Measles virus

I. Organism Information

A. Taxonomy Information
  1. Species:
    1. Measles virus. (Website 1):
      1. GenBank Taxonomy No.: 11234
      2. Description: Measles virus (MV) is the most contagious virus known to humankind and a leading cause of mortality in children worldwide. It primarily causes acute disease in humans, with attack rates of more than 90% in non-immune populations. In 2002, there were 3040 million cases of measles, resulting in 777 000 deaths (Dhimanet al., 2004). Despite the highly contagious nature of the disease, MV can be controlled effectively by immunization with live attenuated vaccines. The effectiveness of MV vaccines is well illustrated by the epidemiology of the disease in the United States. Prior to 1963, before use of the earliest vaccines, there were over 500,000 reported cases per year. Twenty years later, MV incidence was less than 2,000 cases per year (Parks et al., 2001).
      3. Variant(s):
        • Measles virus Edmonston:
          • GenBank Taxonomy No.: 11235
          • Parent: Measles virus.
          • Description: Edmonston wild-type (wt) measles virus (Parks et al., 2001). In 1954, the measles virus was isolated from an 11-year old boy from the US, David Edmonston, and adapted and propagated on chick embryo tissue culture (CE). The CE adapted strain, known as Edmonston A, was too virulent for vaccine purposes. The strain was attenuated by means of further passages on CE fibroblasts, resulting in a 2nd generation attenuated virus designated as Edmonston B. Again, the strain was too virulent to be applied on a large scale. Laboratories continued to pass Edmonston B on CE until a 3rd generation of more attenuated strains was developed. These strains, which are known by different names and differ from each other in the number of times the parent strain was passed on CE, provide the seeds for the vaccines now commercially available. The measles vaccines supplied through the World Health Organization's programme on Immunization in the Americas are prepared from seeds derived from Edmonston B (EPI Newsl., 1980).
        • Measles virus IP-3-Ca:
          • GenBank Taxonomy No.: 11237
          • Parent: Measles virus.
          • Description: A measles virus genome originally derived from brain cells of a subacute sclerosing panencephalitis patient expressed in IP-3-Ca cells an unstable MV matrix protein and was unable to produce virus particles. Transfection of this virus genome into other cell lines did not relieve these defects, showing that they are ultimately encoded by viral mutations. However, these defects were partially relieved in a weakly infectious virus which emerged from IP-3-Ca cells and which produced a matrix protein of intermediate stability (Cattaneo et al., 1988).
        • Measles virus philadelphia-26:
          • GenBank Taxonomy No.: 70148
          • Parent: Measles virus.
          • Description: Comparison of P gene nucleotide sequence of Ph26 with that the Edmonston strain of MV revealed a single synonymous nucleotide difference (Vanchiere et al., 1995).
        • Measles virus Yamagata-1:
          • GenBank Taxonomy No.: 11239
          • Parent: Measles virus.
          • Description: Two virus clones were isolated from a defective SSPE (subacute sclerosing panencephalitis) virus, the Yamagata-1 strain, and designated as the YA and YF clones. The YA clone-infected cells produced neither cell-free virus nor cell-associated virus, whereas the YF clone-infected cells produced both cell-associated and cell-free virus. No difference of epitopes on structural proteins was observed between these two clones. Both clones had hemadsorption activity (Haga et al., 1992).
        • Measles virus ETH10/99:
          • GenBank Taxonomy No.: 151529
          • Parent: Measles virus.
          • Description: In December 1998, a measles outbreak was reported in the regional state of Oromia in western Ethiopia, affecting three districts. The three strains were named as MVs/Bedelle.ETH/5.99 (ETH10/99) from a 5-year-old child from the Bedelle outbreak and MVs/Addis Ababa.ETH/50.98 (ETH54/98) and MVs/Addis Ababa.ETH/2.99 (ETH55/99) from sporadic cases in Addis Ababa, respectively, in a 10- and in a 2-year-old child (Nigatu et al., 2001).
        • Measles virus ETH54/98:
          • GenBank Taxonomy No.: 151530
          • Parent: Measles virus.
          • Description: In December 1998, a measles outbreak was reported in the regional state of Oromia in western Ethiopia, affecting three districts. The three strains were named as MVs/Bedelle.ETH/5.99 (ETH10/99) from a 5-year-old child from the Bedelle outbreak and MVs/Addis Ababa.ETH/50.98 (ETH54/98) and MVs/Addis Ababa.ETH/2.99 (ETH55/99) from sporadic cases in Addis Ababa, respectively, in a 10- and in a 2-year-old child (Nigatu et al., 2001).
        • Measles virus ETH55/99:
          • GenBank Taxonomy No.: 151531
          • Parent: Measles virus.
          • Description: In December 1998, a measles outbreak was reported in the regional state of Oromia in western Ethiopia, affecting three districts. The three strains were named as MVs/Bedelle.ETH/5.99 (ETH10/99) from a 5-year-old child from the Bedelle outbreak and MVs/Addis Ababa.ETH/50.98 (ETH54/98) and MVs/Addis Ababa.ETH/2.99 (ETH55/99) from sporadic cases in Addis Ababa, respectively, in a 10- and in a 2-year-old child (Nigatu et al., 2001).
        • Measles virus genotype A:
          • GenBank Taxonomy No.: 262307
          • Parent: Measles virus.
          • Description: Reference strains: Edmonston-wt.USA/54 (Status: Active) (WHO Report, 2003). Vaccine virus strains originating from the same progenitor of genotype A have been used successfully throughout the world over a 30 year period (Santibanez et al., 2005).
        • Measles virus genotype B3:
        • Measles virus genotype C2:
        • Measles virus genotype D4:
        • Measles virus genotype D6:
          • GenBank Taxonomy No.: 170527
          • Parent: Measles virus.
          • Description: Reference strains: New Jersey.USA/94/1 (Status: Active) (WHO Report, 2003). Isolated in Argentina, Brazil, Bolivia, Dominican Republic, Germany, Italy, Luxembourg, Poland, Russian Federation, Spain, Turkey (WHO Report, 2001).
        • Measles virus AIK-C:
          • GenBank Taxonomy No.: 36408
          • Parent: Measles virus.
          • Description: The AIK-C strain of measles vaccine was developed in 1976 in Japan from the Edmonston strain by plaque cloning through passage in sheep kidney cells and chicken embryonic cells at 33 C (Kumada et al., 2004).
        • Measles virus Edmonston-Zagreb:
          • GenBank Taxonomy No.: 70149
          • Parent: Measles virus.
          • Description: Further attenuation of the EdmonstonMusser virus was initiated by D. Iki (Institute of Immunology, Zagreb) in 1963 by passaging the virus in human diploids (Wi-38) through 19 passages with a triple purification of the virus by plaquing during the 9th, 11th and 13th passages when pre-seed was produced. In each plaquing, only large plaques were selected. Purification of the virus by plaquing developed a homogenous, genetically stable population of the viral particles originated from a single plaque, called the EdmonstonZagreb strain (Baricevic et al., 2005). Edmonston-Zagreb replicates best and induces substantial thymocyte death (Valsamakis et al., 2001).
        • Measles virus Halle:
          • GenBank Taxonomy No.: 11236
          • Parent: Measles virus.
          • Description: Although the Halle strain was originally reported to have been isolated from a patient with subacute salerosing panencephalitis, this lytic virus is now suspected to be a laboratory contaminant derived from the Edmonston strain and is classified with the vaccine MV strains (Lecouturier et al., 1996).
        • Measles virus Moraten:
          • GenBank Taxonomy No.: 132484
          • Parent: Measles virus.
          • Description: The vaccine strain Moraten (Mor) rapidly induced high levels of ICAM-1 mRNA and protein expression, whereas the vaccine strain CAM-70 and the Edmonston wild type (Edwt) strain were far less effective, even when they were used at very high multiplicities of infection (MOIs). Furthermore, induction of ICAM-1 by Mor was not dependent on de novo expression of MV or cellular proteins (Harcourt et al., 1999).
        • Measles virus Schwarz:
          • GenBank Taxonomy No.: 132487
          • Parent: Measles virus.
          • Description: Further passages of Edmonston A and B on chicken embryo fibroblasts (CEF) produced the more attenuated Schwarz and Moraten viruses, whose sequences have recently been shown to be identical (Combredet et al., 2003). The Moraten and Schwarz strains are highly genetically related, reflecting their common ancestry and similar passage history, and they are safe and effective for most children. Their use has dramatically reduced the incidence of measles, from over 100 million cases in the prevaccine era to approximately 31 million cases in 1997. However, fatal infections have been documented in immunodeficient children vaccinated with these strains (Valsamakis et al., 1999).
        • Measles virus UK140/94:
          • GenBank Taxonomy No.: 151532
          • Parent: Measles virus.
          • Description: The entire N gene of two strains, UK140/94 and UK160/94, identifed in the UK in 1994 was sequenced for comparison, and these two strains were renamed as MVi/Manchester.-UNK/30.94 and MVi/Manchester.UNK/32.94 according to the WHO nomenclature (Nigatu et al., 2001).
        • Measles virus UK160/94:
          • GenBank Taxonomy No.: 151533
          • Parent: Measles virus.
          • Description: The entire N gene of two strains, UK140/94 and UK160/94, identifed in the UK in 1994 was sequenced for comparison, and these two strains were renamed as MVi/Manchester.-UNK/30.94 and MVi/Manchester.UNK/32.94 according to the WHO nomenclature (Nigatu et al., 2001).
B. Lifecycle Information :
  1. Human cells infection :
    1. Size: Purified virions examined by negative staining in the electron microscope exhibited a pleomorphic range of particle sizes varying in diameter between 300 nm and 1000 nm. Purified nucleocapsids had dimensions of 21 nm (diameter) X 1254(+/- 7) nm (length) and a central core of diameter about 5 nm. Full-length nucleocapsids were composed of 204 (+/- 3) protein discs. The pitch of the nucleocapsid helix was calculated to be 6.1 nm and the helix angle, alpha, to be 8 degrees 16'. Approximate volume calculations indicate that each enveloped virus particle contains multiple nucleocapsids (Lund et al., 1984).
    2. Shape: The measles virus particles are pleomorphic, spherical structures (Garg, 2002). Both in vivo and in vitro the measles nucleo-protein profiles were surrounded by 'fuzzy' material which could be resolved in a pentagon shape and this stained specifically with ruthenium red. The tubules found in MS appeared not to have a 'fuzzy' coat and also did not stain with ruthenium red. The main difference observed between infected tissue culture cells and mouse brain was that in the latter no alignment of measles nucleoprotein was observed under the cell membrane and no budding particles were seen (Narang, 1981).
    3. Description: Measles virus is an enveloped, negative, nonsegmented strand RNA virus. Two virus-encoded glycoproteins are inserted into the viral envelope: the hemagglutinin (H) protein, which mediates virus attachment to susceptible cells and hemagglutination of certain simian erythrocytes, and the fusion (F) protein, which, together with H, is responsible for fusion with the cell membrane and virus entry. During the incubation period, the virus replicates in the respiratory tract and then spreads to local lymphoid tissue. Amplification of the virus in lymph nodes produces a primary viremia that results in the spread of virus to multiple lymphoid tissues and other organs, including the skin, kidney, gastrointestinal tract, and liver, where it replicates in epithelial cells, endothelial cells, and monocytes-macrophages. Most of the infected cells in peripheral blood are monocytes, although T and B lymphocytes support viral replication after stimulation in vitro (Horvat et al., 1996).
C. Genome Summary:
  1. Genome of Measles virus.
    1. Measles Virus Genome:
      1. GenBank Accession Number: NC_001498
      2. Size: Nucleotide sequence analysis of the IC-B strain revealed that the length of the entire genome (15,894 nucleotides) and the overall genome organizations of the IC-B strain were identical to those of the Edmonston (Ed) strain (Takeuchi et al., 2000).
      3. Gene Count: Protein-encoding nucleotide sequences of the N, P, M, F, H, and L genes were determined for a low-passage isolate of the Edmonston wild-type (wt) measles virus and five Edmonston-derived vaccine virus strains, including AIK-C, Moraten, Schwarz, Rubeovax, and Zagreb. Comparative analysis demonstrated a high degree of nucleotide sequence homology; vaccine viruses differed at most by 0.3% from the Edmonston wt strain (Parks et al., 2001).
      4. Description: The 16-kb MV genome encodes eight known proteins from six nonoverlapping cistrons arranged 3'-N-P-M-F-H-L-5'. The major structural polypeptide is encoded by the N (nucleocapsid) gene. The P cistron specifies three polypeptides: P, C, and V. The P (phosphoprotein) polypeptide is a subunit of the viral RNA polymerase. The C and V polypeptides are nonstructural proteins that are translated from P mRNAs through the use of alternative reading frames; C protein is synthesized from a downstream translation start signal, whereas V protein is translated from an edited mRNA that contains an extra G residue (Parks et al., 2001).

II. Epidemiology Information

A. Outbreak Locations:
  1. During 1989 and 1990 reported measles cases in the United States increased 6- to 9-fold over the annual mean of 3000 between 1985 and 1988. To evaluate recent epidemiology we summarized measles outbreaks. Confirmed measles cases reported to the National Notifiable Disease Surveillance System during 1987 through 1990 were analyzed. An outbreak was defined as more or equal 5 epidemiologically linked cases. There were 815 outbreaks, accounting for 94% of the 52,846 cases reported. Similar to 1985 and 1986, 3 patterns of measles transmission during outbreaks were identified: (1) predominantly among unvaccinated pre-school age children less than 5 years of age (38% of outbreaks); (2) predominantly among vaccinated school age children 5 to 17 years of age (40%); and (3) predominantly among unvaccinated and vaccinated post-school age persons older or equal 18 years of age (22%). Most outbreaks were small (median,12 cases), but very large outbreaks occurred (maximum size, 10,670). Although school age outbreaks (58%) predominated during 1987 and 1988, preschool age (40%) and post-school age (23%) outbreaks were more important during 1989 and 1990. Recent epidemiology suggests that to achieve elimination of measles, ACIP recommendations must be fully implemented, including (1) routine administration of the first dose of measles vaccine from 12 to 15 months of age and (2) use of a routine two-dose schedule to prevent school age and post-school age outbreaks (Hutchins et al., 1996).
  2. Of the 540 measles cases (annual incidence, less than 1/million population) reported during 1997-2001 in the United States, 362 (67%) were associated with international importation: 196 imported cases, 138 cases epidemiologically linked to imported cases, and 28 cases associated with an imported measles virus genotype. The remaining 178 (33%) "unknown-source" cases were analyzed as potential evidence of endemic measles transmission. A total of 83 counties (2.6% of the 3140 US counties) in 27 states reported unknown-source cases; 49 counties reported only 1 unknown-source case, and the maximum reported by any county was 10. Nationally, unknown-source cases were reported in 103 of the 260 weeks. The largest unknown-source outbreak included 13 cases and lasted 5 weeks. The rarity of unknown-source cases, wide gaps in geographic and temporal distribution, and the short duration of the longest unknown-source outbreak indicate that endemic transmission of measles was not sustained in the United States during this period (Papania et al., 2004).
  3. During 2001-2003, of the total 216 measles cases reported, 96 (44%) were imported, and 120 were indigenous. Of the indigenous cases, 59 (49%) were import-linked, 18 (15%) were imported virus, and 43 (36%) were unknown source cases. Import-associated cases (i.e., imported, import-linked, and imported virus cases) accounted for 80% of all reported cases. During 2001--2003, the highest percentage (47%) of imported measles cases was reported in 2001. Imported cases occurred in 55 international visitors traveling to the United States and 41 U.S. residents exposed to measles while traveling abroad. The largest numbers of imported cases were from China and Japan. The 96 imported cases during 2001-2003 resulted in 42 chains of indigenous transmission. The greatest numbers of cases linked epidemiologically to an imported case were 10 in 2001, 12 in 2002, and nine in 2003. The longest durations of measles transmission following imported cases were 34 days in 2001, 27 days in 2002, and 62 days in 2003. Of the unknown source cases, 29 (67%) were isolated cases, eight (19%) were in chains of transmission involving two cases, and six (19%) were in two outbreaks (i.e., three or more linked cases). During 2001--2003, nine genotypes were identified among measles viruses detected in the United States. Measles virus was isolated from 27 chains of transmission, including 14 (16%) of 87 isolated cases, four (31%) of 13 two-case chains of transmission, and nine (56%) of 16 outbreaks. The most commonly identified genotypes were D7 and H1, which occurred in six and five chains of transmission, respectively. During 2001-2003, a total of 21 states reported no confirmed measles cases, and 23 reported one to nine cases. States reporting more than 10 cases (Alabama [12], California [50], Hawaii [27], New York [24], Pennsylvania [18], and Washington [16]) accounted for 69% of all cases. Fifteen states reported unknown source cases, and two states (California [14] and Hawaii [6]) reported more than five such cases. Of the 3,140 counties in the United States, 78 reported one or more confirmed cases; 14 counties reported four or more cases (range: four to 27 cases). Twenty-six counties reported unknown source cases, but no county reported more than six. Of 155 (72%) cases in U.S. residents, 116 (75%) occurred in vaccine-eligible persons (i.e., aged more than 12 months and born after 1957); 27 (23%) had received 1 dose of measles-containing vaccine (MCV), nine (8%) had received 2 doses of MCV, and 80 (69%) were either not vaccinated or had unknown vaccination status. Of 61 (28%) cases in non-U.S. residents, 42 (69%) occurred in vaccine-eligible persons; five (12%) had received 1 dose of MCV, one (2%) had received 2 doses of MCV, and 36 (86%) were either not vaccinated or had unknown vaccination status (CDC Report, 2004).
  4. During 1987-1992, there were 165 measles-associated deaths in the multiple-cause mortality database at the National Center for Health Statistics (NCHS) and 184 reported to the measles surveillance system at the National Immunization Program (NIP). It was estimated that 259 measles deaths actually occurred; the reporting efficiencies were 64% for the NCHS and 71% for the NIP. Overall the death-to-case ratio was 2.54 and 2.83 deaths/1000 reported cases, using the NCHS and NIP data, respectively. Pneumonia was a complication among 67% of measles-related deaths in the NCHS data and 86% of deaths in the NIP data. Encephalitis was reported in 11% of deaths in both databases. Preexisting conditions related to immune deficiency were reported for 16% of deaths in the NCHS system and 14% in the NIP; the most common was human immunodeficiency virus infection. Overall, 90% of deaths reported to the NIP occurred in persons who had not been vaccinated against measles. During 1993-1999, only 1 acute measles-related death was reported to the NCHS and no deaths were reported to the NIP. This is consistent with the extremely low reported incidence of measles in the United States during these years (Gindler et al., 2004).
B. Transmission Information:
  1. From: Human To: Human
    Mechanism: The causative agent, measles virus (MV), is generally transmitted by aerosolized secretions deposited on upper-respiratory-tract mucosal surfaces. Exposure leads to local respiratory tract replication; infection of regional lymphoid tissues then occurs followed by viremia and systemic dissemination as revealed by the characteristic skin rash. Most children recover uneventfully from the illness, but serious complications can occur, including pneumonia and involvement of the central nervous system (Parks et al., 2001). Airflow studies demonstrated that droplet nuclei generated in the examining room used by the source patient were dispersed throughout the entire office suite. Airborne spread of measles from a vigorously coughing child was the most likely mode of transmission (Bloch et al., 1985). People with measles are usually infectious for one to two days before the rash appears but the total period during which an individual is infectious is not known (Bedford, 2004). Measles virus is a highly contagious agent which causes a major health problem in developing countries (Santos et al., 2003). During the resurgence of measles in the United States between 1989 and 1992, only viruses of genotype D3 were isolated. In contrast, virological surveillance conducted after the resurgence period showed that at least 12 different genotypes were associated with the greatly reduced number of measles cases. Eight different genotypes were identified for 27 chains of transmission in which the source of infection was unknown. The diversity of measles virus genotypes observed in the United States between 1994 and 2001 reflected multiple imported sources of virus and indicated that no genotype of measles is endemic in the United States. Therefore, the data obtained from virological surveillance are consistent with the conclusions made by disease surveillance and epidemiological investigations that measles is no longer an endemic disease in the United States (Rota et al., 2004).

C. Environmental Reservoir:
  1. Measles Virus Environmental Reservoir :
    1. Description: Humans are the only natural reservoir of measles virus (Hahm et al., 2003).
    2. Survival Information: The outbreak supports the fact that measles virus when it becomes airborne can survive at least one hour (Bloch et al., 1985). Antiseptics such as PVP-I (povidone-iodine) solution, PVP-I gargle, PVP-I cream, chlorhexidine gluconate, alkyldiaminoethyl-glycine hydrochloride, benzalkonium chloride (BAC) and benzethonium chloride (BEC) were used. PVP-I was effective against all the virus species tested. PVP-I drug products, which were examined in these experiments, inactivated all the viruses within a short period of time. Rubella, measles, mumps viruses and HIV were sensitive to all of the antiseptics, and rotavirus was inactivated by BAC and BEC, while adeno-, polio- and rhinoviruses did not respond to the other antiseptics. PVP-I had a wider virucidal spectrum, covering both enveloped and nonenveloped viruses, than the other commercially available antiseptics (Kawana et al., 1997).
D. Intentional Releases:
  1. Intentional Release information :
    1. Description: In 2001 the World Health Organization and the United Nations Children's Fund published a strategic plan for the control of measles in which it was suggested that a meeting of experts should be convened in 2005 to evaluate the possibility of global eradication of measles. Eradication (i.e., the global elimination of the disease) can bring enormous benefits as cases will no longer occur and vaccination and surveillance efforts can be scaled down (and even completely ended). A recent study suggested that if measles were eliminated by 2010, the United States (USA) could save $500 million to $4.5 billion. These savings are less than previously estimated for the United States, partly because of the assumption that measles vaccines will continue to be delivered in response to possible bioterrorism threats (Carabin and Edmunds, 2003).
    2. Emergency contact: Travelers are at increased risk for several infections, including familiar infections such as measles that are widely distributed but more common in developing countries. Vaccines can markedly decrease the risk for many of these infections and are an important part of pretravel preparation. Travel provides an opportunity to review and update routine vaccines in adults and assess risk from unusual infections (Wilson, 2001).

III. Infected Hosts

  1. Human:
    1. Taxonomy Information:
      1. Species:
        1. Human :
          • GenBank Taxonomy No.: 9606
          • Scientific Name: Homo sapiens (Website 3)

    2. Infection Process:
      1. Description: Measles virus is spread by the respiratory route and causes a well-defined disease in seronegative individuals, usually early in childhood. Tissue-resident macrophages or dendritic cells in the respiratory mucosa may acquire virus directly or from the basolateral side of epithelial cells. After transport from the respiratory tract to the local lymphatic tissues, measles virus is amplified and spreads by a cell-associated viremia. Measles virus-specific RNA and proteins can be detected in a minor proportion of lymphocytes and monocytes during, and for a few days after, the measles rash. The rash clearly marks the onset of immune responses as determined by the appearance of virus-specific T cells and antiviral antibodies (Schneider-Schaulies and ter Meulen, 2002).

    3. Disease Information:
      1. Measles (i.e., Measles, Subacute sclerosing panencephalitis) :
        1. Pathogenesis Mechanism: Human postmortem tissue, neural cell cultures, and animal models have been used to answer major questions concerning morbillivirus neurovirulence. Studies of the Measles virus (MV) central nervous system (CNS) complication subacute sclerosing panencephalitis (SSPE) indicate that virus could enter the CNS either by direct infection of endothelial cells or in infected leucocytes, followed by infection of predominately neurones and oligodendrocytes. It has been established that MV neurovirulence in mice is partially determined by the virus-receptor specificity. The two known MV receptors, CD46 and SLAM, have been examined in normal and SSPE brain tissue and the findings suggest that further receptors may be necessary to explain infection of the CNS with wild-type strains of MV. In both humans and mice (and in vitro), once infection of neurones has been established, virus spreads transneuronally. It is possible that all morbilliviruses transiently infect the CNS in their natural hosts, but development of disease is dependent on the efficiency of the immune response (Cosby et al., 2002).

        2. Incubation Period: The first symptoms of measles occur after a 10- to 12-day incubation period that usually follows airborne or droplet exposure (Berggren et al., 2005).

        3. Prognosis: Measles is the most contagious of the childhood exanthems. Prior to the introduction of the measles vaccine, over 130 million cases and 7 to 8 million deaths occurred worldwide each year. The World Health Organization estimates that around 45 million cases with 1.2 million deaths still occur annually, with the majority of cases arising in less developed countries (Berggren et al., 2005).

        4. Diagnosis Overview: The laboratory plays an increasingly important role in measles surveillance as the level of disease control increases. Recognition of potential measles cases is based on clinical case definition; however, it is well established that clinical diagnosis is inaccurate during the elimination phase and that laboratory confirmation of suspected cases, complimented by genotyping of circulating measles strains, is critical for effective surveillance (Featherstone et al., 2003).

        5. Symptom Information :
          • Syndrome -- Atypical Measles Syndrome:
            • Description: The atypical measles syndrome was first recognized in the 1960s. Initially, it occurred in children who were exposed to wild measles virus several years after they were immunized with killed measles vaccine. The occurrence of a severe, atypical form of measles in individuals previously immunized with a poorly protective, formalin-inactivated, alum-precipitated measles vaccine in the 1960s has complicated the development of new vaccines against the virus. Between 15% and 60% of children immunized with the formalin-inactivated vaccine who contracted measles developed a severe form of disease, called atypical measles. The pathophysiology of atypical measles was postulated to be due to an imbalance in antibodies against the hemagglutinin (H) and fusion (F) glycoproteins, but remained unclear for decades, precluding testing of new vaccines. The evaluation of measles vaccines that use only the H protein should not be precluded in the future by concerns of eliciting atypical measles (Polack et al., 2000).
          • Fever:
            • Description: After an incubation period of 8-12 days, measles begins with increasing fever (to 39.0 C- 40.5C) and cough, coryza, and conjunctivitis. Fever usually persists for 2 or 3 days after the onset of the rash (Perry and Halsey, 2004).
          • Cough:
          • Coryza:
            • Description: At least 3 of the classical signs and symptoms of measles (rash, cough and coryza) were found in 92.3% of the cases (Perry and Halsey, 2004).
          • Koplik's spots:
            • Description: Koplik's spots usually appear 1 day before the onset of rash and persist for 2 or 3 days. These bluish-white, slightly raised, 2- to 3-mm-diameter lesions on an erythematous base appear on the buccal mucosa, usually opposite the first molar, and occasionally on the soft palate, conjunctiva, and vaginal mucosa. Koplik's spots have been reported in 60%-70% of persons with measles but are probably present in most persons who develop measles (Perry and Halsey, 2004).
          • Rash:
            • Description: Symptoms intensify over the 2-4 days before the onset of rash and peak on the first day of rash. The rash is usually first noted on the face and neck, appearing as discrete erythematous patches 3-8 mm in diameter. The lesions increase in number for 2 or 3 days, especially on the trunk and the face, where they frequently become confluent. Discrete lesions are usually seen on the distal extremities, and with careful observation, small numbers of lesions can be found on the palms of 25%-50% of those infected. The rash lasts for 3-7 days and then fades in the same manner as it appeared, sometimes ending with a fine desquamation that may go unnoticed in children who are bathed daily. An exaggerated desquamation is commonly seen in malnourished children (Perry and Halsey, 2004).
          • Complications-Conjunctivitis:
            • Description: OCULAR COMPLICATIONS. Conjunctivitis occurs in most persons with measles, and inflammation of the cornea (keratitis) is common. In a study of 61 Turkish military personnel with measles, 57% had keratitis detected by slit lamp examination. In well-nourished persons, these lesions usually heal without residual damage. However, secondary bacterial (e.g., Pseudomonas or Staphylococcus) or viral infections (e.g., HSV or adenovirus) can lead to permanent scarring and blindness. Vitamin A deficiency predisposes to more severe keratitis, corneal scarring, and blindness. Measles associated with vitamin A deficiency is one of the most common causes of acquired blindness in children in developing countries. Blindness can also result from cortical damage from measles encephalitis (Perry and Halsey, 2004).
          • Complications-Laryngotracheobronchitis:
            • Description: RESPIRATORY COMPLICATIONS. Laryngotracheobronchitis or "measles croup" was noted in 9%-32% of US children hospitalized with measles. The majority of affected children were less than 2 years old. In one-third to one-half of such cases, culture of samples from the trachea yields positive results for bacterial pathogens, with a purulent exudate and evidence of secondary bacterial tracheitis, pneumonia, or both. The most commonly cultured organism is Staphylococcus aureus, although Streptococcus pneumoniae, Haemophilus influenzae, Pseudomonas aeruginosa, Escherichia coli, and Enterobacter species have also been identified. In a series of 6 children intubated because of measles croup, viral cultures revealed that 1 child was coinfected with adenovirus and another with herpes simplex virus (HSV). Laryngotracheobronchitis was the second most common cause of death in US children hospitalized with measles, after pneumonia (Perry and Halsey, 2004).
          • Complications-Pneumonia:
            • Description: RESPIRATORY COMPLICATIONS. Measles infects the respiratory tracts of nearly all affected persons. Pneumonia is the most common severe complication of measles and accounts for most measles-associated deaths. In studies of unselected hospitalized children with measles, 55% had radiographic changes of bronchopneumonia, consolidation, or other infiltrates; 77% of children with severe disease and 41% of children with mild disease had radiographic changes. In recent years, pneumonia was present in 9% of children less than 5 years old with measles in the United States, in 0%-8% of cases during outbreaks, and in 49%-57% of adults. Pneumonia may be caused by measles virus alone, secondary viral infection with adenovirus or HSV, or secondary bacterial infection. Measles is one cause of Hecht's giant cell pneumonia, which usually occurs in immunocompromised persons but can occur in otherwise normal adults and children. Studies that included culture of blood, lung punctures, or tracheal aspirations revealed bacteria as the cause of 25%-35% of measles-associated pneumonia. S. pneumoniae, S. aureus, and H. influenzae were the most commonly isolated organisms. Other bacteria (e.g., Pseudomonas species, Klebsiella pneumoniae, and E. coli) are less common causes of severe pneumonia associated with measles. Neisseria meningitidis was a probable cause in some cases (Perry and Halsey, 2004).
          • Complications-Otitis media:
            • Description: RESPIRATORY COMPLICATIONS. Otitis media is the most common complication of measles reported in the United States and occurs in 14% of children less than 5 years old. Presumably, inflammation of the epithelial surface of the eustachian tube causes obstruction and secondary bacterial infection. Lower rates of otitis media are noted with increasing age, most likely a function of the increasing diameter of the eustachian tube and the decreasing risk of obstruction (Perry and Halsey, 2004).
          • Complications-Diarrhea:
            • Description: GASTROINTESTINAL COMPLICATIONS. Measles probably infects the intestinal tracts of most persons with measles. Several cases of appendicitis have developed before and during measles rash, and characteristic giant cells typical for measles have been found in appendix tissue. In the United States, 8% of all reported measles cases during 1987-2000 were complicated by diarrhea. Rates were higher in those less than 5 or less than 30 years old. Among hospitalized persons with measles in the United States, 30%-70% had diarrhea. Feachem and Koblinsky found that 15%-63% of measles cases from community-based studies from developing countries in the prevaccine era were complicated by diarrhea and that 9%-77% of all diarrheal deaths were measles-associated. Stools of children with measles-associated diarrhea usually have the same bacteria as those of children with diarrhea not associated with measles. Measles-associated diarrhea typically begins just before rash onset, suggesting that measles virus is responsible for most of the diarrhea episodes but that secondary bacterial or viral infections may contribute to the severity and duration of illness (Perry and Halsey, 2004).
          • Complications-Febrile seizures:
            • Description: NEUROLOGICAL COMPLICATIONS. Febrile seizures occur in 0.1%-2.3% of children with measles in the United States and England and are usually benign and not associated with residual damage. Most children with uncomplicated measles have changes visible on electroencephalography, but these changes are most likely due to fever and other metabolic changes. Postinfectious encephalomyelitis (PIE) occurs in 1-3 per 1000 infected persons, usually 3-10 days after onset of rash. Higher rates of PIE due to measles occur in adolescents and adults than in school-aged children. PIE usually begins with the abrupt onset of new fever, seizures, altered mental status, and multifocal neurological signs. Although measles virus was found in cerebrovascular endothelial cells in a person who died during the first few days of rash, the virus usually is not found in the central nervous systems of persons with PIE. PIE appears to be caused by an abnormal immune response that affects myelin basic protein. As many as 25% of people with PIE due to measles die, and ~33% of survivors have lifelong neurological sequelae, including severe retardation, motor impairment, blindness, and sometimes hemiparesis (Perry and Halsey, 2004).
          • Complications-Measles encephalitis in immunocompromised patients:
            • Description: NEUROLOGICAL COMPLICATIONS. A progressive central nervous system measles virus infection, termed "measles inclusion body encephalitis," occurs in immunocompromised persons with disorders such as human immunodeficiency virus (HIV) infection or leukemia. Onset is usually 5 weeks to 6 months after acute measles. The illness begins with mental-status changes and seizures in the absence of fever; >80% of deaths occur within weeks (Perry and Halsey, 2004).

        6. Treatment Information:
          • Ribavirin: Five patients with subacute sclerosing panencephalitis (SSPE) were treated with ribavirin by intraventricular administration. Clinical effectiveness (significant neurologic improvement and/or a significant decrease in titers of hemagglutination inhibition antibodies against measles virus in cerebrospinal fluid (CSF)) was observed for four of five patients. For these four patients, CSF ribavirin concentrations were maintained at a level at which SSPE virus replication was almost completely inhibited in vitro and in vivo, whereas the concentration was lower in the patient without clinical improvement. These results suggest that intraventricular administration of ribavirin is effective against SSPE if the CSF ribavirin concentration is maintained at a high level (Hosoya et al., 2004).
            • Applicable: Ribavirin is a broad-spectrum antiviral drug with inhibitory activity against many RNA viruses, including measles virus (Hosoya et al., 2004).
            • Contraindicator: Ribavirin was toxic at a concentration close to the effective concentration in vitro and in vivo. Therefore, monitoring of the CSF ribavirin concentration is necessary. Ribavirin concentrations in the CSF after the initial treatment at a dose of 1 mg/kg twice a day should be measured, and the results should be used to adjust the dose and frequency of the next treatment (Hosoya et al., 2004).
            • Complication: Although there were transient side effects attributed to ribavirin, such as drowsiness, headache, lip and gingival swelling, and conjunctival hyperemia, intraventricular ribavirin therapy was generally safe and well tolerated (Hosoya et al., 2004).
          • Vitamin A: In 1990, results of a placebo-controlled double-blinded randomised trial89 indicated that two doses of 200 000 units of vitamin A reduced the severity and duration of complications as well as mortality (relative risk of death if treated with vitamin A 0.51, 95%, confidence interval (CI) 0.350.74) of measles in children ill enough to be admitted to hospital. Findings of a meta-analysis showed the protective effect of vitamin A on case fatality to be greatest when two doses are given in severe measles in areas with high case fatality. One community-based study of vitamin A supplementation with a single-dose of 200 000 units of vitamin A for mild measles in Zambia did not show a benefit. In 1997, WHO recommended that two doses of 200 000 units of vitamin A be given to all children with measles (Duke and Mgone, 2003). Vitamin A has profound and diverse effects on the immune system and the integrity of epithelial barriers, and its beneficial effect on measles is almost certainly mediated in part by effects on the immune system. However, the immunologic basis for the reduction in measles mortality following vitamin A administration is not understood (Moss et al., 2004).
          • Measles virus vaccine. : Each year, countries provide information on routine coverage with the first dose of measles-containing vaccine (MCV1) among children aged 12--23 months and supplemental immunization activities (SIAs) for measles and rubella. In 2003, of 52 countries in EUR, 27 (52%) reported MCV1 coverage of more than 95%, and 36 (69%) achieved MCV1 coverage of more than 90%. In 2004, all 52 countries had a routine 2-dose measles vaccination schedule, compared with 49 (96%) in 2001. In 2004, a total of 47 (90%) countries used a rubella-containing vaccine; 45 (87%) used combined measles-mumps-rubella vaccine (MMR), one (2%) used measles-rubella vaccine (MR), and one (2%) used a single antigen rubella vaccine. In contrast, in 2001, a total of 39 (76%) countries used a rubella-containing vaccine. During 1990--2004, nine countries conducted SIAs; five countries used an MR vaccine for SIAs, three simultaneously offered rubella vaccination for women of childbearing age, and one used routine services to reach susceptible cohorts by using MMR. Approximately 27.7 million persons were vaccinated during these SIAs (CDC Report, 2005 (b)).
            • Applicable: Since 1963, the live attenuated Measles virus vaccine has protected hundreds of millions of people from acute infection. The vaccine is inexpensive and long lasting, and two doses are sufficient for protection of young children. As a result, the number of cases of acute Measles virus plummeted 98% in the United States after introduction of the vaccine (Rall, 2003).
            • Contraindicator: The presence of maternal antibodies interferes with effectiveness of the vaccine before 9 months of age; again, for children in developing countries where clinic visits may be infrequent, vaccines are often administered when the child is first born. This too is suboptimal because extant maternal antibodies can clear the vaccine, leaving the child unprotected (Rall, 2003).
            • Complication: There are appreciated side effects with the live, attenuated vaccine, including an increased risk of fever, aches, rash, and febrile seizures from 8 to 14 days post vaccination (Rall, 2003). Many rigorously controlled studies performed in the United Kingdom, Finland, Denmark, and the United States found no evidence that MMR vaccine causes autism. Despite these studies, some parents remain concerned that the MMR vaccine is not safe (Offit and Coffin, 2003).
          • Immune Globulin (Human): BayGam, a solution of immune globulin prepared from plasma pools from human donors is for intramuscular administration and contains no preservatives. If administered within 6 days of exposure, BayGam can prevent or modify measles in a susceptible person. The usual recommended dose of BayGam is 0.25 ml/kg of body weight, intramuscular (maximum dose -15 ml) (Sawyer, 2000).
            • Applicable: The Advisory Committee on Immunization Practices (ACIP) recommends immune globulin for susceptible household contacts of measles patients, particularly those for whom the risk for complications is increased (i.e. infants aged less than or equal to 12 months, pregnant women, or immunocompromised persons). Immune Globulin (Human), BayGam (Bayer, Pharmaceutical Division, Elkhart, IN), is licensed for use as prophylaxis in susceptible persons exposed to measles (Sawyer, 2000).
            • Contraindicator: Immune globulin is not recommended for routine prophylaxis following rubella or mumps exposures. Administration of immune globulin should be considered only if a pregnant woman who has been exposed to rubella will not consider termination of pregnancy (Sawyer, 2000).
            • Complication: Immune globulin and measles vaccine should not be given at the same time. Passively acquired measles antibodies can interfere with the immune response to measles vaccine (Sawyer, 2000).

    4. Prevention:
      1. Measles Prevention:
        • Description: Combined live attenuated mumps, measles and rubella (MMR) vaccine was introduced in the United States in the 1970s, in Britain in October 1988 and is included in WHOs Expanded Program on Immunization. The single-component live attenuated vaccines of MMR had been licensed in the USA in the 1960s. Vaccination with MMR provides significant improvement in the efficiency of pediatric immunization through the administration of three vaccines in a single injection, reducing costs while increasing immunization coverage against the three diseases. MMR is usually administered at 1215 months and 45 years of age (Jefferson et al., 2003). In the joint Strategic Plan for Measles Mortality Reduction, 2001-2005, the World Health Organization (WHO) and the United Nations Children's Fund (UNICEF) targeted 45 priority countries with high measles burden for implementation of a comprehensive strategy for accelerated and sustained measles mortality reduction. Components of this strategy include achieving high routine vaccination coverage (more than 90%) in every district and ensuring that all children receive a second opportunity for measles immunization. In May 2003, the World Health Assembly endorsed a resolution urging member countries to reduce deaths attributed to measles by half (compared with 1999 estimates) by the end of 2005. On the basis of WHO/UNICEF estimates, global routine measles vaccination coverage among children aged 1 year increased from 71% in 1999 to 77% in 2003. Coverage varied substantially by region. Moreover, an increase was observed in the proportion of countries offering children a second opportunity for measles immunization. In 2003, a total of 164 (85%) countries offered children a second opportunity, compared with 150 (78%) countries in 2001. During 2000-2003, approximately 197 million children received measles vaccination through "catch-up" and "follow-up" supplementary immunization activities (SIAs) in 30 of the 45 priority countries. Of the 30 countries that conducted measles SIAs during this period, 23 (77%) were nationwide and 23 (77%) were in the African Region. Median reported coverage for these SIAs was 98% (range: 65% - 99%) (CDC Report, 2005 (a)).
        • Efficacy:
          • Rate: On the basis of results from the natural history model, overall global measles mortality decreased 39%, from 873,000 deaths (uncertainty bounds: 645,000--1,196,000 deaths) in 1999 to 530,000 deaths (bounds: 383,000--731,000 deaths) in 2003. The largest reduction was in Africa, where estimated measles mortality decreased by 46% during this period (CDC Report, 2005 (a)). Genetic polymorphisms of the human leukocyte antigen (HLA) system significantly influence the variation in immune responses to the measles vaccine. HLA class I and class II, transporter associated with antigen processing (TAP), and HLA-DM allele associations with measles-specific antibody levels following measles vaccination have revealed, in part, the immunologic basis for mechanisms of measles immunity variation (Ovsyannikova et al., 2004).
          • Duration: WHO still officially adheres to the view that a single successful measles vaccination, without natural boosters, induces a lifelong immunity and deems secondary failures epidemiologically irrelevant - in the belief that the latter are rare and do not participate in the transmission chain (Paunio et al., 2003).
        • Contraindicator: The Measles and MMR vaccines may be more teratogenic than the rubella vaccine. Vaccination of women around conception may lead to stillbirths, premature delivery and vanishing twins.' It can also be frequently associated with early-onset autism. The safety of the presently accepted and encouraged practice of postpartum vaccination for low or absent rubella immunity is questionable and should be thoroughly re-evaluated. Delaying the administration of live virus vaccines beyond the period of breastfeeding appears wise. Previous failure to develop antibodies after vaccination is probably due to an immune problem with the mother, and not necessarily to a vaccine failure. Informed Consent' should therefore include the full disclosure that revaccination does not guarantee immunity and that systemic, immune and obstetrical difficulties may result from the administration of the rubella, measles and MMR vaccines. Until serious independent research can prove that maternal re-vaccination does not pose substantial risk of autism in subsequent children, the possibility of this disastrous complication should be similarly fully disclosed. There may be a risk in combining the MMR and varicella vaccines, in administering them simultaneously and in giving the MMR to children recovering from chickenpox (Yazbak and Yazbak, 2002).
        • Complication: Measles, mumps and rubella (MMR) vaccine has been used for almost 30 years in the US, 20 years in Sweden and Finland, and over 10 years in most of the rest of Europe. During this time, it has brought about a dramatic reduction in the morbidity and mortality due to measles and mumps, as well as a considerable reduction in the number of babies with the congenital rubella syndrome. In spite of extensive evidence confirming the efficacy and safety of the vaccine, concerns have recently been raised about a possible link with autism and bowel problems. These arose principally from a research group in the UK, but have now spread to other countries. In the UK this has caused a fall in the uptake of the vaccine with fears of possible outbreaks of measles and mumps in some groups of children. Over the last 3 years a number of studies have addressed this possible link between MMR and autism and inflammatory bowel disease. Studies from the US, UK, Sweden, and Finland have all failed to demonstrate a link. Amongst others, the American Academy of Pediatrics, the Royal College of Paediatrics and Child Health, the Institute of Medicine, and the World Health Organization have all considered the evidence and endorsed the continuing use of the vaccine. No regulatory body in the world has changed its policy as a result of this hypothesized link. Professionals and parents can be assured that MMR is well tried and tested and one of the most successful interventions in healthcare (Elliman and Bedford, 2002). If MMR vaccine does induce clinically significant immunosuppression, susceptibility to infection should be increased in the post-vaccination period. It has tested this hypothesis using cases of invasive bacterial infection and pneumonia in children aged 1223 months admitted to hospital between April 1991 and March 1995 in selected districts in the Thames region of southern England. Combined measles, mumps, and rubella (MMR) vaccine did not increase the risk of hospitalisation with invasive bacterial infection in the three months after vaccination; rather there was a protective effect. These results provide no support for the concept of "immunological overload" induced by multiple antigen vaccinations, nor calls for single antigen vaccines (Miller et al., 2003).

    5. Model System:
      1. Asian macaques:
        1. Model Host: Asian macaques model measles virus pathogenesis (Premenko-Lanier et al., 2003).
        2. Model Pathogens:
        3. Description: Asian macaques are the best model to study measles pathogenesis and vaccine development. Infected animals develop a maculopapular skin rash beginning on the face and spreading to the chest and abdomen lasting for 35 days. Additional signs include depression, loss of appetite and shortness of breath with coughing. All animals recover within 57 days but have frequent episodes of bacterial gastroenteritis. Systemic infection is quantified by viremia which peaks on day 7 and is undetectable by day 28 post-inoculation. Rhesus macaques administered the currently used live-attenuated measles vaccine do not have any of the above signs and systemic infection is reduced to a very low or undetectable level (Premenko-Lanier et al., 2003).
      2. Cotton rats:
        1. Model Host: Cotton rats (Niewiesk, 1999, Pfeuffer et al., 2003)
        2. Model Pathogens:
        3. Description: Using the cotton rat model, it was investigated whether vaccine and wild-type viruses differ in viral spread and whether this is correlated with inhibition of of proliferation of spleen cells ex vivo after mitogen stimulation. After intranasal infection of cotton rats with wild-type and vaccine strains, it was found that wild-type virus replicates better in lung tissue, spreads to the mediastinal lymph nodes, and induces a more pronounced and longer-lasting inhibition of proliferation of spleen cells ex vivo after mitogen stimulation than does vaccine virus (Pfeuffer et al., 2003). The difference in virulence between wild-type and vaccine strains seen in humans is not reflected in vitro in a contact- inhibition assay of mitogen-stimulated proliferation of human cells. When a similar assay was applied to cotton rat cells in vitro, no difference in proliferation inhibition was found between vaccine and wild-type strains. A likely explanation for the in vivo differences is a difference in viral replication and spread. In monkeys, wild-type strains disseminate more widely than vaccine strains, leading to higher titers and acute measles. Viral spread in humans has not been studied comparatively between wild-type and vaccine strains in detail. However, the appearance of rash after a wild-type infection that is not seen after vaccination also indicates the growth of wild-type virus to higher titers and enhanced virus spread after infection. In cotton rats, both viral titers in lung tissue and the presence of virus in lung-draining mediastinal lymph nodes (MDLN) after wild-type virus infection correlate well with proliferation inhibition ex vivo. Using the presence of virus in draining lymph nodes and proliferation inhibition as parameters, it is possible to distinguish between vaccine and wild-type virus strains in cotton rats (Pfeuffer et al., 2003).
      3. Transgenic mice:
        1. Model Host: Transgenic mice (Patterson et al., 2001)
        2. Model Pathogens:
        3. Description: Some primates can be experimentally infected with measles virus but their usefulness is limited because of the quantity of animals needed and their cost. The potential of using a small animal model was first appreciated when in 1993 and 1994 different laboratories showed that the CD46 molecule was a receptor for measles virus, and that rodent cells were rendered permissive for measles virus upon genetically engineering the expression of CD46. Within the next few years multiple laboratories created transgenic mice expressing CD46. Expression in NSE (neuron-specific enolase)-CD46 transgenic mice is restricted to neurons, which is useful for understanding not only measles virus-induced CNS disease, but also how measles virus traffics in the CNS. By contrast, YAC (yeast artificial chromosome)-CD46 mice express the major CD46 isoforms at human-like levels and tissue specificity, resulting in a model which is a better murine mimic of natural CD46 expression in humans. This YAC-CD46 model allows dissection not only of MVCNS interactions, but of MVimmune cell interactions and the resultant immunosuppression (Patterson et al., 2001).

IV. Labwork Information

A. Biosafety Information:
  1. General biosafety information :
    • Biosafety Level: Biosafety level 2 practices, containment equipment and facilities for activities involving known or potentially infectious clinical materials or cultures.
    • Applicable: Measles Virus Precautions (Website 2)
    • Precautions:
      • PROTECTIVE CLOTHING: Laboratory coat; gloves when direct contact with infectious materials is unavoidable; gloves and gown (tight wrists and ties in back) when working in a biosafety cabinet. OTHER PRECAUTIONS: Procedures that are likely to generate aerosols should be conducted in a biosafety cabinet (Website 2).
B. Culturing Information:
  1. Measles Virus Culturing :
    1. Description: Measles virus is excreted from infected cases only for the first 57 days after rash onset, often in low titer, necessitating a laboratory with cell culture or polymerase chain reaction (PCR) expertise to detect the virus. For these reasons, attempts to detect virus from suspected measles cases is not considered to be a useful diagnostic tool. However, the detection of measles virus, subsequent genomic analysis, and the availability of an extensive sequence database for wild type measles viruses have enabled molecular epidemiologic studies of measles (Featherstone et al., 2003).

    2. Medium:
      1. B95-8, an Epstein-Barr (EB) virus-transformed marmoset B-lymphoblastoid cell line, and its derivative B95a, capable of attachment to a substrate surface, were 10,000-fold more sensitive to measles virus present in clinical specimens than were Vero cells. B95-8 and B95a cells were thus thought to be useful host cells for the isolation of measles virus. Quantitation of measles virus present in clinical specimens showed that a large quantity of virus, exceeding 10(6) 50% tissue culture infective doses per ml of a nasal-swab eluate, is shed into secretions by patients with acute measles, consistent with the contagiousness of the disease. Measles viruses isolated in B95a cells differed in some biological properties from those adapted to Vero cells. First, the viruses isolated in B95a cells did replicate in Vero cells, but release into the fluid phase was less efficient than that of Vero cell-adapted viruses. Second, minor antigenic differences were found between virus strains isolated in B95a cells and those isolated in Vero cells from the same clinical specimens. Third, the viruses isolated and propagated in B95a cells caused clinical signs in experimentally infected monkeys resembling those of human measles. It was suspected that measles virus is subject to host cell-mediated selection and that the viruses grown in B95a cells are more representative of measles virus circulating among humans than are the viruses selected in Vero cells (Kobune et al., 1990). CELLS. B95a is an Epstein-Barr virus-transformed marmoset B cell line. Vero and Cos cells are fibroblast cell lines established from African green monkey kidney. Cos cells are transformed by SV40. The following human cell lines were also used; Jurkat (T cell), BJAB (EB virus-transformed B cell), K562 (erythroleukemia), and HeLa. All of the cell lines used express CD46 on the cell surface. Human peripheral blood mononuclear cells (PBMC) were isolated as described previously. Vero, HeLa, and Cos cells were grown in Dulbeccos modified Eagles medium supplemented with 7% heat-inactivated fetal bovine serum, 2 mM L glutamine, 0.15% sodium bicarbonate, and 50 mg/ml kanamycin. B95a, Jurkat, BJAB, K562 and PBMC were grown in RPMI 1640 medium supplemented with 7% heat-inactivated fetal bovine serum, 2 mM L-glutamine, and 50 mg/ml Kanamycin. Culture medium for PBMC also contained 2 mg/ml phytohemagglutinin (PHA). VIRUS PRODUCTION. HeLa, Vero or Cos cells are plated in 6-well plate (100000 cells per well), and infected with one of the MV strains at a multiplicity of infection (m.o.i.) of 0.1. After 2 h of infection, cells were washed with phosphate-buffered saline (PBS) twice, replenished with 2 ml of fresh medium, and incubated at 37C in a 5% CO2 incubator. Jurkat, K562, BJAB or B95a cells (1000000 cells) were infected at a m.o.i. of 0.1. After 2 h of infection, they were washed twice, replenished with 5 ml of medium (Tanaka et al., 1998).
    3. Optimal Temperature: 37 C (Tanaka et al., 1998).
C. Diagnostic Tests :
  1. Organism Detection Tests:
    1. FACS-measured immunofluorescence assay:
      1. Description: A Fluorescence activated cell scanner (FACS)-measured immunofluorescence assay was developed for the detection of antibodies directed against the hemagglutinin (H) and fusion (F) glycoproteins of measles virus (MV). Human melanoma cell lines transfected with either the MV H or F genes, which showed a high surface expression of the respective proteins in their native conformation, were used as target cells. The cells were incubated with diluted plasma samples, and stained subsequently with fluorescein isothiocyanate (FITC)-conjugated secondary antibodies. The FACS-measured fluorescence signals correlated directly with the amount of specific immunoglobulins over a wide concentration range. The use of different conjugates enabled the separate detection of MV-specific IgG, IgM, IgA and IgG subclasses, with relatively low backgrounds. Hemagglutinin-specific IgG, IgM and IgA fluorescence signals were shown to correlate well with MV-specific IgG ELISA titers and MV-specific IgM or IgA capture ELISA OD450-values, respectively. The polyclonal conjugates with specificity for human immunoglobulins offered sufficient cross-reactivity to detect MV-specific IgG, IgM and IgA in plasma samples of cynomolgus macaques, making this technique a useful tool for studying serological responses in vaccination and challenge experiments in non-human primate models (de Swart et al., 1998).

  2. Immunoassay Tests:
    1. Serum-based IgM Enzyme Immunoassay:
      1. Description: ELISA/EIA (Enzyme Immunoassay) test. Serum-based IgM EIAs are the current recommended laboratory assays for the confirmation of clinically diagnosed measles. Both indirect and capture EIA formats appear to work reasonably well, with most tests having high reported sensitivity (83% - 89%; higher after the first week of rash onset) and specificity (95% - 100%) with serum specimens collected 3 - 28 days after rash onset. The EIAs can be done with a single serum specimen, are relatively rapid and simple to perform by trained laboratory technicians, require only a small volume sample (20 mkL of serum), and can be used to diagnose acute measles infection from the time of rash onset until 4 weeks after rash onset (Bellini, Helfand, 2003).
      2. False Positive: False-positive tests due to the presence of rheumatoid factor (RF) appear to be more frequent with the indirect IgM assay. RF is an IgM class immunoglobulin that reacts with IgG and is produced as a result of some viral, rheumatologic, and vasculitic diseases. Similar false-positive results can occur in capture assays but appear to be enhanced by the presence of high levels of both antigen-specific antibody and RF. In addition, serum specimens from patients with parvovirus B19 and rubella, two rash illnesses that occur as outbreaks of disease, have inherent rates of false-positive reactions (overall rate, 4%) when tested in measles IgM EIAs and vice versa. False-positive or equivocal results have also been noted with sera from patients with Epstein-Barr virus, cytomegalovirus, human herpes virus 6, and mycoplasma. To aid in the interpretation of IgM-positive laboratory results from isolated suspect measles cases, many laboratories use the results generated from indirect IgG EIAs in conjunction with the IgM results to resolve some false-positive tests (Bellini, Helfand, 2003).
    2. ELISA-IgG avidity assay:
      1. Description: A measles-specific enzyme-linked immunosorbent assay (ELISA)-IgG avidity test for serologic evaluation of the efficacy of measles vaccines with only one blood sample was evaluated after vaccination with three measles vaccine strains. Avidity indices were determined by the urea elution technique in samples presenting antibody titers more or 100 mIU/ml. All 127 sera collected 2-8 weeks after primary vaccination with Biken-CAM70 measles vaccine had low avidity indices (LAI, when less or 29%) with a time-dependent increase in avidity. In samples collected 6-10 weeks after vaccination with Edmonston-Zagreb, LAI were also observed in all 31 sera tested (mean 15%) and in 233/242 (96.3%) filter paper samples from primary vaccination with Schwarz vaccine (mean 14%). There was no difference in the mean avidity among the three groups of primary vaccinees, although the Schwarz group had higher antibody titers. In contrast, only 1/36 (2.8%) serum samples from children who were seropositive at the time of measles vaccination had LAI (mean 56%), despite the fact that they were collected early (2-5 weeks after vaccination). Of 90 serum samples from children vaccinated in the past with two doses and of 42 cord blood serum samples, none had LAI. It is concluded that this test is a good tool for evaluating serologically the efficacy of a single dose schedule of measles vaccine. With only one postvaccination sample, the test can discriminate nonresponders (antibody titers below 100 mIU/ml), primary responders (antibody titers more or 100 mIu/ml with LAI), and those previously immunized (antibody titers more or 100 mIU/ml with high avidity indices). The seroconversion rate can be calculated after excluding the latter (de Souza et al., 1997).

  3. Nucleic Acid Detection Tests: :
    1. Measles Virus PCR Rota/Katz:
      1. Description: Analysis of urine specimens by using reverse transcriptase-PCR was evaluated as a rapid assay to identify individuals infected with measles virus. For the study, daily urine samples were obtained from either 15-month-old children or young adults following measles immunization. Overall, measles virus RNA was detected in 10 of 12 children during the 2-week sampling period. In some cases, measles virus RNA was detected as early as 1 day or as late as 14 days after vaccination. Measles virus RNA was also detected in the urine samples from all four of the young adults between 1 and 13 days after vaccination. This assay will enable continued studies of the shedding and transmission of measles virus and, it is hoped, will provide a rapid means to identify measles infection, especially in mild or asymptomatic cases For the measles virus-specific RT-PCR, a nested set of primers that hybridized to the nucleoprotein (N) gene was developed. The target sequences for these primers are located between bases 57 and 389 of the coding region of the N gene, and these sequences are conserved among the N genes of all wild-type measles viruses examined thus far. The internal primers (MV43, digoxigenin [DIG]-GA GCC ATC AGA GGA ATC A; and MV44, DIG-CA TGT TGG TAC CTC TTG A) were 5' labeled with DIG (Rota et al., 1995).
      2. Primers:
    2. Measles Virus PCR Chibo:
      1. Description: Clinical specimens from which Measles Virus (MV) isolates were obtained included throat swabs, nasopharyngeal aspirates and acute phase IgM-positive sera (Chibo et al., 2000). Total RNA was extracted from the supernatant of infected cells and serum using a guanidinium isothiocyanate extraction technique. MV RNA was reverse-transcribed using avian myeloblastosis virus reverse transcriptase (Promega) at 42 C for 1 h. Following reverse transcription, specific primers targeted to the MV Edmonston strain N gene were used to amplify a 644 bp and a 528 bp fragments and the protein-coding sequence of MV H gene, to amplify a 2036 bp fragment (Chibo et al., 2000).
      2. Primers:
    3. Measles Virus PCR Swart:
      1. Description: It was shown that in vitro measles virus (MV)-infected cells diluted in human blood and spotted on filter paper can be detected by RT-PCR. Small amounts of infected cells remained detectable after 25 weeks of storage of the filter paper at room temperature, 4 weeks at 37 degrees C, or 2 weeks at 45 degrees C. In addition, MV-specific IgM levels measured in reconstituted filter paper samples correlated well with those measured in plasma samples. Measles diagnosis based on the combination of filter paper RT-PCR and IgM detection had a sensitivity and specificity of 99 and 96%, respectively. An advantage of this diagnostic approach is that sequencing of RT-PCR products allows phylogenetic analysis of the MV strain involved. RNA was isolated from filter paper using a High Pure viral nucleic acid kit (Roche Diagnostics). A circle with a diameter of approximately 1 cm is cut out of the filter paper, inserted in an RNase-free vial, and incubated with 300 l of kit binding buffer supplemented with poly(A) carrier RNA. After addition of 300 l of distilled water and 60 l of proteinase K (20 mg/ml), the sample is mixed using micropestles and vortexing and subsequently incubated at 72 C for 10 min. After this incubation, 150 l of isopropanol is added and mixed using micropestles. Further steps are carried out according to the manufacturer's instructions. The PCR products are blotted and hybridized with 32P-labeled oligonucleotide probe MV-prN2. Oligonucleotide probe 5'-GCCATGGCAGGAATCTCGGAA-3' (MV-prN2, positions 1498 to 1518) (De Swart et al., 2001).
      2. Primers:
    4. Measles Virus PCR Jin:
      1. Description: A polymerase chain reaction (PCR) method was used for detecting measles virus MV RNA in a variety of clinical samples using primer pairs in the nucleocapsid (N) and matrix (M) genes in one reaction (dual target-PCR). The dual target-PCR detected MV RNA in tissue culture fluid. The dual target-PCR method is suitable for the diagnosis of measles infection and, based on the sequencing of the PCR product DNA, for investigating the molecular epidemiology of MV strains (Jin et al., 1996). The nested primer sets used in this study successfully amplify the cDNA target sequences of the measles virus RNA in some clinical specimens. However, the PCR using the M gene primers is more sensitive than the PCR with the N primers (Jin et al., 1996). It is possible that the observed difference in sensitivity in clinical samples might be due to the size of the products produced by the two sets of primer pairs. Thus, the PCR for the M gene might work more efficiently because the less size of the amplicon (Jin et al., 1996).
      2. Primers:

  4. Other Types of Diagnostic Tests:

    No other tests available here.

V. References

A. Journal References:
Baricevic et al., 2005: Baricevic M, Forcic D, Gulija TK, Jug R, Mazuran R. Determination of the coding and non-coding nucleotide sequences of genuine Edmonston-Zagreb master seed and current working seed lot. Vaccine. 2005; 23(8): 1072 - 1078. [PubMed: 15620481].
Bedford, 2004: Bedford H Measles and the importance of maintaining vaccination levels. Nursing Times. 2004; 100(26): 52 - 55. [PubMed: 15318694].
Bellini, Helfand, 2003: Bellini WJ, Helfand RF. The challenges and strategies for laboratory diagnosis of measles in an international setting. The Journal of Infectious Diseases. 2003; 187(Suppl 1): 283 - 290. [PubMed: 12721927].
Berggren et al., 2005: Berggren KL, Tharp M, Boyer KM. Vaccine-associated "wild-type" measles. Pediatric Dermatology. 2005; 22(2): 130 - 132. [PubMed: 15804301].
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B. Book References:

No book references used.

C. Website References:
Website 1: NCBI. Measles Virus [ ].
Website 2: MSDS. Measles Virus [ ].
Website 3: NCBI. Homo Sapiens [ ].
D. Thesis References:

No thesis or dissertation references used.

VI. Curation Information