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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
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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.  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
5.  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
6.  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
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.
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PMCID: PMC353270  PMID: 448796
8.  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.
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PMCID: PMC2466721  PMID: 5798690
9.  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.
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PMCID: PMC350930  PMID: 7333668
10.  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
11.  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.
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PMCID: PMC1788232  PMID: 4554157
12.  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.
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PMCID: PMC240972  PMID: 2033668
13.  Measles virus and subacute neurological disease: an unusual presentation of measles inclusion body encephalitis. 
A 20-year-old girl developed a subacute neurological illness characterized by seizures and epilepsia partialis continua, which resulted in her death within 10 weeks of her first symptom. Although she had a history of unusual reactions to viral infections, there was no evidence of any underlying disorder resulting in immunosuppression. Histopathology demonstrated the presence of dense infection with measles virus. The unusual clinical features of this cases suggest that measles virus may be responsible for a wide spectrum of neurological disease ranging from measles inclusion body encephalitis on the one hand to subacute sclerosing panencephalitis on the other.
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PMCID: PMC1083156  PMID: 6813426
14.  Brain endothelial cell infection in children with acute fatal measles. 
Journal of Clinical Investigation  1995;96(5):2478-2481.
Neurologic diseases are important complications of measles. The role of virus infection of the central nervous system as well as the route of virus entry has been unclear. Five autopsied cases of individuals who died with severe acute measles 3-10 d after the onset of the rash were studied for evidence of viral involvement of the central nervous system. In all cases, in situ hybridization and RT-PCR in situ hybridization techniques showed endothelial cell infection. Immunoperoxidase staining with an anti-ferritin antibody revealed a reactive microgliosis. These data suggest that endothelial cells in the brain are frequently infected during acute fatal measles. This site of infection may provide a portal of entry for virus in individuals who subsequently develop subacute sclerosing panencephalitis or measles inclusion body encephalitis and a target for immunologic reactions in post-measles encephalomyelitis.
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PMCID: PMC185901  PMID: 7593637
15.  Measles inclusion-body encephalitis in a child with treated acute lymphoblastic leukaemia. 
Journal of Clinical Pathology  1976;29(10):865-872.
A child with acute lymphoblastic leukaemia, being treated in the UKALL II Trial, had while in remission an attack of measles and made a normal recovery. Four months later she developed an acute encephalopathy and died within two weeks. The brain showed mild inflammatory features and widespread inclusion bodies in neurones and glial cells. Immunofluorescence proved an infection with measles virus. Similar cases have been called SSPE; reasons are given for preferring the term "measles inclusion-body encephalitis".
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PMCID: PMC476203  PMID: 789401
16.  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
17.  Seroprevalence of Antibodies to Measles, Mumps, and Rubella among Thai Population: Evaluation of Measles/MMR Immunization Programme 
Stored serum specimens, from four regions of Thailand, of healthy children attending well baby clinics and of healthy people with acute illnesses visiting outpatient clinics were randomly sampled and tested for IgG antibody to measles, mumps, and rubella (MMR). The immunity patterns of rubella and mumps fitted well with the history of rubella and MMR vaccination, seroprotective rates being over 85% among those aged over seven years. A high proportion of younger children acquired the infection before the age of vaccination. MMR vaccination should preferably be given to children at an earlier age. For measles, 73% seroprotective rates among children, aged 8-14 years, who should have received two doses of measles/MMR vaccine, were lower than expected. This finding was consistent with the age-group reported in outbreaks of measles in Thailand. The apparent ineffectiveness (in relation to measles) of MMR immunization of 1st grade students warrants further studies.
PMCID: PMC2761801  PMID: 19248651
Antibodies; Immunization; Measles; Measles vaccine; Mumps; MMR vaccine; Rubella; Seroepidemiologic studies; Seroprevalence; Vaccination; Thailand
18.  Measles control – Can measles virus inhibitors make a difference? 
Infection by measles virus (MV) is a major cause of human morbidity and mortality worldwide. In 2001, the WHO, UNICEF and their partners launched the Measles Initiative, the goals of which are to interrupt the transmission of MV in large geographic areas by increasing vaccination coverage and to assess the feasibility of eradicating MV worldwide. An estimated 74% reduction in mortality resulting from measles was achieved between 2000 and 2007, equivalent to a reduction of approximately 200,000 deaths annually. Despite this progress in the control of measles, the highest number of measles cases in more than a decade was observed in 2008 in several European countries and the US, and the virus was again declared endemic in the UK. In the light of this resurgence in the UK and the limitations associated with the current live-attenuated vaccine, this review discusses the means by which safe and effective measles antivirals could augment vaccination and strengthen global efforts to control measles. Important aspects of treatment are the potential to prevent infection effectively after exposure to MV, the improvement of case management, the amelioration of complications that frequently follow MV infection and the influence of antivirals on a potential strategy for global measles eradication.
PMCID: PMC2728049  PMID: 19649926
Antiviral; drug; eradication; measles; vaccine; virus
19.  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.
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PMCID: PMC288976  PMID: 1548746
20.  The F Gene of the Osaka-2 Strain of Measles Virus Derived from a Case of Subacute Sclerosing Panencephalitis Is a Major Determinant of Neurovirulence▿  
Journal of Virology  2010;84(21):11189-11199.
Measles virus (MV) is the causative agent for acute measles and subacute sclerosing panencephalitis (SSPE). Although numerous mutations have been found in the MV genome of SSPE strains, the mutations responsible for the neurovirulence have not been determined. We previously reported that the SSPE Osaka-2 strain but not the wild-type strains of MV induced acute encephalopathy when they were inoculated intracerebrally into 3-week-old hamsters. The recombinant MV system was adapted for the current study to identify the gene(s) responsible for neurovirulence in our hamster model. Recombinant viruses that contained envelope-associated genes from the Osaka-2 strain were generated on the IC323 wild-type MV background. The recombinant virus containing the M gene alone did not induce neurological disease, whereas the H gene partially contributed to neurovirulence. In sharp contrast, the recombinant virus containing the F gene alone induced lethal encephalopathy. This phenotype was related to the ability of the F protein to induce syncytium formation in Vero cells. Further study indicated that a single T461I substitution in the F protein was sufficient to transform the nonneuropathogenic wild-type MV into a lethal virus for hamsters.
doi:10.1128/JVI.01075-10
PMCID: PMC2953189  PMID: 20719945
21.  Measles viral load may reflect SSPE disease progression 
Virology Journal  2006;3:49.
Subacute sclerosing panencephalitis (SSPE) is a rare, slowly progressive neurological disorder caused by the persistent infection with measles virus (MV). Despite much research into SSPE, its pathology remains obscure. We examined autopsy tissues of eight SSPE patients by real time quantitative PCR, immunohistochemistry and immunoblotting to determine viral load. MV N, M and H gene RNA could be detected in the central nervous system (CNS) of all patients and in two non-CNS tissues of one patient. The viral burden between patients differed up to four-fold by quantitative PCR and corresponded with detection of MV protein. The level of both viral RNA and antigen in the brain may correlate with disease progression.
doi:10.1186/1743-422X-3-49
PMCID: PMC1526435  PMID: 16790043
22.  Functional analysis of matrix proteins expressed from cloned genes of measles virus variants that cause subacute sclerosing panencephalitis reveals a common defect in nucleocapsid binding. 
Journal of Virology  1993;67(4):1848-1853.
We have developed an in vitro nucleocapsid-binding assay for studying the function of the matrix (M) protein of measles virus (MV) (A. Hirano, A. H. Wang, A. F. Gombart, and T. C. Wong, Proc. Natl. Acad. Sci. USA, 89:8745-8749, 1992). In this communication we show that the M proteins of three MV strains that cause acute infection (Nagahata, Edmonston, and YN) bind efficiently to the viral nucleocapsids whereas the M proteins of four MV strains isolated from patients with subacute sclerosing panencephalitis (SSPE) (Biken, IP-3, Niigata, and Yamagata) fail to bind to the viral nucleocapsids. MV Biken (an SSPE-related virus) produces variant M sequences which encode two antigenically distinct forms of M protein. A serine-versus-leucine difference is responsible for the antigenic variation. MV IP-3 (an SSPE-related virus) also produces variant M sequences, some of which have been postulated to encode a functional M protein responsible for the production of an infectious revertant virus. However, the variant M proteins of Biken and IP-3 strains show no nucleocapsid-binding activity. These results demonstrate that the nucleocapsid-binding function is conserved in the M proteins of MV strains that cause acute infection and that the M proteins of MV strains that cause SSPE exhibit a common defect in this function. Analysis of chimeric M proteins indicates that mutations in the amino-terminal, carboxy-proximal, or carboxy-terminal region of the M protein all abrogate nucleocapsid binding, suggesting that the M protein conformation is important for interaction with the viral nucleocapsid.
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PMCID: PMC240246  PMID: 8445713
23.  Mutant Fusion Proteins with Enhanced Fusion Activity Promote Measles Virus Spread in Human Neuronal Cells and Brains of Suckling Hamsters 
Journal of Virology  2013;87(5):2648-2659.
Subacute sclerosing panencephalitis (SSPE) is a fatal degenerative disease caused by persistent measles virus (MV) infection in the central nervous system (CNS). From the genetic study of MV isolates obtained from SSPE patients, it is thought that defects of the matrix (M) protein play a crucial role in MV pathogenicity in the CNS. In this study, we report several notable mutations in the extracellular domain of the MV fusion (F) protein, including those found in multiple SSPE strains. The F proteins with these mutations induced syncytium formation in cells lacking SLAM and nectin 4 (receptors used by wild-type MV), including human neuronal cell lines, when expressed together with the attachment protein hemagglutinin. Moreover, recombinant viruses with these mutations exhibited neurovirulence in suckling hamsters, unlike the parental wild-type MV, and the mortality correlated with their fusion activity. In contrast, the recombinant MV lacking the M protein did not induce syncytia in cells lacking SLAM and nectin 4, although it formed larger syncytia in cells with either of the receptors. Since human neuronal cells are mainly SLAM and nectin 4 negative, fusion-enhancing mutations in the extracellular domain of the F protein may greatly contribute to MV spread via cell-to-cell fusion in the CNS, regardless of defects of the M protein.
doi:10.1128/JVI.02632-12
PMCID: PMC3571373  PMID: 23255801
24.  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
25.  Expression of defective measles virus genes in brain tissues of patients with subacute sclerosing panencephalitis. 
Journal of Virology  1986;59(2):472-478.
The persistence of measles virus in selected areas of the brains of four patients with subacute sclerosing panencephalitis (SSPE) was characterized by immunohistological and biochemical techniques. The five measles virus structural proteins were never simultaneously detectable in any of the brain sections. Nucleocapsid proteins and phosphoproteins were found in every diseased brain area, whereas hemagglutinin protein was detected in two cases, fusion protein was detected in three cases, and matrix protein was detected in only one case. Also, it could be shown that the amounts of measles virus RNA in the brains differed from patient to patient and in the different regions investigated. In all patients, plus-strand RNAs specific for these five viral genes could be detected. However, the amounts of fusion and hemagglutinin mRNAs were low compared with the amounts in lytically infected cells. The presence of particular measles virus RNAs in SSPE-infected brains did not always correlate with mRNA activity. In in vitro translations, the matrix protein was produced in only one case, and the hemagglutinin protein was produced in none. These results indicate that measles virus persistence in SSPE is correlated with different defects of several genes which probably prevent assembly of viral particles in SSPE-infected brain tissue.
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PMCID: PMC253098  PMID: 3735490

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