Evolution, geographic spreading, and demographic distribution of Enterovirus D68

Abstract

Worldwide outbreaks of enterovirus D68 (EV-D68) in 2014 and 2016 have caused serious respiratory and neurological disease. We collected samples from several European countries during the 2018 outbreak and determined 53 near full-length genome (‘whole genome’) sequences. These sequences were combined with 718 whole genome and 1,987 VP1-gene publicly available sequences. In 2018, circulating strains clustered into multiple subgroups in the B3 and A2 subclades, with different phylogenetic origins. Clusters in subclade B3 emerged from strains circulating primarily in the US and Europe in 2016, though some had deeper roots linking to Asian strains, while clusters in A2 traced back to strains detected in East Asia in 2015-2016. In 2018, all sequences from the USA formed a distinct subgroup, containing only three non-US samples. Alongside the varied origins of seasonal strains, we found that diversification of these variants begins up to 18 months prior to the first diagnostic detection during a EV-D68 season. EV-D68 displays strong signs of continuous antigenic evolution and all 2018 A2 strains had novel patterns in the putative neutralizing epitopes in the BC- and DE-loops. The pattern in the BC-loop of the USA B3 subgroup had not been detected on that continent before. Patients with EV-D68 in subclade A2 were significantly older than patients with a B3 subclade virus. In contrast to other subclades, the age distribution of A2 is distinctly bimodal and was found primarily among children and in the elderly. We hypothesize that EV-D68’s rapid evolution of surface proteins, extensive diversity, and high rate of geographic mixing could be explained by substantial reinfection of adults. Better understanding of evolution and immunity across diverse viral pathogens, including EV-D68 and SARS-CoV-2, is critical to pandemic preparedness in the future.

Genome Sequences of Rare Human Enterovirus Genotypes Recovered from Clinical Respiratory Samples in Bern, Switzerland

“…Outbreaks of EV-D68 were reported widely in Europe in 2018 ( 16 , 21 , 22 ). Together with six published sequences reported in 2018 in Basel, Switzerland ( 17 ), our study sheds light on the recent circulation of EV-D68 in Switzerland, a country with few data on this genotype to date. Furthermore, we present the first two sequences of the rarely reported EV-C105 genotype in Switzerland.…”

“…Sequence analysis showed that the Bern EV-D68 case clustered with subclade B3 sequences isolated from the United States ( Fig. 1A ), one of the most commonly reported EV-68 clades circulating worldwide in 2018 ( 16 , 17 ). Analysis of all EV-C105 sequences (VP1) in GenBank showed that the two identified Bern EV-C105 isolates may correspond to different circulating strains ( Fig.…”

“…Sequence analysis showed that the Bern EV-D68 case clustered with subclade B3 sequences isolated from the United States (Fig. 1A), one of the most commonly reported EV-68 clades circulating worldwide in 2018 (16,17). Analysis of all EV-C105 sequences…”

Acute flaccid myelitis in Switzerland – association with enterovirus D68

“…In Europe, recent seroprevalence studies from the Netherlands [23] and the UK [24] indicate that primary infection with this pathogen occurs early in life. Reinfections by different strains may be common later in life [25]. Data from Switzerland are scanty, but the isolation of EV-D68 from Swiss patients has recently been reported [25,26].…”

“…Reinfections by different strains may be common later in life [25]. Data from Switzerland are scanty, but the isolation of EV-D68 from Swiss patients has recently been reported [25,26]. Most infections solely induce an acute respiratory syndrome, but EV-D68 is -or has recently become [27] -neurotropic and has clearly been linked to acute flaccid myelitis epidemiologically [10], virologically [28], immunologically [29] and in animal models [30].…”