Evolution, geographic spreading, and demographic distribution of Enterovirus D68

Abstract

BackgroundWorldwide outbreaks of enterovirus D68 (EV-D68) in 2014 and 2016 have caused serious respiratory and neurological disease.MethodsWe collected samples from several European countries during the 2018 out-break 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.FindingsIn 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.InterpretationWe 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.FundingUniversity of Basel and Swedish Foundation for Research and Development in Medical Microbiology

Enterovirus D68 epidemic, UK, 2018, was caused by subclades B3 and D1, predominantly in children and adults, respectively, with both subclades exhibiting extensive genetic diversity

“…Here we found a highly significant association between age and clade type, with subclade B3 predominantly affecting children and adolescents, whilst conversely D1 was seen in older adults and the elderly. This finding is in agreement with previous observations [8, 20, 22], but only one other study of sufficient size and scope to assign statistical significance [44].…”

“…We observed considerable genetic diversity within the VP1 regions of both the B3 and D1 subclades within our single epidemic season analysis, consistent and co-mingling with other contemporary European cohorts [19,20]. In conjunction with the post-summer spike in case incidence, this is suggestive of a high level of community infection seeded by many regional and international introductions, as described in more detail elsewhere [44]. Our complete VP1 sequencing, in conjunction with a detailed clinical audit, provides greater granularity than many other studies.…”

Enterovirus D68 epidemic, UK, 2018, was caused by subclades B3 and D1, predominantly in children and adults respectively, with both subclades exhibiting extensive genetic diversity

“…Here we found a highly significant association between age and clade type, with clade B3 predominantly affecting children and adolescents, whilst conversely D1 was seen in older adults and the elderly. This finding is in agreement with previous observations (8,19,21), but only one other study of sufficient size and scope to assign statistical significance (41).…”

“…We observed a considerable genetic diversity within the VP1 regions of both the B3 and D1 clades within our single epidemic season analysis, consistent and co-mingling with other contemporary European cohorts (18,19). In conjunction with the post-summer spike in case incidence, this is suggestive of a high level of community infection seeded by many regional and international introductions as described in more detail elsewhere (41) and foreshadowing SARS-CoV-2 pandemic dynamics (50). Our complete VP1 sequencing in conjunction with a detailed clinical audit provides greater granularity than many other studies.…”

“…The predominance of the novel D1 clade in hospitalized older adults may indicate an evolutionary adaptation of EV-D68 to evade a pre-existing immune response and facilitate repeat infection. Recent and rapid evolution of antigenic regions of the outer viral capsid corresponding to neutralizing epitopes has been suggested to be implicated (8, 21, 41). Lineage specific protection determined by a primary infection influencing virus-type age distribution has been described for several other viral infections, notably Influenza A and B (42, 43).…”