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Genetic Analysis of Measles Viruses

Molecular epidemiology of measles viruses is an important component in outbreak investigations and for global surveillance of circulating wild–type measles strains.

Genotyping in Public Health Investigations

Measles virus genotyping can play an important role in tracking transmission pathways during outbreak investigations. Genotyping results can help confirm, disprove, or detect connections among cases. If two cases have matching genotypes, they may be connected even if the connection is not obvious.

Genotyping is also the only way to distinguish whether a person has wild-type measles virus infection, or a rash caused by a recent measles vaccination. During outbreaks, measles vaccine is administered to help control the outbreak, and in these situations, vaccine reactions may be mistakenly classified as measles cases. A small number of measles vaccine recipients experience rash and fever 10 to 14 days following vaccination. The vaccine strain of measles virus can be distinguished from wild-type viruses by determination of the genotype from clinical samples or virus isolates. (See Specimens for Detection of Measles RNA by RT-PCR or Virus Isolation.)

Lastly, measles virus genotyping can help establish which foreign country may be the source of an imported U.S. case, since different genotypes circulate in different countries.  However, genotyping alone is not sufficient, since each genotype can circulate in multiple countries and even in different regions of the world.  Genotype data should be reviewed in conjunction with epidemiological information, such as travel and exposure histories, to determine which country may be the source of an imported US case.

It is important to note that genotyping information does not change the basic steps of public health investigations of measles, which include laboratory confirmation of measles infection, obtaining immunization histories for confirmed cases, identifying sources of infection, assessing potential for transmission and identifying contacts without presumptive evidence of immunity, classifying importation status, and obtaining specimens for viral isolation.

 

Genetic Characterization and Sequencing

Wild-type measles viruses have been divided into distinct genetic groups, referred to as genotypes, based on the nucleotide sequences of their hemagglutinin (H) and nucleoprotein (N) genes, which are the most variable genes on the viral genome.

The 450 nucleotides encoding the carboxy-terminal 150 amino acids of the nucleoprotein has up to 12% nucleotide variation between genotypes. The 450 nucleotides that encode the carboxy-terminal region of the nucleoprotein (N–450) are required for determination of the genotype. The measles genotyping protocol is available from CDC.

For each genotype, a reference strain is designated for use in genetic analysis (phylogenetic analysis), usually the earliest known virus isolation of that group. The means of referring to the genotypes has been standardized using alphabetical designations for the main groupings (clades). Within the main clades, numerals are added to identify the individual genotypes.

The following 19 genotypes have been detected since 1990:

A*, B2, B3, C1, C2, D2, D3, D4, D5, D6, D7, D8, D9, D10, D11, G2, G3, H1, H2

*Vaccine strains Moraten, Edmonston, Zagreb are all genotype A.
There were 2 putative wild-type cases of measles identified as genotype A in 2008.

During 2011, 8 genotypes were identified by global surveillance:

B2, B3, D4, D8, D9, D11, G3, H1

 

Reporting Measles Sequences

A global measles sequence database, MeaNS, has been established at the Health Protection Agency in London, UK, and contains sequence information from more than 10,000 measles samples. Full access to MeaNS is given only to members of the WHO Measles and Rubella Laboratory Network (LabNet).

For more information, see CDC contact information. Sequences submitted to MeaNS are automatically submitted to the WHO Global Measles Genotype Database at WHO Headquarters in Geneva (https://workspace.who.int/sites/genotype/ for registered users). Sequences can also be submitted to GenBank. Measles sequences in GenBank are imported into MeaNS on a bi-weekly basis.

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Guidelines for Naming Measles Strains or Sequences

The strain names will provide information that is essential for interpretation of the molecular data. Since sequence data may be derived from viruses isolated in cell culture or from RNA extracted directly from clinical material, strains or sequences will be designated as either:

  • MVi: measles virus isolated in cell culture was source of RNA for sequencing or
  • MVs: measles virus sequence derived from RNA extracted from clinical specimen

Other information to be included in the strain/sequence name:

  • City/province where case of measles was diagnosed, write full name or abbreviation (required)
  • Country, use WHO 3-letter ISO designation (required)
  • Date of rash onset if know, otherwise date of specimen collection by epidemic week (1-52) and year (required)
  • Isolate number if more than 1 per week in the same location (optional)
  • Genotype [optional initially, required after sequencing of at least 450 nucleotides of the N gene (text-only) is completed]
  • Special designation for sequences derived from measles inclusion-body encephalitis (MIBE), subacute sclerosing panencephalitis (SSPE) cases or vaccine reactions (VAC) (optional)

The following examples illustrate the WHO-approved nomenclature:

  • MVi/NewYork.USA/03.98/2 [D2]
  • MVs/London.UNK/17.97 [G3] SSPE

Download Measles Virus Nomenclature Update: 2012, published online in WHO's Weekly Epidemiological Record (WER), 2 March 2012. 87(9):73-80.

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Measles Strain Banks

In order to maintain reference stocks of viruses and provide facilities capable of conducting viral sequencing, two global Measles Strain Banks have been established. The Measles, Mumps, Rubella and Herpesvirus Laboratory Branch of the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, USA, and Health Protection Agency (HPA) in London, UK, were selected to serve this purpose.

Upon request, viral sequencing and analysis can be provided for measles virus characterization as well as storage of viral strains. Laboratorians are requested to consult with the CDC Measles Laboratory before reporting a new measles genotype. To report a possible new genotype of measles, contact prota@cdc.gov

Contact information:

CDC

Dr. Paul Rota
Centers for Disease Control and Prevention
MMR and Herpesvirus Laboratory Branch
Mailstop C-22
Atlanta, Georgia, 30333
USA
Email: prota@cdc.gov

HPA

Dr. Kevin Brown
Virus Reference Department
Health Protection Agency
61 Colindale Avenue
London NW95EQ
United Kingdom
Email: kevin.brown@hpa.org.uk

References

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