Antigenic Drift Defines a New D4 Subgenotype of Measles Virus

Abstract

The measles virus hemagglutinin (MeV-H) protein is the main target of protective neutralizing antibodies. Using a panel of monoclonal antibodies (MAbs) that recognize known major antigenic sites in MeV-H, we identified a D4 genotype variant that escapes neutralization by MAbs targeting the neutralizing epitope (NE) antigenic site. By site-directed mutagenesis, L249P was identified as the critical mutation disrupting the NE in this genotype D4 variant. Forty-two available D4 genotype gene sequences were subsequently analyzed and divided into 2 groups according to the presence or absence of the L249P MeV-H mutation. Further analysis of the MeV-N gene sequences of these 2 groups confirmed that they represent clearly definable, sequence-divergent D4 subgenotypes, which we named subgenotypes D4.1 and D4.2. The subgenotype D4.1 MeVs were isolated predominantly in Kenya and Ethiopia, whereas the MAb-resistant subgenotype D4.2 MeVs were isolated predominantly in France and Great Britain, countries with higher vaccine coverage rates. Interestingly, D4.2 subgenotype viruses showed a trend toward diminished susceptibility to neutralization by human sera pooled from approximately 60 to 80 North American donors. Escape from MAb neutralization may be a powerful epidemiological surveillance tool to monitor the evolution of new MeV subgenotypes.IMPORTANCE Measles virus is a paradigmatic RNA virus, as the antigenic composition of the vaccination has not needed to be updated since its discovery. The vaccine confers protection by inducing neutralizing antibodies that interfere with the function of the hemagglutinin protein. Viral strains are indistinguishable serologically, although characteristic nucleotide sequences differentiate 24 genotypes. In this work, we describe a distant evolutionary branch within genotype D4. Designated subgenotype D4.2, this virus is distinguishable by neutralization with vaccine-induced monoclonal antibodies that target the neutralizing epitope (NE). The subgenotype D4.2 viruses have a higher predominance in countries with intermediary levels of vaccine coverage. Our studies demonstrate that subgenotype D4.2 lacks epitopes associated with half of the known antigenic sites, which significantly impacts our understanding of measles virus evolution.KEYWORDS virus evolution, antibody-mediated neutralization, antigenic variation, measles virus hemagglutinin, viral epitopes, measles virus genotypes, immune evasion M easles ranks as one of the most deadly diseases in the history of humankind (1, 2). The advent of an effective measles virus (MeV) vaccine 46 years ago dramatically reduced the number of measles deaths (3), making the MeV live-attenuated vaccine one of the most successful public health interventions ever undertaken (4, 5). Nonetheless, measles is still a leading cause of death globally for children younger than 5 years of age and was responsible for 134,200 deaths in 2015 (6). All 194 WHO member states have committed to reducing measles deaths, and the Global Measles and Rubella

Measles Virus Infection and Immunity in a Suboptimal Vaccination Coverage Setting

“…Reduced efficacy of vaccine-induced immunity against wild type MeV strains has been hypothesized to play a role in measles reemergence [11,38]. In the case of mumps, infection in fully vaccinated individuals are not uncommon, and serum samples from vaccinated individuals have been shown to neutralize the currently circulating mumps virus genotype G less efficiently than other genotypes and the vaccine strain [39,40].…”

Laboratory Methods Supporting Measles surveillance in Queensland, Australia, 2010 – 2017

“…9,13,18 No strains of genotype B1-2, C1-2, D1-3, D5-7, D10-11, E, F, G1-2 or H2 were identified. We did not detect any genotypes considered extinct (B1, C1, D1, E, F,G1) 12 or inactive (D2, D3, D10, G2, H3). 10 The sequenced region includes the World Health Organization-recommended N450 amplicon encoding the carboxyl-terminal of the N gene.…”

“…MeV sequences associated with sequenced patients are marked in red, MeVV strain sequences in blue and WHO reference sequences, used to define genotypes and subtypes are marked in green. 12 Sequences are labelled using GenBank accession numbers. The phylogenetic analysis used the Neighbor-Joining method in a bootstrap test (500 replicates) in MEGA7.…”

“…The World Health Organization (WHO) has declared six genotypes, not detected for at least 15 years, as officially inactive and there are a further five genotypes with no documented cases since 2006. 12 RT-rPCR can also be designed to discriminate between wild-type MeV and vaccinederived measles virus (MeVV). This approach is useful to distinguish between wildtype MeV infection and MeVV in individuals who received MeV-containing vaccine as post-exposure prophylaxis following exposure to wild-type virus.…”

Bornaviruses in naturally infected Psittacus erithacus in Portugal: insights of molecular epidemiology and ecology

“…Therefore, co-infected reservoirs can play a role in the emergence of new virus variants, providing conditions for the occurrence of changes in virulence and in host range by two major ways: through recombination exchange between virus strains and through accumulation of amino acid changes that are under pressure by the immune system (antigenic drift event). Both events have been reported to occur within viruses belonging to the order Mononegavirales [31][32][33][34][35]. A previous study reported findings of Borna disease virus 1 (BoDV-1) genome segments in samples from wild birds (such as Anas spp.…”