Rotavirus alphagastroenteritidis (rotavirus) infects a broad range of hosts, including humans and various animal species. Its genome comprises 11 segments of double-stranded RNA, making it highly prone to genetic diversity through gene reassortment. Although rotavirus strains are typically host-specific, novel human strains with global impact often originate from interspecies transmission of animal rotaviruses. This review explores the critical role of interspecies transmission coupled with genetic reassortment in rotavirus adaptation to humans, contextualizing key studies and methodological advances. Central to this progress was the development of tools to analyse entire genomes and distinguish homologous from heterologous strains. We trace the evolution from RNA-RNA hybridisation to whole-genome sequencing, which underpins genotype constellation and sub-genotype phylogeny. A decade-long surveillance of the bovine-like G8 rotavirus in Vietnam offers a compelling model: for an animal rotavirus to become a successful human pathogen, it must replace its animal-derived genes with human-derived counterparts through reassortment. Retaining the animal-origin G8 VP7 gene is enabled by acquiring a compatible human VP4 gene (specifically P[8]) and DS-1-like backbone genes. Building on this model of reassortment-driven adaptation, our investigation into the unusual G1P[6] strain AU19, of wholly porcine origin, supports the hypothesis that the predominant human G1 rotavirus also evolved from a successful interspecies transmission event. Phylogenetic analysis suggests the ancestral human G1 gene emerged from a porcine rotavirus between 1915 and 1948, later reassorting with human strains to acquire Wa-like backbone genes, ultimately becoming a stable and dominant part of the human rotavirus population. In conclusion, genetic reassortment is a key mechanism transforming sporadic zoonotic events into sustained human-pathogens, although other factors remain to be fully defined. We conclude by highlighting key areas for further research.

Vaccine Effectiveness against DS-1–Like Rotavirus in Infants with Acute Gastroenteritis

Rotavirus A (RVA) is a leading cause of severe diarrhoea in children, and interspecies transmission significantly drives the genomic diversity of human RVAs. Cats represent a key host species, requiring in-depth analysis regarding RVA transmission to humans. This review evaluated the literature on the complex genotype constellations of feline RVAs in relation to relevant canine and human RVAs to define the role of feline RVAs in the evolutionary history of human strains. The review traces the methodological shift from genogrouping by RNA-RNA hybridisation to the current genotype constellation system enabled by whole-genome sequencing. While early methods identified a shared genomic closeness between human AU-1 and feline FRV-1, whole-genome sequencing indicated that several human RVA strains, including AU-1, HCR3A, and Ro1845, likely resulted from direct transmission of feline/canine strains, due to shared genotype constellations and high sequence identity with animal strains like feline FRV-1, Cat97 and canine CU-1. Evidence of reassortment—such as the emergence of G1P[9] and G9P[9] strains after the feline-derived G3P[9] crossed into the human population—suggests these feline-like strains have successfully overcome the host-species barrier and are capable of onward human-to-human transmission, not just dead-end spillover events. However, definitive confirmation of sustained transmission or contemporary spillover requires stringent phylogenetic criteria: multiple human strains with >99% identical sequences in a monophyletic lineage for sustained transmission, or an identical human–feline pair across all genome segments for contemporary spillover. Confirming the status of the AU-1-like constellation as a third, low-frequency human RVA type requires future studies applying these strict criteria.

Most human rotaviruses belong to the Wa-like, DS-1-like, or AU-1-like genotype constellation. The AU-1-like constellation, albeit minor, captured attention because its prototype strain AU-1 originated from feline rotavirus, leading to the concept of interspecies transmission of rotavirus. The AU-1 genome sequence determined by various laboratories over the years has documented two conflicting VP7 sequences in the GenBank. As culture-adaptation may introduce changes in the viral genome, the original fecal (wild-type) and the seed stock of culture-adapted AU-1 genomes were sequenced using the Illumina’s MiSeq platform to determine the authentic AU-1 sequence and to identify what mutational changes were selected during cell-culture adaptation. The wild-type and culture-adapted AU-1 genomes were identical except for one VP4-P475L substitution. Their VP7 gene was 99.9% identical to the previously reported AU-1 VP7 under accession number AB792641 but only 92.5% to that under accession number D86271. Thus, the wild-type sequences determined in this study (accession numbers OR727616-OR727626) should be used as the reference. The VP4-P475L mutation was more likely incidental than inevitable during cell-culture adaptation. This was the first study in which the whole genomes of both wild-type and cultured RVA strains were simultaneously determined by deep sequencing.

In parts of Asia, including Vietnam, Rotavirus alphagastroenteritidis (formerly known as Rotavirus A ; RVA) strains of porcine origin, particularly G4P[6] strains, have been detected in humans at relatively high frequencies. This study investigated the origins of G4P[6] strains identified in Vietnamese children and examined possible factors underlying their frequent detection, based on molecular epidemiological analyses. Among the 1,252 RVA-positive faecal specimens collected over a 2-year period, 28 (2.2%) contained only the G4P[6] strain. Of these, 23 (1.8%) G4P[6] strains were successfully sequenced for their whole genomes, all of which were confirmed to be entirely of porcine RVA origin, with no evidence of genomic reassortment with human RVA strains. Two distinct clusters of G4P[6] strains (comprising two and three strains, respectively) shared identical genome sequences, suggesting the possibility of limited human-to-human transmission. In contrast, the remaining 18 G4P[6] strains were genetically distinct from one another, indicating multiple, independent interspecies transmission events from pigs to humans. Phylogenetic analysis revealed that the P[6] genome segments of porcine RVA or porcine-like human RVA strains, including those identified in this study, were genetically distinct from those of typical human RVA strains and showed notable geographic variation in detection frequency. Comparative analysis of the variable regions of P[6] amino acid sequences identified characteristic residues that distinguish porcine RVA-like P[6] from human RVA-like P[6], some of which correspond to known glycan-binding sites. This study revealed a high frequency of pig-to-human spillover transmission of porcine-derived G4P[6] rotavirus strains in Vietnamese children. The findings suggest that these cases were not the result of newly emerging strains capable of sustained human-to-human transmission. Furthermore, distinct amino acid characteristics in the porcine RVA P[6] protein were identified that may play a role in facilitating the cross-species transmission of rotavirus from pigs to humans.

Rotavirus vaccines carry a small risk of intussusception mainly 1–7 days after vaccination in the United States of America, Europe, Australia, and Latin America where the background rate of intussusception is relatively low. Such risks are undetectable in Africa and India where the background rate is the lowest. Because few studies were carried out in high-background-rate countries such as Japan, we examined how intussusception occurred in infants living in Akita prefecture, Japan, while the vaccines were sold in the private market. Between 2011 and 2018, an estimated 21,677 infants (46%) were vaccinated and 54% were not. Through a retrospective survey of medical records in 18 hospitals in the prefecture, we identified 58 infants, 28 of whom were vaccinated and 30 of whom were unvaccinated, as having intussusception that met level 1 of the Brighton criteria. Thus, the intussusception rate was 123 per 100,000 infant-years (95% confidence interval [CI]: 94–160). Despite the high rate, none developed intussusception 1–7 days after the first dose of either the monovalent human rotavirus vaccine (GSK) or the pentavalent human–bovine reassortant vaccine (MSD). The incidence rate ratio of vaccinated to unvaccinated infants between 42 and 245 days of life was estimated at 0.96 (95%CI: 0.43–2.1; p = 0.92). Given that over 95% of infants received the first dose before 15 weeks of age, the risk of intussusception associated with the rotavirus vaccines in high-incidence-rate countries can be reduced to a minimum by adhering to the recommended schedule at 2, 3, and 4 months of age.