIU/mL) MeV neutralizing antibodies. At 1-month post-MMR3, 1 (0.2%) subject was seronegative and 6 (0.9%) had low neutralizing antibodies with only 21/662 (3.2%) showing a ≥4-fold rise in neutralizing antibodies. At 1-year post-MMR3, none were negative and 10 (1.6%) of 617 subjects had low neutralizing antibodies. CMI results showed low-levels of spot-forming cells after stimulation, suggesting T-cell memory, but the response was minimal post-MMR3. MeV IgG avidity results did not correlate with neutralization results. CONCLUSIONS: Most subjects were seropositive pre-MMR3 and very few had a secondary immune response post-MMR3. Similarly, CMI and avidity results showed minimal qualitative improvements in immune response post-MMR3. We did not find compelling data to support a routine third dose of MMR vaccine. |
Late Onset Hypomorphic RAG2 Deficiency Presentation with Fatal Vaccine-Strain VZV Infection.
Dutmer CM , Asturias EJ , Smith C , Dishop MK , Schmid DS , Bellini WJ , Tirosh I , Lee YN , Notarangelo LD , Gelfand EW . J Clin Immunol 2015 35 (8) 754-60 ![]() PURPOSE: Hypomorphic mutations in RAG1 and RAG2 are associated with significant clinical heterogeneity and symptoms of immunodeficiency or autoimmunity may be late in appearance. As a result, immunosuppressive medications may be introduced that can have life-threatening consequences. We describe a previously healthy 13-month-old girl presenting with rash and autoimmune hemolytic anemia, while highlighting the importance of vigilance and consideration of an underlying severe immunodeficiency disease prior to instituting immunosuppressive therapy. METHODS: Given clinical deterioration of the patient and a temporal association with recently administered vaccinations, virus genotyping was carried out via 4 real-time Forster Resonance Energy Transfer PCR protocols targeting vaccine-associated single nucleotide polymorphisms. Genomic DNA was extracted from whole blood and analyzed via the next-generation sequencing method of sequencing-by-synthesis. Immune function studies included immunophenotyping of peripheral blood lymphocytes, mitogen-induced proliferation and TLR ligand-induced production of TNFalpha. Analysis of recombination activity of wild-type and mutant RAG2 constructs was performed. RESULTS: Virus genotyping revealed vaccine-strain VZV, mumps, and rubella. Next-generation sequencing identified heterozygosity for RAG2 R73H and P180H mutations. Profound lymphopenia was associated with intense corticosteroid therapy, with some recovery after steroid reduction. Residual, albeit low, RAG2 protein activity was demonstrated. CONCLUSIONS: Because of the association of RAG deficiency with late-onset presentation and autoimmunity, live virus vaccination and immunosuppressive therapies are often initiated and can result in negative consequences. Here, hypomorphic RAG2 mutations were linked to disseminated vaccine-strain virus infections following institution of corticosteroid therapy for autoimmune hemolytic anemia. |
A 29-year-old pregnant woman with worsening left hemiparesis, encephalopathy, and hemodynamic instability: a case report of subacute sclerosing panencephalitis
Reis GF , Ritter JM , Bellini WJ , Rota PA , Bollen AW . Clin Neuropathol 2015 34 (5) 258-66 A 29-year-old pregnant woman developed progressively worsening encephalopathy, left hemiparesis, and hemodynamic instability over a 6-week period. Initial brain MRI and work-up for infectious and autoimmune causes were normal, although elevated IgG and oligoclonal bands were seen on analysis of the cerebrospinal fluid (CSF). After uncomplicated spontaneous delivery of a preterm healthy infant, her condition worsened. Repeat brain MRI demonstrated generalized volume loss and evidence of corticospinal tract degeneration. She underwent a brain biopsy, which showed characteristic viral inclusions of the type seen in subacute sclerosing panencephalitis (SSPE). The diagnosis was confirmed by immunohistochemistry and electron microscopy, and additional CSF analysis also showed markedly elevated IgG titer for measles. Sequence analysis of the nucleoprotein gene N-450 demonstrated a close relationship to the sequences of viruses in genotype D7. This case documents an ~ 6-month progression to death of SSPE in a pregnant woman. |
Measles outbreak associated with vaccine failure in adults - Federated States of Micronesia, February-August 2014
Breakwell L , Moturi E , Helgenberger L , Gopalani SV , Hales C , Lam E , Sharapov U , Larzelere M , Johnson E , Masao C , Setik E , Barrow L , Dolan S , Chen TH , Patel M , Rota P , Hickman C , Bellini W , Seward J , Wallace G , Papania M . MMWR Morb Mortal Wkly Rep 2015 64 (38) 1088-92 On May 15, 2014, CDC was notified of two laboratory-confirmed measles cases in the Federated States of Micronesia (FSM), after 20 years with no reported measles. FSM was assisted by the World Health Organization (WHO), the United Nations Children's Fund (UNICEF), and CDC in investigating suspected cases, identify contacts, conduct analyses to guide outbreak vaccination response, and review vaccine cold chain practices. During February-August, three of FSM's four states reported measles cases: Kosrae (139 cases), Pohnpei (251), and Chuuk (3). Two thirds of cases occurred among adults aged >/=20 years; of these, 49% had received >/=2 doses of measles-containing vaccine (MCV). Apart from infants aged <12 months who were too young for routine vaccination, measles incidence was lower among children than adults. A review of current cold chain practices in Kosrae revealed minor weaknesses; however, an absence of historical cold chain maintenance records precluded an evaluation of earlier problems. Each state implemented vaccination campaigns targeting children as young as age 6 months through adults up to age 57 years. The preponderance of cases in this outbreak associated with vaccine failure in adults highlights the need for both thorough case investigation and epidemiologic analysis to guide outbreak response vaccination. Routine childhood vaccination coverage achieved in recent years limited the transmission of measles among children. Even in areas where transmission has not occurred for years, maintaining high 2-dose MCV coverage through routine and supplemental immunization is needed to prevent outbreaks resulting from increased measles susceptibility in the population. |
A toddler with rash, encephalopathy, and hemolytic anemia
Smith C , Dutmer C , Schmid DS , Dishop MK , Bellini WJ , Gelfand EW , Asturias EJ . J Pediatric Infect Dis Soc 2015 4 (4) 376-80 A 13-month-old female from New Mexico presented to a local emergency department with 5 days of fever, diarrhea, nasal congestion, and cough, 2 days of jaundice, and 1 day of an erythematous papular rash on her trunk, arms, and groin. Initial laboratory studies revealed severe macrocytic anemia, reticulocytosis, and a positive direct Coombs test. She was hospitalized at a local facility for management of severe hemolytic anemia. Hemolysis was persistent despite daily blood transfusions, intravenous immune globulin (IVIG), and high-dose methylprednisolone. A bone marrow aspirate revealed tri-lineage marrow with reactive erythroid hyperplasia and absence of blasts. Her rash subsequently progressed from papules to ulcerated, crusted lesions. A lesional skin biopsy revealed intranuclear inclusion bodies typical of herpesviridae; therefore, acyclovir was initiated 3 weeks into her illness. She later developed encephalopathy characterized by loss of truncal tone and speech, decreased alertness, and difficulty managing oral secretions. After 4 weeks of progressive illness, she was transferred to our facility for further management. |
Seroprevalence of measles, mumps, rubella and varicella antibodies in the United States population, 2009-2010
Lebo EJ , Kruszon-Moran DM , Marin M , Bellini WJ , Schmid S , Bialek SR , Wallace GS , McLean HQ . Open Forum Infect Dis 2015 2 (1) ofv006 BACKGROUND: In the United States, measles, mumps, rubella, and varicella immunity is now primarily achieved through vaccination. Monitoring population immunity is necessary. METHODS: We evaluated seroprevalence of antibodies to measles, mumps, rubella, and varicella using the National Health and Nutrition Examination Survey during 2009-2010. RESULTS: Measles, mumps, rubella, and varicella seroprevalence was 92.0% (95% confidence interval [CI], 90.9%-93.0%), 87.6% (CI, 85.8%-89.2%), 95.3% (CI, 94.3%-96.2%), and 97.8% (CI, 97.1%-98.3%), respectively. United States (US)-born persons had lower mumps seroprevalence and higher varicella seroprevalence than non-US born persons. CONCLUSIONS: Seroprevalence was high (88%-98%) for all 4 viruses in the US population during 2009-2010. |
Susceptibility to measles among perinatally HIV-infected adolescents and young adults
Morris LE , Posada R , Hickman CJ , Latner DR , Singh TA , Rautenberg A , Jao J , Bellini WJ , Sperling R . J Pediatric Infect Dis Soc 2015 4 (1) 63-66 Among our cohort of adolescents and young adults with perinatally acquired human immunodeficiency virus, few (17.6%) had measles protective antibodies by plaque reduction neutralization (PRN). Agreement was demonstrated between the commercial enzyme immunoassay and the PRN assay (K = 0.59 [95% confidence interval: 0.23-0.95]). Further studies are needed to understand the determinants of immunity in this population. |
Evolutionary genetics of genotype H1 measles viruses in China from 1993 to 2012.
Xu S , Zhang Y , Rivailler P , Wang H , Ji Y , Zhen Z , Mao N , Li C , Bellini WJ , Xu W , Rota P . J Gen Virol 2014 95 1892-1899 ![]() Virologic surveillance is a critical component of measles surveillance because one of the criteria for verification of elimination of endemic measles is genetic analysis of wild-type viruses to demonstrate lack of an indigenous genotype. Measles has not yet been eliminated in China, and genotype H1 has been detected continuously since virologic surveillance was initiated in 1993. Virologic surveillance has been very strong in China and this provided a unique opportunity to conduct a detailed study of the evolution of a single, endemic genotype over a time span of nearly 20 years. Phylogenetic analysis performed on the 450 nucleotides coding for the COOH terminal 150 amino acids of the nucleoprotein (N-450), the fusion (F) gene and the hemagglutinin (H) gene confirmed the continued circulation of genotype H1 viruses for 19 years. No evidence was found for selective pressure on the H protein. The substitution rates ranged from 0.75 x 10-3 substitutions/site/year for H to 1.65 x10-3 substitutions/site/year for N-450. An estimate of the time of the most recent common ancestor for genotype H1 was approximately 1985 (95% Highest Probability Density = 1979-1989). Finally, the overall diversity of the measles sequences from China decreased from 2005 to 2012 which is coincident with a substantial decrease in measles cases. Overall, the results suggest that detailed evolutionary analyses will help to document the eventual elimination of measles in China, and the molecular approaches used in this study can be applied in other countries that are approaching measles elimination. |
Measles - United States, January 1-May 23, 2014
Gastanaduy PA , Redd SB , Fiebelkorn AP , Rota JS , Rota PA , Bellini WJ , Seward JF , Wallace GS . MMWR Morb Mortal Wkly Rep 2014 63 (22) 496-9 Measles is a highly contagious, acute viral illness that can lead to serious complications and death. Although measles elimination (i.e., interruption of year-round endemic transmission) was declared in the United States in 2000, importations of measles cases from endemic areas of the world continue to occur, leading to secondary measles cases and outbreaks in the United States, primarily among unvaccinated persons. To update national measles data in the United States, CDC evaluated cases reported by states from January 1 through May 23, 2014. A total of 288 confirmed measles cases have been reported to CDC, surpassing the highest reported yearly total of measles cases since elimination (220 cases reported in 2011). Fifteen outbreaks accounted for 79% of cases reported, including the largest outbreak reported in the United States since elimination (138 cases and ongoing). The large number of cases this year emphasizes the need for health-care providers to have a heightened awareness of the potential for measles in their communities and the importance of vaccination to prevent measles. |
Outbreak of measles among persons with prior evidence of immunity, New York City, 2011
Rosen JB , Rota JS , Hickman CJ , Sowers SB , Mercader S , Rota PA , Bellini WJ , Huang AJ , Doll MK , Zucker JR , Zimmerman CM . Clin Infect Dis 2014 58 (9) 1205-10 ![]() 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. |
Wild-type measles viruses with non-standard genome lengths.
Bankamp B , Liu C , Rivailler P , Bera J , Shrivastava S , Kirkness EF , Bellini WJ , Rota PA . PLoS One 2014 9 (4) e95470 ![]() The length of the single stranded, negative sense RNA genome of measles virus (MeV) is highly conserved at 15,894 nucleotides (nt). MeVs can be grouped into 24 genotypes based on the highly variable 450 nucleotides coding for the carboxyl-terminus of the nucleocapsid protein (N-450). Here, we report the genomic sequences of 2 wild-type viral isolates of genotype D4 with genome lengths of 15,900 nt. Both genomes had a 7 nt insertion in the 3' untranslated region (UTR) of the matrix (M) gene and a 1 nt deletion in the 5' UTR of the fusion (F) gene. The net gain of 6 nt complies with the rule-of-six required for replication competency of the genomes of morbilliviruses. The insertions and deletion (indels) were confirmed in a patient sample that was the source of one of the viral isolates. The positions of the indels were identical in both viral isolates, even though epidemiological data and the 3 nt differences in N-450 between the two genomes suggested that the viruses represented separate chains of transmission. Identical indels were found in the M-F intergenic regions of 14 additional genotype D4 viral isolates that were imported into the US during 2007-2010. Viral isolates with and without indels produced plaques of similar size and replicated efficiently in A549/hSLAM and Vero/hSLAM cells. This is the first report of wild-type MeVs with genome lengths other than 15,894 nt and demonstrates that the length of the M-F UTR of wild-type MeVs is flexible. |
Elimination of endemic measles, rubella, and congenital rubella syndrome from the Western hemisphere: the US experience.
Papania MJ , Wallace GS , Rota PA , Icenogle JP , Fiebelkorn AP , Armstrong GL , Reef SE , Redd SB , Abernathy ES , Barskey AE , Hao L , McLean HQ , Rota JS , Bellini WJ , Seward JF . JAMA Pediatr 2013 168 (2) 148-55 ![]() IMPORTANCE: To verify the elimination of endemic measles, rubella, and congenital rubella syndrome (CRS) from the Western hemisphere, the Pan American Health Organization requested each member country to compile a national elimination report. The United States documented the elimination of endemic measles in 2000 and of endemic rubella and CRS in 2004. In December 2011, the Centers for Disease Control and Prevention convened an external expert panel to review the evidence and determine whether elimination of endemic measles, rubella, and CRS had been sustained. OBJECTIVE: To review the evidence for sustained elimination of endemic measles, rubella, and CRS from the United States through 2011. DESIGN, SETTING, AND PARTICIPANTS: Review of data for measles from 2001 to 2011 and for rubella and CRS from 2004 to 2011 covering the US resident population and international visitors, including disease epidemiology, importation status of cases, molecular epidemiology, adequacy of surveillance, and population immunity as estimated by national vaccination coverage and serologic surveys. MAIN OUTCOMES AND MEASURES: Annual numbers of measles, rubella, and CRS cases, by importation status, outbreak size, and distribution; proportions of US population seropositive for measles and rubella; and measles-mumps-rubella vaccination coverage levels. RESULTS: Since 2001, US reported measles incidence has remained below 1 case per 1 000 000 population. Since 2004, rubella incidence has been below 1 case per 10 000 000 population, and CRS incidence has been below 1 case per 5 000 000 births. Eighty-eight percent of measles cases and 54% of rubella cases were internationally imported or epidemiologically or virologically linked to importation. The few cases not linked to importation were insufficient to represent endemic transmission. Molecular epidemiology indicated no endemic genotypes. The US surveillance system is adequate to detect endemic measles or rubella. Seroprevalence and vaccination coverage data indicate high levels of population immunity to measles and rubella. CONCLUSIONS AND RELEVANCE: The external expert panel concluded that the elimination of endemic measles, rubella, and CRS from the United States was sustained through 2011. However, international importation continues, and health care providers should suspect measles or rubella in patients with febrile rash illness, especially when associated with international travel or international visitors, and should report suspected cases to the local health department. |
Viruses detected among sporadic cases of parotitis, United States, 2009-2011
Barskey AE , Juieng P , Whitaker BL , Erdman DD , Oberste MS , Chern SW , Schmid DS , Radford KW , McNall RJ , Rota PA , Hickman CJ , Bellini WJ , Wallace GS . J Infect Dis 2013 208 (12) 1979-86 BACKGROUND: Sporadic cases of parotitis are generally assumed to be mumps, which often requires a resource-intensive public health response. This project surveyed the frequency of viruses detected among such cases. METHODS: During 2009-2011, 8 jurisdictions throughout the United States investigated sporadic cases of parotitis. Epidemiologic information, serum, and buccal and oropharyngeal swabs were collected. Polymerase chain reaction methods were used to detect a panel of viruses. Anti-mumps virus immunoglobulin M (IgM) antibodies were detected using a variety of methods. RESULTS: Of 101 specimens, 38 were positive for a single virus: Epstein-Barr virus (23), human herpesvirus (HHV)-6B (10), human parainfluenza virus (HPIV)-2 (3), HPIV-3 (1), and human bocavirus (1). Mumps virus, enteroviruses (including human parechovirus), HHV-6A, HPIV-1, and adenoviruses were not detected. Early specimen collection did not improve viral detection rate. Mumps IgM was detected in 17% of available specimens. Patients in whom a virus was detected were younger, but no difference was seen by sex or vaccination profile. No seasonal patterns were identified. CONCLUSIONS: Considering the timing of specimen collection, serology results, patient vaccination status, and time of year may be helpful in assessing the likelihood that a sporadic case of parotitis without laboratory confirmation is mumps. |
Estimates of mumps seroprevalence may be influenced by antibody specificity and serologic method
Latner DR , McGrew M , Williams NJ , Sowers SB , Bellini WJ , Hickman CJ . Clin Vaccine Immunol 2013 21 (3) 286-97 Neutralizing antibodies are assumed to be essential for protection against mumps virus infection, but their measurement is labor and time intensive. For this reason ELISA assays are typically used to measure mumps specific IgG. However, since there is poor correlation between mumps neutralization titers and ELISA assays that measure the presence of mumps specific IgG, ELISA assays that better correlate with neutralization are needed. To address this issue, we measured mumps antibody 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 ELISA may be overstated. |
Improving molecular tools for global surveillance of measles virus.
Bankamp B , Byrd-Leotis LA , Lopareva EN , Woo GK , Liu C , Jee Y , Ahmed H , Lim WW , Ramamurty N , Mulders MN , Featherstone D , Bellini WJ , Rota PA . J Clin Virol 2013 58 (1) 176-82 ![]() BACKGROUND: The genetic characterization of wild-type measles viruses plays an important role in the description of viral transmission pathways and the verification of measles elimination. The 450 nucleotides that encode the carboxyl-terminus of the nucleoprotein (N-450) are routinely sequenced for genotype analysis. OBJECTIVES: The objectives of this study were to develop improved primers and controls for RT-PCR reactions used for genotyping of measles samples and to develop a method to provide a convenient, safe, and inexpensive means to distribute measles RNA for RT-PCR assays and practice panels. STUDY DESIGN: A newly designed, genetically defined synthetic RNA and RNA isolated from cells infected with currently circulating genotypes were used to compare the sensitivity of primer pairs in RT-PCR and nested PCR. FTA(R) cards loaded with lysates of measles infected cells were tested for their ability to preserve viral RNA and destroy virus infectivity. RESULTS: A new primer pair, MeV216/MeV214, was able to amplify N-450 from viruses representing 10 currently circulating genotypes and a genotype A vaccine strain and demonstrated 100-fold increased sensitivity compared to the previously used primer set. A nested PCR assay further increased the sensitivity of detection from patient samples. A synthetic positive control RNA was developed that produced PCR products that are distinguishable by size from PCR products amplified from clinical samples. FTA(R) cards completely inactivated measles virus and stabilized RNA for at least six months. CONCLUSIONS: These improved molecular tools will advance molecular characterization of circulating measles viruses globally and provide enhanced quality control measures. |
Seroprevalence of measles, mumps and rubella among children in American Samoa, 2011, and progress towards West Pacific Region goals of elimination
Mahamud A , Masunu-Faleafaga Y , Walls L , Williams N , Garcia P , Teshale E , Williams R , Dulski T , Bellini WJ , Kutty PK . Vaccine 2013 31 (36) 3683-7 INTRODUCTION: In line with the global goals for measles elimination, countries in the West Pacific Region (WPR) have set a goal to eliminate measles by 2012. Due to its contagiousness, high population immunity is needed for achieving and documenting measles elimination. We assessed population immunity to measles, mumps and rubella among first grade children in American Samoa (AS) through a seroprevalance study. METHODS: Using commercial indirect enzyme-linked immunosorbant IgG assays (Wampole Laboratories, Cranbury, NJ) we determined IgG antibodies against the measles, mumps, and rubella (MMR) viruses in sera collected from first grade students in AS in April-May 2011. Vaccination status was retrieved from the immunization cards. Factors associated with seropositivity of measles, mumps, and rubella were analyzed separately. RESULT: Among 509 first grade students, measles, mumps, and rubella seroprevalence were 92%, 90%, and 93%, respectively. The proportions of first grade students with documented one or two doses of MMR vaccine were 93% and 84%, respectively. The vaccination status of 6% of the first graders was unknown and 1% was unvaccinated. Receiving two-doses of MMR vaccines was associated with high measles and mumps seropositivity (p<0.01). CONCLUSION: The high measles seroprevalence among children shows the progress by American Samoa towards measles elimination. Achieving and maintaining high two-dose MMR vaccine coverage in all age groups will aid in attaining the measles elimination status and prevent transmission of measles from potential imported measles cases from other countries. |
Cell culture and electron microscopy for identifying viruses in diseases of unknown cause
Goldsmith CS , Ksiazek TG , Rollin PE , Comer JA , Nicholson WL , Peret TC , Erdman DD , Bellini WJ , Harcourt BH , Rota PA , Bhatnagar J , Bowen MD , Erickson BR , McMullan LK , Nichol ST , Shieh WJ , Paddock CD , Zaki SR . Emerg Infect Dis 2013 19 (6) 864-9 During outbreaks of infectious diseases or in cases of severely ill patients, it is imperative to identify the causative agent. This report describes several events in which virus isolation and identification by electron microscopy were critical to initial recognition of the etiologic agent, which was further analyzed by additional laboratory diagnostic assays. Examples include severe acute respiratory syndrome coronavirus, and Nipah, lymphocytic choriomeningitis, West Nile, Cache Valley, and Heartland viruses. These cases illustrate the importance of the techniques of cell culture and electron microscopy in pathogen identification and recognition of emerging diseases. |
Poor immune responses of newborn rhesus macaques to measles virus DNA vaccines expressing the hemagglutinin and fusion glycoproteins.
Polack FP , Lydy SL , Lee SH , Rota PA , Bellini WJ , Adams RJ , Robinson HL , Griffin DE . Clin Vaccine Immunol 2013 20 (2) 205-10 ![]() A vaccine that would protect young infants against measles could facilitate elimination efforts and decrease morbidity and mortality in developing countries. However, immaturity of the immune system is an important obstacle to the development of such a vaccine. In this study, DNA vaccines expressing the measles virus (MeV) hemagglutinin (H) protein or H and fusion (F) proteins, previously shown to protect juvenile macaques, were used to immunize groups of 4 newborn rhesus macaques. Monkeys were inoculated intradermally with 200 mcg of each DNA at birth and at 10 months of age. As controls, 2 newborn macaques were similarly vaccinated with DNA encoding the influenza virus H5, and 4 received one dose of the current live attenuated MeV vaccine (LAV) intramuscularly. All monkeys were monitored for development of MeV-specific neutralizing and binding IgG antibody and cytotoxic T lymphocyte (CTL) responses. These responses were poor compared to the responses induced by LAV. At 18 months of age, all monkeys were challenged intratracheally with a wild-type strain of MeV. Monkeys that received the DNA vaccine encoding H and F, but not H alone, were primed for an MeV-specific CD8(+) CTL response but not for production of antibody. LAV-vaccinated monkeys were protected from rash and viremia, while DNA-vaccinated monkeys developed rashes, similar to control monkeys, but had 10-fold lower levels of viremia. We conclude that vaccination of infant macaques with DNA encoding MeV H and F provided only partial protection from MeV infection. |
Analysis of whole genome sequences of 16 strains of rubella virus from the United States, 1961-2009.
Abernathy E , Chen MH , Bera J , Shrivastava S , Kirkness E , Zheng Q , Bellini W , Icenogle J . Virol J 2013 10 32 ![]() Rubella virus is the causative agent of rubella, a mild rash illness, and a potent teratogenic agent when contracted by a pregnant woman. Global rubella control programs target the reduction and elimination of congenital rubella syndrome. Phylogenetic analysis of partial sequences of rubella viruses has contributed to virus surveillance efforts and played an important role in demonstrating that indigenous rubella viruses have been eliminated in the United States. Sixteen wild-type rubella viruses were chosen for whole genome sequencing. All 16 viruses were collected in the United States from 1961 to 2009 and are from 8 of the 13 known rubella genotypes. Phylogenetic analysis of 30 whole genome sequences produced a maximum likelihood tree giving high bootstrap values for all genotypes except provisional genotype 1a. Comparison of the 16 new complete sequences and 14 previously sequenced wild-type viruses found regions with clusters of variable amino acids. The 5' 250 nucleotides of the genome are more conserved than any other part of the genome. Genotype specific deletions in the untranslated region between the non-structural and structural open reading frames were observed for genotypes 2B and genotype 1G. No evidence was seen for recombination events among the 30 viruses. The analysis presented here is consistent with previous reports on the genetic characterization of rubella virus genomes. Conserved and variable regions were identified and additional evidence for genotype specific nucleotide deletions in the intergenic region was found. Phylogenetic analysis confirmed genotype groupings originally based on structural protein coding region sequences, which provides support for the WHO nomenclature for genetic characterization of wild-type rubella viruses. |
- Page last reviewed:Feb 1, 2024
- Page last updated:Jan 27, 2025
- Content source:
- Powered by CDC PHGKB Infrastructure