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1.  Subacute Sclerosing Panencephalitis in Papua New Guinean Children: The Cost of Continuing Inadequate Measles Vaccine Coverage 
Introduction
Subacute sclerosing panencephalitis (SSPE) is a late, rare and usually fatal complication of measles infection. Although a very high incidence of SSPE in Papua New Guinea (PNG) was first recognized 20 years ago, estimated measles vaccine coverage has remained at ≤70% since and a large measles epidemic occurred in 2002. We report a series of 22 SSPE cases presenting between November 2007 and July 2009 in Madang Province, PNG, including localized clusters with the highest ever reported annual incidence.
Methodology/Principal Findings
As part of a prospective observational study of severe childhood illness at Modilon Hospital, the provincial referral center, children presenting with evidence of meningo-encephalitis were assessed in detail including lumbar puncture in most cases. A diagnosis of SSPE was based on clinical features and presence of measles-specific IgG in cerebrospinal fluid and/or plasma. The estimated annual SSPE incidence in Madang province was 54/million population aged <20 years, but four sub-districts had an incidence >100/million/year. The distribution of year of birth of the 22 children with SSPE closely matched the reported annual measles incidence in PNG, including a peak in 2002.
Conclusions/Significance
SSPE follows measles infections in very young PNG children. Because PNG children have known low seroconversion rates to the first measles vaccine given at 6 months of age, efforts such as supplementary measles immunisation programs should continue in order to reduce the pool of non-immune people surrounding the youngest and most vulnerable members of PNG communities.
Author Summary
Subacute sclerosing panencephalitis (SSPE) is a disabling and usually fatal brain disorder that typically occurs 3–10 years after acute measles infection. Papua New Guinea (PNG) has particularly high rates of SSPE. We report 22 cases of PNG children presenting to the provincial referral hospital in Madang Province who probably contracted acute measles when <12 months of age during a national epidemic in 2002 and who developed SSPE 5–7 years later. Based on these cases, the estimated annual SSPE incidence in Madang province in 2007–2009 was 54/million population aged <20 years. Four sub-districts had an annual incidence >100/million population aged <20 years, the highest rates ever reported. Young PNG children do not respond well to measles vaccine. Because of this, efforts such as supplementary measles immunisation programs should continue in order to reduce the pool of non-immune older people surrounding the youngest and most vulnerable members of PNG communities.
doi:10.1371/journal.pntd.0000932
PMCID: PMC3014974  PMID: 21245918
2.  Case Based Surveillance for Measles in Lagos, South Western Nigeria, September 2011 
Objective
The objective of this study was to describe the performance of the measles surveillance in Lagos, characterize the epidemiologic pattern of measles infection and determine the measles vaccine efficacy.
Introduction
Measles is a vaccine preventable disease that has been successfully eliminated in some parts of the world. It causes high morbidity and mortality with the potential of large outbreaks. About a third of reported measles cases involve one or more complications including diarrhea, pneumonia, otitis media, blindness, post infections encephalitis and subacute sclerosing panencephalitis. It is however, one of the leading causes of childhood morbidity and mortality in Nigeria despite availability of safe and effective vaccines
Methods
We obtained the measles surveillance data for all the 20 Local Governments Areas (LGAs) in Lagos and reviewed all the measles case based investigation forms between the period 1st January to 31st December 2010.The WHO Recommended Surveillance Standards for Measles was used. Data was analyzed using EPI INFO version 3.5.3.
Results
Of the 615 suspected measles cases, 63(10.2%) were laboratory confirmed (measles IGM+) and 3(0.5%) clinically confirmed. Cases investigated within 48 hours was 222 (36%) (target ≥ 80%), 510 (83%) had adequate blood sample collected (target ≥ 80%) and 595 (97%) of sample results were received from the lab within 7 days (target ≥ 80%). The surveillance system sensitivity was 6.5/100,000 (target >2/100,000) with a predictive value positive of 10.73%. The overall attack rate was 0.73/100,000 population with 1 mortality (case fatality rate 1.5%). The Under 1 year attack rate (8.33/100,000) was higher than the 1– 4 years attack rate (3.48/100,000) (p= 0.01). Those vaccinated with at least 1 dose of measles vaccine had a 3 times lower risk of measles infection than the unvaccinated. The proportion of unvaccinated cases was 36%. The measles vaccine efficacy was 60%.
Conclusions
The quality of surveillance need to be strengthened by improving the time lapse between notification and investigation of suspected cases. Measles is still a significant cause of morbidity particularly among the under 1 year age group.The proportion of unvaccinated cases is also high, suggesting a low vaccine coverage among susceptibles.
Prompt investigation of cases, good vaccine coverage and high vaccine efficacy are all vital in eliminating measles from Nigeria.
Morbidity and Mortality rates
No of Reported Measles Cases in Lagos, South Western Nigeria by LGA with onset date from 1st January – 31st December 2010
Legend
PMCID: PMC3692800
Surveillance; Measles; Case based; Lagos
3.  Comparison of wild-type and subacute sclerosing panencephalitis strains of measles virus. Neurovirulence in ferrets and biological properties in cell cultures 
The neurovirulence of two wild type (wt) and seven Subacute Sclerosing Panencephalitis (SSPE) measles virus strains was tested in young adult ferrets by intracerebral (IC) inoculation of infected Vero cell suspensions. Wt strains Edmonston and Woodfolk and SSPE strains Mantooth, Halle, and LEC-S did not produce a detectable encephalitis in the ferrets, but caused a significant formation of serum antibodies against measles virus. SSPE strains LEC, IP-3, Biken, and D.R., on the other hand, were all neurovirulent in ferrets, particularly strain D.R. which caused an acute encephalitis in all inoculated animals. Strain Biken was of particular interest since it caused a subacute encephalitis in four of seven ferrets. The subacute encephalitis was characterized by a long incubation time, persistence of virus in the brain for at least 8 mo, widespread inflammatory lesions, and production of measles virus specific IgG in the brain. A study of the biological properties of the various measles virus strains showed that wt strains Edmonston and Woodfolk and SSPE strains Mantooth, Halle, and LEC-S produced free virus particles in significant titers both in Vero and ferret brain (FB) cultures. Cytopathic effect (CPE) with cell- fusion was marked in Vero cultures, whereas only minimal CPE and no cell-fusion were observed in the FB cultures. SSPE strains LEC, IP-3, Biken, and D.R., on the other hand, were mostly cell-associated in Vero and FB cultures, although atypical cell-free particles were produced by strains Biken and IP-3. All four strains showed cell-fusing activity in FB cultures, particularly strain D.R., which was the only strain that spread more actively by fusion in FB than in Vero cultures. The results are discussed in relation to the neurovirulence of the various measles virus strains in adult ferrets. Pronounced cell-fusing activity in FB cells and cell-association with minimal or no production of cell-free virus seem to be essential to establish a brain infection in the animals.
PMCID: PMC2185000  PMID: 702052
4.  Unacceptably High Mortality Related to Measles Epidemics in Niger, Nigeria, and Chad 
PLoS Medicine  2007;4(1):e16.
Background
Despite the comprehensive World Health Organization (WHO)/United Nations Children's Fund (UNICEF) measles mortality–reduction strategy and the Measles Initiative, a partnership of international organizations supporting measles mortality reduction in Africa, certain high-burden countries continue to face recurrent epidemics. To our knowledge, few recent studies have documented measles mortality in sub-Saharan Africa. The objective of our study was to investigate measles mortality in three recent epidemics in Niamey (Niger), N'Djamena (Chad), and Adamawa State (Nigeria).
Methods and Findings
We conducted three exhaustive household retrospective mortality surveys in one neighbourhood of each of the three affected areas: Boukoki, Niamey, Niger (April 2004, n = 26,795); Moursal, N'Djamena, Chad (June 2005, n = 21,812); and Dong District, Adamawa State, Nigeria (April 2005, n = 16,249), where n is the total surveyed population in each of the respective areas. Study populations included all persons resident for at least 2 wk prior to the study, a duration encompassing the measles incubation period. Heads of households provided information on measles cases, clinical outcomes up to 30 d after rash onset, and health-seeking behaviour during the epidemic. Measles cases and deaths were ascertained using standard WHO surveillance-case definitions. Our main outcome measures were measles attack rates (ARs) and case fatality ratios (CFRs) by age group, and descriptions of measles complications and health-seeking behaviour. Measles ARs were the highest in children under 5 y old (under 5 y): 17.1% in Boukoki, 17.2% in Moursal, and 24.3% in Dong District. CFRs in under 5-y-olds were 4.6%, 4.0%, and 10.8% in Boukoki, Moursal, and Dong District, respectively. In all sites, more than half of measles cases in children aged under 5 y experienced acute respiratory infection and/or diarrhoea in the 30 d following rash onset. Of measles cases, it was reported that 85.7% (979/1,142) of patients visited a health-care facility within 30 d after rash onset in Boukoki, 73.5% (519/706) in Moursal, and 52.8% (603/1,142) in Dong District.
Conclusions
Children in these countries still face unacceptably high mortality from a completely preventable disease. While the successes of measles mortality–reduction strategies and progress observed in measles control in other countries of the region are laudable and evident, they should not overshadow the need for intensive efforts in countries that have just begun implementation of the WHO/UNICEF comprehensive strategy.
Three household retrospective mortality surveys in parts of West Africa affected by recent measles epidemics found that, despite progress made elsewhere, mortality rates remain unacceptably high.
Editors' Summary
Background.
In most developed countries, measles is often now regarded as an uncommon and not very serious childhood illness. The situation in developing countries is totally different; many children get measles, and the consequences can be severe. The main factor accounting for this difference is the much greater availability of vaccination against measles in developed countries. Globally, approximately 410,000 children under the age of 5 y die of measles each year. In developing countries, the death rate among children with measles is 1%–5%, but in refugee situations and among malnourished children, it may reach 10%–30%. The complications of the disease include pneumonia, diarrhea, encephalitis, and corneal scarring, which can lead to blindness. It costs less than US$1 to vaccinate a child against measles but, tragically, it remains the leading cause of vaccine-preventable death among children.
Why Was This Study Done?
There are many national and international initiatives intended to improve measles vaccination rates, and in many developing countries things are improving; measles death rates in Africa as a whole are believed to be less than half of what they were 10 y ago. However, in certain countries—for example in West Africa—serious measles epidemics do still occur. It has been some years since any major studies have been conducted to try to establish how many children die during these epidemics. It is important to know this in order to help with efforts to improve the situation.
What Did the Researchers Do and Find?
They focused on three epidemics of measles in West Africa and their impact on one neighborhood in each of three countries that were severely affected: Chad, Niger, and Nigeria. The total population of these neighborhoods was more than 64,000. The researchers spoke to the heads of households and asked for information about measles cases. They recorded details of symptoms of children who were taken ill during the epidemic and the outcome, including deaths. They also noted what action families took when children had measles. The percentage of children who developed measles was around 17% in the neighborhoods in Chad and Niger, and 24% in the Nigerian neighborhood. The death rate among the children who had measles was around 4% in Chad and Niger, and 11% in Nigeria. Most parents took their children to a health-care facility within 30 d of a rash appearing but this varied: 86% did so in Chad, 74% in Niger, and 53% in Nigeria.
What Do These Findings Mean?
Children in these countries still face an unacceptably high risk of death from a completely preventable disease. Much more needs to be done to increase the number of children who are vaccinated.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040016
Wikipedia information on measles (note that Wikipedia is an online encyclopedia that anyone can edit)
More detailed information on measles may be obtained from MedlinePlus and the World Health Organization
Information about the Measles Initiative
For information about the three countries in this study, consult their country profiles on the BBC website: Chad, Niger, and Nigeria.
doi:10.1371/journal.pmed.0040016
PMCID: PMC1761051  PMID: 17199407
5.  Local public health response to vaccine-associated measles: case report 
BMC Public Health  2013;13:269.
Background
The most appropriate public health approach to vaccine-associated measles in immunocompromised patients is unknown, mainly because these cases are rare and transmission of vaccine-associated measles has not been previously documented. In this case report, we describe Peel Public Health’s response to a vaccine-associated measles case in an immunocompromised child in Ontario, Canada.
Case presentation
A five-year-old Canadian-born boy with a history of a hematopoetic stem cell transplant three years previously received live attenuated measles, mumps, and rubella (MMR) vaccine. Over the subsequent 7 to 14 days, he developed an illness clinically consistent with measles. There was no travel history or other measles exposure. Serology and polymerase chain reaction (PCR) testing confirmed acute measles infection. Following discussion with pediatric infectious diseases specialists, but prior to the availability of virus sequencing, it was felt that this case was most likely due to vaccine strain. Although no microbiologically confirmed secondary cases of vaccine-associated measles have been previously described, we sent notification letters to advise all contacts of measles symptoms since the likelihood of transmission from an immunocompromised patient was low, but theoretically possible. We decided to stratify contacts into immune competent and compromised and to deal with the latter group conservatively by excluding them as if they were exposed to wild-type measles because the risk of transmission of disease in this population, while presumably very low, is unknown. However, no contacts self-identified as immunocompromised and there were no secondary cases. Subsequent genotyping confirmed that this case was caused by vaccine strain measles virus.
Conclusion
The public health approach to contact tracing and exclusions for vaccine-associated measles in immunocompromised patients is unclear. The rarity of secondary cases provides further evidence that the risk to the general public is likely extremely low. Although the risk appears negligible, exclusion and administration of immune globulin may be considered for susceptible, immunocompromised contacts of cases of vaccine-associated measles in immunocompromised patients.
doi:10.1186/1471-2458-13-269
PMCID: PMC3623646  PMID: 23531102
(3–10): measles; Immunization; Vaccine associated; Vaccine strain; Contact tracing; Adverse event
6.  Performance and reliability of the Enzygnost measles enzyme-linked immuno-sorbent assay for detection of measles virus-specific immunoglobulin M antibody during a large measles epidemic. 
Journal of Clinical Microbiology  1992;30(3):564-569.
Evaluation of the Enzygnost Measles Enzyme-Linked Immuno-Sorbent Assay kit (Behring) performance to detect specific immunoglobulin M (IgM) was carried out with 3,297 single serum samples and 898 paired serum samples collected during a measles epidemic (10,184 reported cases) in Quebec, Canada. Anti-measles IgM and IgG were detected by using the Enzygnost kit with the appropriate conjugates. Complement-fixing (CF) antibody (Ab) titers were assessed by the laboratory branch complement fixation micromethod. The Centers for Disease Control's clinical measles case definition was used. A modification of the manufacturer's optical density interpretation algorithm was introduced to allow for equivocal results, in addition to positive and negative ones. These three categories differed as to their association with a significant increase in CF Ab titer and the time between the onset of symptoms and phlebotomy. The IgM positivity rate for complement fixation-confirmed measles cases was 96.6% for vaccinated subjects and 100% for nonvaccinated subjects. The daily percentage of IgM seropositivity that was detected for subjects who became IgM positive within 30 days increased gradually from 40 to 90% for sera taken 1 to 7 days after the onset of symptoms, and it plateaued at 100% for sera taken 16 to 30 days after the onset of symptoms. IgM seropositivity was strongly associated with IgG seroconversion, CF Ab titer increase, and clinical measles (P less than 0.0001). Reproducibility was 100% for nonreactive sera and 99.1% for reactive sera. In conclusion, the Enzygnost Measles Enzyme-Linked Immuno-Sorbent Assay kit performed adequately to confirm measles virus infection during this epidemic. A second serum sample should be tested when an early-acute-phase serum sample is IgM negative.
PMCID: PMC265110  PMID: 1551971
7.  Characterization of Measles Virus-Specific Proteins Synthesized In Vivo and In Vitro from Acutely and Persistently Infected Cells 
Journal of Virology  1979;29(3):1099-1106.
Measles virus protein synthesis has been analyzed in acutely and persistently infected cells. To assess the role of measles in subacute sclerosing panencephalitis (SSPE), measles viral proteins synthesized in vivo or in vitro were tested for reactivity with serum from a guinea pig(s) immunized with measles virus and sera from patients with SSPE. Guinea pig antimeasles virus serum immunoprecipitates the viral polypeptides of 78,000 molecular weight (glycosylated [G]), 70,000 molecular weight (phosphorylated [P]), 60,000 molecular weight (nucleocapsid [N]), and 35,000 molecular weight (matrix [M]) from cells acutely infected with measles virus as well as from chronically infected cells, but in the latter case, immunoprecipitated M protein has a reduced electrophoretic migration. Sera of SSPE patients immunoprecipitated all but the G protein in acutely infected cells and only the P and N proteins from chronically infected cells. In immunoprecipitates of viral polypeptides synthesized in a reticulocyte cell-free translation system, in response to mRNA from acutely or persistently infected cells, the 78,000-molecular-weight form of the G protein was not detected among the cell-free products of either mRNA. Guinea pig antimeasles virus serum immunoprecipitated P, N, and M polypeptides from the products of either form of mRNA, whereas SSPE serum immunoprecipitated the P and N polypeptides but not the M polypeptide. The differences in immunoreactivity of the antimeasles virus antiserum and the SSPE serum are discussed in terms of possible modifications of measles virus proteins in SSPE.
Images
PMCID: PMC353270  PMID: 448796
8.  Western blot analyses of measles virus antibody in normal persons and in patients with multiple sclerosis, subacute sclerosing panencephalitis, or atypical measles. 
Journal of Clinical Microbiology  1986;24(3):324-329.
A version of the Western blot was developed to detect serum antibodies against measles virus polypeptides. With this technique, a seroepidemiological survey of antibodies to the several measles virus proteins in diverse measles-related conditions was conducted. The sera were obtained from individuals with a recent or long-past history of natural measles, from persons with a history of immunization with live attenuated measles vaccine, and from patients with multiple sclerosis, subacute sclerosing panencephalitis, or atypical measles. The findings indicated that live attenuated measles vaccine elicits an antibody response qualitatively resembling that of a natural infection. In addition, multiple sclerosis patients made less antibody to the measles virus M protein than did individuals with a long-past history of natural measles. Thus, the immunological reaction of multiple sclerosis patients to measles virus is qualitatively, as well as quantitatively, different from that of normal persons. Finally, persons with subacute sclerosing panencephalitis and atypical measles mounted abnormally high antibody responses to measles virus polypeptides, in particular the P protein.
PMCID: PMC268906  PMID: 3531224
9.  Obstacles in measles elimination: an in-depth description of a measles outbreak in Ghent, Belgium, spring 2011 
Archives of Public Health  2013;71(1):17.
Background
From Mid-February to April 2011 one of the largest measles-outbreak in Flanders, since the start of the 2-dose vaccination scheme in 1995, took place in Ghent, Belgium. The outbreak started in a day care center, infecting children too young to be vaccinated, after which it spread to anthroposophic schools with a low measles, mumps and rubella vaccination coverage. This report describes the outbreak and evaluates the control measures and interventions.
Methods
Data collection was done through the system of mandatory notification of the public health authority. Vaccination coverage in the schools was assessed by a questionnaire and the electronic immunization database ‘Vaccinnet’. A case was defined as anyone with laboratory confirmed measles or with clinical symptoms and an epidemiological link to a laboratory confirmed case. Towards the end of the outbreak we only sought laboratory confirmation for persons with an atypical clinical presentation or without an epidemiological link. In search for an index patient we determined the measles IgG level of infants from the day care center.
Results
A total of 65 cases were reported of which 31 were laboratory confirmed. Twenty-five were confirmed by PCR and/or IgM. In 6 infants, too young to be vaccinated, only elevated measles IgG levels were found. Most cases (72%) were young children (0–9 years old). All but two cases were completely unimmunized. In the day care center all the infants who were too young to be vaccinated (N=14) were included as cases. Thirteen of them were laboratory confirmed. Eight of these infants were hospitalized with symptoms suspicious for measles. Vaccination coverage in the affected anthroposophic schools was low, 45-49% of the pupils were unvaccinated. We organized vaccination campaigns in the schools and vaccinated 79 persons (25% of those unvaccinated or incompletely vaccinated).
Conclusions
Clustering of unvaccinated persons, in a day care center and in anthroposophic schools, allows for measles outbreaks and is an important obstacle for the elimination of measles. Isolation measures, a vacation period and an immunization campaign limited the spread of measles within the schools but could not prevent further spread among unvaccinated family members. It was necessary to raise clinicians' awareness of measles since it had become a rare, less known disease and went undiagnosed.
doi:10.1186/0778-7367-71-17
PMCID: PMC3716678  PMID: 23834074
Outbreak; Vaccine-preventable-disease; Measles; Immunization registry; Anti-vaccination
10.  Immunoglobulin G avidity testing in serum and cerebrospinal fluid for analysis of measles virus infection. 
We studied a variety of patients with measles virus infection by using avidity testing for measles virus-specific immunoglobulin G (IgG) in serum and cerebrospinal fluid samples. For the avidity testing, an Enzygnost measles IgG enzyme-linked immunosorbent assay kit was used with an 8 M urea denaturing method. With this method, low-avidity IgG (acute primary infection, avidity of < 30% within 15 days of the onset of rash) and high-avidity IgG (subacute sclerosing panencephalitis, avidity of > 75%) could be clearly distinguished by using serum samples. One patient, who developed a typical course of measles despite a previous vaccination, showed a positive IgM response with an initial low titer of measles virus-specific IgG of low avidity, but a later sample revealed a high titer of IgG of intermediate (40%) avidity, suggesting previous immunological priming. Two patients with breakthrough infection (secondary vaccine failure), both having central nervous system involvement, showed a positive IgM response with initial high titers of serum IgG of high avidity. In addition, one of the patients had a detectable level of measles-specific IgG in cerebrospinal fluid. In this patient, the avidity of both serum and cerebrospinal fluid IgG decreased during the short follow-up period. This phenomenon has never before been reported. In subacute sclerosing panencephalitis patients, the avidity of cerebrospinal fluid IgG was consistently lower than that of serum IgG. The difference in avidity between cerebrospinal fluid and serum IgG may be used as a direct indicator of intrathecal production of IgG. In conclusion, the avidity testing is simple to perform, reliable, and highly informative in the analysis of measles virus infection.
PMCID: PMC170280  PMID: 8991638
11.  Subacute sclerosing panencephalitis virus dominantly interferes with replication of wild-type measles virus in a mixed infection: implication for viral persistence. 
Journal of Virology  1992;66(4):1891-1898.
Interaction between the Edmonston or Nagahata strain of acute measles virus (MV) and the defective Biken strain of MV isolated from a patient with subacute sclerosing panencephalitis (SSPE) was examined by a cell fusion protocol. Biken-CV-1 cells nonproductively infected with Biken strain SSPE virus were fused with neomycin-resistant CV-1 cells. All the fused cells selected with the neomycin analog G418 expressed Biken viral proteins, as determined by an immunofluorescence assay. This procedure enabled the transfer of Biken viral genomes into cells previously infected with MV. In the fused cells coinfected by Biken strain SSPE virus and Edmonston or Nagahata strain MV, early MV gene expression was suppressed, as determined by immunoprecipitation with strain-specific antibodies. Maturation of Edmonston strain MV was also suppressed. When the coinfected fused cells were selected with G418, Biken viral proteins remained at a constant level for up to 7 weeks. Wild-type MV proteins gradually decreased to a barely detectable level after 4 weeks and became undetectable after 7 weeks. Immunofluorescence studies showed a steady decline in cells expressing wild-type MV proteins in the coinfected cultures. These results suggest that Biken strain SSPE virus dominantly interferes with the replication of wild-type MV. The possible mechanisms of dominant interference and the implication for evolution of a persistent MV infection are discussed.
Images
PMCID: PMC288976  PMID: 1548746
12.  Antibodies against measles virus polypeptides in different disease conditions. 
Infection and Immunity  1981;34(3):718-724.
The occurrence of antibodies to the nucleoprotein and matrix (M) antigens of measles virus was determined in early and late measles convalescent sera and in sera from patients with multiple sclerosis, subacute sclerosing panencephalitis, chronic active hepatitis, and atypical measles. Antibodies to the two components were identified separately in serially diluted samples both by radioimmune precipitation assays and by complement fixation tests employing purified nucleoprotein and M components as antigens. The antibody response to M antigen in connection with acute infections was weak, and with time titers of antibodies to M antigen were reduced below detectable levels in most cases. A different situation was seen in patients with atypical measles. A pronounced antibody response to M antigen was shown to be a part of the generally accentuated immune response in these patients. Confirming results of others, it was shown that in spite of the increased antibody titers against most measles components in sera from patients with subacute sclerosing panencephalitis, no or only low titers of antibodies to M antigen were present. However, a similar representation of antibodies to measles virus components was also seen in sera from patients with active chronic hepatitis. The significance of this finding for the interpretation of a weak antibody response to M antigen in the presence of a pronounced antibody response to other components is discussed.
Images
PMCID: PMC350930  PMID: 7333668
13.  Measles encephalitis during immunosuppressive treatment for acute lymphoblastic leukaemia. 
Archives of Disease in Childhood  1993;68(6):775-778.
Between 1971 and 1989 measles encephalitis was identified in five children receiving chemotherapy for acute lymphoblastic leukaemia. Review of these and previously reported cases of measles encephalitis in immunosuppressed patients failed to identify any pathognomonic features in the history, the clinical presentation, or the results of electroencephalography or computed tomography. Detection of measles virus antigen in nasopharyngeal secretions or intrathecal synthesis of specific antibody was not possible in all instances. Early diagnosis by direct detection of viral antigen in the brain was confounded by difficulties in identifying areas of the brain suitable for biopsy. Increasing herd immunity to measles in the general population by vaccination is the only effective intervention against measles encephalitis in immunosuppressed children. Measles encephalitis must be remembered as a possible explanation of encephalopathy in the immunocompromised child: the benefits of early use of antiviral agents need to be evaluated.
PMCID: PMC1029373  PMID: 8333771
14.  Reasons for non-uptake of measles, mumps, and rubella catch up immunisation in a measles epidemic and side effects of the vaccine. 
BMJ : British Medical Journal  1995;310(6995):1629-1632.
OBJECTIVE--To investigate the reasons for poor uptake of immunisation (non-immunisation) and the possible side effects of measles, mumps, and rubella vaccine in a catch up immunisation campaign during a community outbreak of measles. DESIGN--Descriptive study of reasons for non-immunisation and retrospective cohort study of side effects of the vaccine. SETTING--Secondary schools in South Glamorgan. SUBJECTS--Random cluster sample of the parents of 500 children targeted but not immunised and a randomised sample of 2866 of the children targeted. MAIN OUTCOME MEASURES--Reasons for non-immunisation; symptoms among immunised and non-immunised children. RESULTS--Immunisation coverage of the campaign was only 43.4% (7633/17,595). The practical problems experienced included non-return of consent forms (6698/17,595), refusal of immunisation (2061/10,897 forms returned), and absence from school on day of immunisation (1203/8836 children with consent for immunisation). The most common reasons cited for non-immunisation were previous measles infection (145/232), previous immunisation against measles (78/232), and concern about side effects (55/232). Symptoms were equally common among immunised and non-immunised subjects. However, significantly more immunised boys than non-immunised boys reported fever (relative risk 2.31 (95% confidence interval 1.36 to 3.93)), rash (2.00 (1.10 to 3.64), joint symptoms (1.58; 1.05 to 2.38), and headache (1.31 (1.04 to 1.65)). CONCLUSIONS--Many of the objections raised by parents could be overcome by emphasising that primary immunisation does not necessarily confer immunity and that diagnosis of measles is unreliable. Measles, mumps, and rubella vaccine is safe in children aged 11-15.
PMCID: PMC2550008  PMID: 7795447
15.  Measles Virus IgG Avidity Assay for Use in Classification of Measles Vaccine Failure in Measles Elimination Settings 
Clinical and Vaccine Immunology : CVI  2012;19(11):1810-1817.
In regions where endemic measles virus has been eliminated, diagnostic assays are needed to assist in correctly classifying measles cases irrespective of vaccination status. A measles IgG avidity assay was configured using a commercially available measles-specific IgG enzyme immunoassay by modifying the protocol to include three 5-min washes with diethylamine (60 mM; pH 10.25) following serum incubation; serum was serially diluted, and the results were expressed as the end titer avidity index. Receiver operating characteristic analysis was used for evaluation and validation and to establish low (≤30%) and high (≥70%) end titer avidity thresholds. Analysis of 319 serum specimens expected to contain either high- or low-avidity antibodies according to clinical and epidemiological data indicated that the assay is highly accurate, with an area under the curve of 0.998 (95% confidence interval [CI], 0.978 to 1.000), sensitivity of 91.9% (95% CI, 83.2% to 97.0%), and specificity of 98.4% (95% CI, 91.6% to 100%). The assay is rapid (<2 h) and precise (standard deviation [SD], 4% to 7%). In 18 samples from an elimination setting outbreak, the assay identified 2 acute measles cases with low-avidity results; both were IgM-positive samples. Additionally, 11 patients (15 samples) with modified measles who were found to have high-avidity IgG results were classified as secondary vaccine failures; one sample with an intermediate-avidity result was not interpretable. In elimination settings, measles IgG avidity assays can complement existing diagnostic tools in confirming unvaccinated acute cases and, in conjunction with adequate clinical and epidemiologic investigation, aid in the classification of vaccine failure cases.
doi:10.1128/CVI.00406-12
PMCID: PMC3491540  PMID: 22971778
16.  Subacute sclerosing panencephalitis: measles encephalitis of temperate evolution 
Postgraduate Medical Journal  1969;45(524):401-407.
Subacute sclerosing panencephalitis is a rare disorder of late childhood and early adolescence Affected patients usually show behavioural and intellectual disturbance and involuntary movements before dying in coma after about 12 months. At some stage most have characteristic electroencephalographic abnormalities. Pathologically, changes in the brain are those of subacute encephalitis with a variable gliosis of the white matter, and sometimes intranuclear inclusion bodies in neurones and glial cells.
Recent studies in many patients have shown high levels of circulating anti-measles antibodies, measles antigen in cells in the brain, and sometimes, myxo-virus filaments in cells there. These findings suggest that SSPE may be a slow measles virus infection of the nervous system. Possible explanations for the slow evolution of the encephalitis include disordered immune mechanisms and intracellular persistence of virus in a defective phase.
Images
PMCID: PMC2466721  PMID: 5798690
17.  Comparison of LiST measles mortality model and WHO/IVB measles model 
BMC Public Health  2011;11(Suppl 3):S33.
Background
The Lives Saved Tool (LiST) has been developed to estimate the impact of health interventions and can consider multiple interventions simultaneously. Given its increasing usage by donor organizations and national program planner, we compare the LiST measles model to the widely used World Health Organization's Department of Immunization, Vaccines and Biologicals (WHO/IVB) measles model which is used to produce estimates serving as a major indicator of monitoring country measles epidemics and the progress of measles control.
Methods
We analyzed the WHO/IVB models and the LiST measles model and identified components and assumptions held in each model. We contrasted the important components, and compared results from the two models by applying historical measles containing vaccine (MCV) coverages and the default values of all parameters set in the models. We also conducted analyses following a hypothetical scenario to understand how both models performed when the proportion of population protected by MCV declined to zero percent in short time period.
Results
The WHO/IVB measles model and the LiST measles model structures differ: the former is a mixed model which applies surveillance data adjusted for reporting completeness for countries with good disease surveillance system and applies a natural history model for countries with poorer disease control program and surveillance system, and the latter is a cohort model incorporating country-specific cause-of-death (CoD) profiles among children under-five. The trends of estimates of the two models are similar, but the estimates of the first year are different in most of the countries included in the analysis. The two models are comparable if we adjust the measles CoD in the LiST to produce the same baseline estimates. In addition, we used the models to estimate the potential impact of stopping using measles vaccine over a 7-year period. The WHO/IVB model produced similar estimates to the LiST model with adjusted CoD. But the LiST model produced low estimates for countries with very low or eliminated measles infection that may be inappropriate.
Conclusions
The study presents methodological and quantitative comparisons between the WHO/IVB and the LiST measles models that highlights differences in model structures and may help users to better interpret and contrast estimates of the measles death from the two models. The major differences are resulted from the usage of case-fatality rate (CFR) in the WHO/IVB model and the CoD profile in the LiST. Both models have their own advantages and limitations. Users should be aware of the issue and apply as update country parameters as possible. Advanced models are expected to validate the policy-planning tools in the future.
doi:10.1186/1471-2458-11-S3-S33
PMCID: PMC3231907  PMID: 21501452
18.  Practical Observations from an Epidemiological Investigation of a Measles Outbreak in a District of India 
Background:
Measles is a major cause of childhood morbidity and mortality, accounting for nearly half of the morbidity associated with global vaccine preventable diseases. Regular outbreaks of Measles are reported in India, of which only a few are investigated. This study was conducted in the Shivpuri District of Madhya Pradesh (India) to investigate and asses various epidemiological factors associated with measles outbreak.
Materials and Methods:
A cross-sectional study was carried out in 30 randomly selected sub-centers in 8 blocks of the Shivpuri District of Madhya Pradesh, covering 212 villages, selected by cluster sampling. The villages, which had reported measles cases, were extensively investigated by the field teams through extensive house-to-house surveys during 12-19 May 2004.
Results:
A total of 1204 cases with 14 deaths were reported with an attack rate of 6.2% and a case fatality rate of 1.2%. In this study, 17.7% of the cases reported post-measles complications with diarrhea as the most common post measles complication. The routine measles vaccine and Vitamin A supplementation in the area was also less than 30%.
Conclusions:
The majority of the cases had occurred in the unvaccinated children and in under 5 year old population. There are repeated outbreaks and a long delay in reporting of the cases. The occurrence of cases, in a reasonable proportion of the vaccinated population, points toward the fact that there is a possibility of a vaccine failure in older children. This study calls for an improved surveillance system, an improvement in the cold chain, and enhancements for measles vaccination if India is to achieve the goal of measles elimination.
doi:10.4103/0970-0218.51234
PMCID: PMC2781117  PMID: 19966957
Attack rate; case fatality rate; measles epidemic; post measles complication; vaccine failure
19.  Screening Random Peptide Libraries with Subacute Sclerosing Panencephalitis Brain-Derived Recombinant Antibodies Identifies Multiple Epitopes in the C-Terminal Region of the Measles Virus Nucleocapsid Protein 
Journal of Virology  2006;80(24):12121-12130.
Infectious and inflammatory diseases of the CNS are often characterized by a robust B-cell response that manifests as increased intrathecal immunoglobulin G (IgG) synthesis and the presence of oligoclonal bands. We previously used laser capture microdissection and single-cell PCR to analyze the IgG variable regions of plasma cells from the brain of a patient with subacute sclerosing panencephalitis (SSPE). Five of eight human IgG1 recombinant antibodies (rAbs) derived from SSPE brain plasma cell clones recognized the measles virus (MV) nucleocapsid protein, confirming that the antibody response in SSPE targets primarily the agent causing disease. In this study, as part of our work on antigen identification, we used four rAbs to probe a random phage-displayed peptide library to determine if epitopes within the MV nucleocapsid protein could be identified with SSPE brain rAbs. All four of the SSPE rAbs enriched phage-displayed peptide sequences that reacted specifically to their panning rAb by enzyme-linked immunosorbent assay. BLASTP searches of the NCBI protein database revealed clear homologies in three peptides and different amino acid stretches within the 65 C-terminal amino acids of the MV nucleocapsid protein. The specificities of SSPE rAbs to these regions of the MV nucleocapsid protein were confirmed by binding to synthetic peptides or to short cDNA expression products. These results indicate the feasibility of using peptide screening for antigen discovery in central nervous system inflammatory diseases of unknown etiology, such as multiple sclerosis, neurosarcoidosis, or Behcet's syndrome.
doi:10.1128/JVI.01704-06
PMCID: PMC1676253  PMID: 17130301
20.  Measles Virus Spread between Neurons Requires Cell Contact but Not CD46 Expression, Syncytium Formation, or Extracellular Virus Production 
Journal of Virology  2000;74(4):1908-1918.
In patients with subacute sclerosing panencephalitis (SSPE), which is associated with persistent measles virus (MV) infection in the brain, little infectious virus can be recovered despite the presence of viral RNA and protein. Based on studies of brain tissue from SSPE patients and our work with MV-infected NSE-CD46+ mice, which express the measles receptor CD46 on neurons, several lines of evidence suggest that the mechanism of viral spread in the central nervous system differs from that in nonneuronal cells. To examine this alternate mechanism of viral spread, as well as the basis for the loss of normal transmission mechanisms, infection and spread of MV Edmonston was evaluated in primary CD46+ neurons from transgenic mice and differentiated human NT2 neurons. As expected, unlike that between fibroblasts, viral spread between neurons occurred in the absence of syncytium formation and with minimal extracellular virus. Electron microscopy analysis showed that viral budding did not occur from the neuronal surface, although nucleocapsids were present in the cytoplasm and aligned at the cell membrane. We observed many examples of nucleocapsids present in the neuronal processes and aligned at presynaptic neuronal membranes. Cocultures of CD46+ and CD46− neurons showed that cell contact but not CD46 expression is required for MV spread between neurons. Collectively, these results suggest that the neuronal environment prevents the normal mechanisms of MV spread between neurons at the level of viral assembly but allows an alternate, CD46-independent mechanism of viral transmission, possibly through the synapse.
PMCID: PMC111669  PMID: 10644364
21.  Measles outbreak in Northern Central African Republic 3 years after the last national immunization campaign 
BMC Infectious Diseases  2013;13:103.
Background
Despite huge efforts to promote widespread vaccination, measles remains an important cause of morbidity and mortality worldwide, especially in African children. In March 2011, an abnormally high number of cases were reported from the Ouham Prefecture, Central African Republic to the national measles case-based surveillance system. In response, reactive vaccination activities were implemented. The aims of this study were to investigate this outbreak and describe the response.
Methods
Measles cases were defined according to WHO recommendations. In the first weeks of the outbreak, blood samples were collected and sent to the Institut Pasteur in Bangui for laboratory confirmation by detection of IgM antibodies against measles virus. In addition, a portion of viral RNA was amplified from 5 IgM positive patient samples and the amplicons were sequenced for phylogenetic analysis.
Results
Between March and September 2011, 723 clinical cases originated from the Ouham Prefecture, including 2 deaths, were reported. Amongst 59 blood samples collected, 49 were positive for the detection of IgM. A high number of self-declared vaccinated subjects (31%) were found amongst the cases. Most of the cases were under 5 years. The causative virus was found to belong to genotype B3.1. In response, 2 sub-national supplementary immunization activities were quickly conducted and limited this outbreak to mainly 2 sub-prefectures.
Conclusions
This outbreak was the largest epidemic of measles in CAR since 2002. Its occurrence, 3 years after the last national immunization campaign, highlights the necessity to pursue efforts and improve and extend immunization programs in order to reach measles elimination goal in Africa.
doi:10.1186/1471-2334-13-103
PMCID: PMC3599156  PMID: 23442214
Measles; Outbreak; Central African Republic; Supplementary immunization activities
22.  Costs and benefits of a second measles inoculation of children in Israel, the West Bank, and Gaza. 
STUDY OBJECTIVE--Measles has been targeted by the WHO as a disease which should be eradicated. Use of existing vaccines during infancy has resulted in a substantial decline in cases in Israel, the West Bank, and Gaza. However the disease continues to occur in epidemic waves with large scale morbidity and mortality in all of these populations. This paper estimates the costs and benefits of three alternative strategies of adding immunisation at school age, and during young adult life to the present vaccination at 15 months. MEASUREMENTS AND MAIN RESULTS--A policy of immunising all Israeli children aged 6 (option A) would cost around $1 million and have estimated benefits of $4.5 million, yielding a benefit cost ratio of 4.53/1. Despite relatively lower medical care costs and work absence costs (as a result of the lower per capita GNP and lower female participation rate in the workforce), the West Bank and Gaza situations yield benefit to cost ratios of 5.74/1 and 9.59/1 respectively because of their relatively higher incidence rates. If implemented in Israel, a vaccination programme (such as option A) would prevent, over the next 10 years, approximately 28,700 simple cases, 3400 hospital admissions, eight non-fatal cases of encephalitis, and 2.2 cases of SSPE. It would save 28 lives. The adoption of option A, is expected to reduce incidence and mortality by around 13,600 and 32 cases in the West Bank, and by 18,000 and 64 cases in Gaza. CONCLUSION--The adoption of a two dose policy appears to be economically justifiable.
PMCID: PMC1060669  PMID: 2126028
23.  Immune Complexes and Visceral Deposits of Measles Antigens in Subacute Sclerosing Panencephalitis 
British Medical Journal  1972;2(5810):374-376.
Immunofluorescence has been used to study visceral organs from a case of subacute sclerosing panencephalitis. Immune complexes were shown as granular deposits of IgG, complement, and measles antigens in renal glomeruli. Measles antigens were detected in the spleen, liver, and lymph nodes from many parts of the body.
Immune-complex formation may be important in the aetiology of this disease and perhaps in causing some of its tissue damage. The rarity of subacute sclerosing panencephalitis may be due to an unusual pattern of immunological reactivity required in a patient before a measles infection can produce a subacute encephalitis.
Images
PMCID: PMC1788232  PMID: 4554157
24.  Functional and nonfunctional measles virus matrix genes from lethal human brain infections. 
Journal of Virology  1991;65(6):3161-3166.
Subacute sclerosing panencephalitis (SSPE) is a lethal disease induced by the persistence of measles virus in the human brain. In many SSPE cases, the viral matrix (M) protein cannot be detected; in others, M proteins of the expected size are found and sequence analysis of M cDNAs has confirmed that the reading frames are intact, showing only several missense mutations. To determine whether these alterations result in nonfunctional proteins, we have replaced the M gene of an infectious full-length genomic cDNA (from vaccine strain Edmonston) with different M genes derived from four patients with SSPE. One of the SSPE M genes tested proved to be functionally competent, giving rise to a virus yielding titers similar to those of viruses containing the M gene from control lytic strains. The other three SSPE M genes were not functionally competent in the same test. In all three cases, the inactivating changes resided in the carboxyl-terminal half of the M protein, as shown by the exchange of either of the two genes halves. In summary, mutational M gene alterations, which either prevent synthesis of M protein altogether or only allow synthesis of nonfunctional M protein, have been detected by us and by others in 9 of 10 SSPE cases. The one functional M gene appears to be an exception to the rule, indicating that M gene alteration might not be an absolute requirement for disease development.
Images
PMCID: PMC240972  PMID: 2033668
25.  Transcription inhibition and other properties of matrix proteins expressed by M genes cloned from measles viruses and diseased human brain tissue. 
Journal of Virology  1994;68(3):1532-1543.
Ribonucleoprotein (RNP) cores extracted from virions of wild-type (Edmonston strain) measles virus (MV) or obtained from MV-infected cells (cRNP) were shown to be capable of transcribing RNA in vitro but at relatively low efficiency. The tightly bound matrix (M) protein could be effectively removed from virion RNP (vRNP) and from cRNP by exposure to buffers of high ionic strength (0.5 to 1.0 M KCl) but only at pH 8.0 or higher. The vRNP and cRNP cores complexed with M protein exhibited markedly reduced transcriptional activity at increasing concentrations, whereas vRNP and cRNP cores free of M protein exhibited linear and substantially higher transcriptional activity; these data suggest that M protein is the endogenous inhibitor of MV RNP transcription. M-gene cDNA clones derived from three strains of wild-type (wt) MV and 10 clones from mRNAs isolated from the brain tissue of patients who had died from subacute sclerosing panencephalitis (SSPE) and from measles inclusion body encephalitis (MIBE) were recloned in the pTM-1 expression vector driven by the bacteriophage T7 RNA polymerase expressed by a coinfecting vaccinia virus recombinant. All 10 mutant SSPE and MIBE clones expressed in vitro and in vivo M proteins that reacted with monospecific anti-M polyclonal antibody and migrated on polyacrylamide gels to positions identical to or only slightly different from those of the M proteins expressed by wt MV clones. When reconstituted with cRNP cores, the three expressed wt M proteins and 6 of the 10 mutant-expressed M proteins showed equivalent capacity to down-regulate MV transcription. Three of the M proteins from SSPE clones and one from the MIBE clone showed little or no capacity to down-regulate transcription when reconstituted with cRNP cores. The only plausible explanations for loss of transcription inhibition activity by the four SSPE/MIBE M proteins were exceedingly high degrees of hypermutations leading to U-->C transitions and cloning-corrected mutations in the initiator codon (ATG-->ACG) of the four M genes. However, only the hypermutated M protein expressed by the MIBE cDNA clone exhibited virtually no capacity to bind cRNP cores in a reconstitution assay. These experiments provide some preliminary data to support the hypothesis that MV encephalitis may result from certain selective mutations in the M gene.
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PMCID: PMC236610  PMID: 8107216

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