title: Measles virus genetic evolution throughout an imported epidemic outbreak in a highly vaccinated population.
abstract: Measles virus circulates endemically in African and Asian large urban populations, causing outbreaks worldwide in populations with up-to-95% immune protection. We studied the natural genetic variability of genotype B3.1 in a population with 95% vaccine coverage throughout an imported six month measles outbreak. From first pass viral isolates of 47 patients we performed direct sequencing of genomic cDNA. Whilst no variation from index case sequence occurred in the Nucleocapsid gene hyper-variable carboxy end, in the Hemagglutinin gene, main target for neutralizing antibodies, we observed gradual nucleotide divergence from index case along the outbreak (0% to 0.380%, average 0.138%) with the emergence of transient and persistent non-synonymous and synonymous mutations. Little or no variation was observed between the index and last outbreak cases in Phosphoprotein, Nucleocapsid, Matrix and Fusion genes. Most of the H non-synonymous mutations were mapped on the protein surface near antigenic and receptors binding sites. We estimated a MV-Hemagglutinin nucleotide substitution rate of 7.28 × 10-6 substitutions/site/day by a Bayesian phylogenetic analysis. The dN/dS analysis did not suggest significant immune or other selective pressures on the H gene during the outbreak. These results emphasize the usefulness of MV-H sequence analysis in measles epidemiological surveillance and elimination programs, and in detection of potentially emergence of measles virus neutralization-resistant mutants.
authors.affiliation: Virology Unit and National Reference Laboratory for Measles, Ramón y Cajal Hospital, Madrid, Spain.
authors.forename: Miguel Ángel
authors.initials: MÁ
authors.lastname: Muñoz-Alía
authors.affiliation: Virology Unit and National Reference Laboratory for Measles, Ramón y Cajal Hospital, Madrid, Spain. Electronic address: rafael.fernandez.mu@gmail.com.
authors.forename: Rafael
authors.initials: R
authors.lastname: Fernández-Muñoz
authors.affiliation: Centro Nacional de Biotecnología, Laboratorio de Estructura de Proteínas. CSIC, Cantoblanco, Madrid, Spain.
authors.forename: José María
authors.initials: JM
authors.lastname: Casasnovas
authors.affiliation: Virology Unit and National Reference Laboratory for Measles, Ramón y Cajal Hospital, Madrid, Spain.
authors.forename: Rebeca
authors.initials: R
authors.lastname: Porras-Mansilla
authors.affiliation: Virology Unit and National Reference Laboratory for Measles, Ramón y Cajal Hospital, Madrid, Spain.
authors.forename: Ángela
authors.initials: Á
authors.lastname: Serrano-Pardo
authors.affiliation: Centro de Biotecnología y Genómica de Plantas UPM-INIA and ETSI Agrónomos, Campus Montegancedo, Madrid, Spain.
authors.forename: Israel
authors.initials: I
authors.lastname: Pagán
authors.affiliation: Epidemiology Service, Madrid Health Ministry, Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Ordobás
authors.affiliation: Epidemiology Service, Madrid Health Ministry, Madrid, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Ramírez
authors.affiliation: Virology Unit and National Reference Laboratory for Measles, Ramón y Cajal Hospital, Madrid, Spain.
authors.forename: María Luisa
authors.initials: ML
authors.lastname: Celma
mesh_terms: D004196:Disease Outbreaks; D019143:Evolution, Molecular; D005814:Genes, Viral; D005838:Genotype; D006389:Hemagglutinins, Viral / Q000737:chemistry / Q000235:genetics; D006801:Humans; D008457:Measles / Q000453:epidemiology / Q000517:prevention & control / Q000821:virology*; D008459:Measles virus / Q000235:genetics* / Q000276:immunology*; D008958:Models, Molecular; D009154:Mutation; D059645:Mutation Rate; D011487:Protein Conformation
chemical_list: D006389:Hemagglutinins, Viral
keywords: Genotype B3.1 outbreak; Hemagglutinin protein; Measles virus; Natural Mutation rate