Review

Zoonotic aspects of rotaviruses

V. Martella a,*, Krisztian Banyai b, Jelle Matthijnssens c, Canio Buonavoglia a, Max Ciarlet d

a Department of Veterinary Public Health, University of Bari, Bari, Italyb Veterinary Medical Research Institute, Hungarian Academy of Sciences, Budapest, Hungaryc Department of Microbiology & Immunology, Rega Institute for Medical Research, University of Leuven, Leuven, Belgiumd Vaccine & Biologics Clinical Research, Merck Research Laboratories, North Wales, PA, USA

Veterinary Microbiology 140 (2010) 246–255

A R T I C L E I N F O

Article history:

Received 3 July 2009

Received in revised form 3 July 2009

Accepted 21 August 2009

Keywords:

Rotaviruses

Zoonoses

A B S T R A C T

Rotaviruses are important enteric pathogens of humans and animals. Group A rotaviruses

(GARVs) account for up to 1 million children deaths each year, chiefly in developing

countries and human vaccines are now available in many countries. Rotavirus-associated

enteritis is a major problem in livestock animals, notably in young calves and piglets. Early

in the epidemiological GARV studies in humans, either sporadic cases or epidemics by

atypical, animal-like GARV strains were described. Complete genome sequencing of

human and animal GARV strains has revealed a striking genetic heterogeneity in the 11

double stranded RNA segments across different rotavirus strains and has provided

evidence for frequent intersections between the evolution of human and animal

rotaviruses, as a result of multiple, repeated events of interspecies transmission and

subsequent adaptation.

� 2009 Elsevier B.V. All rights reserved.

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Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246

2. History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247

3. Impact of rotaviruses on human health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248

4. Rotavirus disease in domestic animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249

5. Evidence for interspecies infections by GARVs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249

6. Reassortment and interspecies transmission may generate novel human GARVs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251

7. Rotavirus vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252

8. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253

* Corresponding author at: Department of Veterinary Public Health, S.p.

per Casamassim km 3, 70010 Valenzano, Bari, Italy.

Tel.: +39 080 4679805; fax: +39 080 4679843.

E-mail address: v.martella@veterinaria.uniba.it (V. Martella).

0378-1135/$ – see front matter � 2009 Elsevier B.V. All rights reserved.

doi:10.1016/j.vetmic.2009.08.028

1. Introduction

Rotaviruses are enteric pathogens causing acute waterydehydrating diarrhea in various host species, includingbirds and mammals. Rotaviruses account for �611,000child deaths each year, mainly in developing countries(Parashar et al., 2006). Likewise, rotavirus-associatedenteritis is a major problem in young calves (Saif et al.,1994), weaning and post-weaning piglets (Kapikian and

Table 1

Distribution of group A rotavirus G types across the various animal species. Full circles indicate that the G type is epidemiologically relevant for the species.

Empty circles indicate sporadic description or low epidemiological relevance.

Species 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

Humans � � � � * * * � * * �Pig * � � � � * * � * � *Monkey � *Cattle * * * � � � *Sheep/Goat * � � * � �Horse � � * * � �Dog �Cat �Mouse �Rabbit �Birds � � � �

V. Martella et al. / Veterinary Microbiology 140 (2010) 246–255 247

Chanock, 1996) and foals (Conner and Darligton, 1980).Vaccines against the most important serologic group ofrotaviruses, GARVs, are available for the prevention ofrotavirus diseases in cows, pigs and horses, and, morerecently, they have been made available for the preventionof rotavirus disease in infants and young children (Heatonand Ciarlet, 2007).

Rotaviruses are classified into an individual genuswithin the family Reoviridae. Rotaviruses are 70–75 nm indiameter, icosahedral, triple-layered, and nonenveloped.The genome consists of 11 segments of double-stranded(ds)RNA (Estes, 2001; Kapikian et al., 2001). These 11genome segments encode at least six structural proteins(VP1 to VP4, VP6 and VP7) and, depending on strain, five orsix non-structural proteins. The virion is complex, and byelectron microscopy, its structure resembles a wheel (fromLatin rota). The genome is associated with two sub-coreproteins, the RNA dependent RNA polymerase, VP1, andthe guanylyltransferase, VP3. This structure is encased inthe core made up by the VP2 protein. The VP2 layer issurrounded by a middle-layer, containing the serogroupspecific antigen, VP6. The outer protein layer is made up bytwo proteins, the VP4 and the VP7. Because both surfaceantigens induce neutralizing antibodies and segregate in adependent manner, they formed the basis of a widelyaccepted binomial nomenclature, developed for GARVs. Inthis system, the VP4 is referred to as the P (protease-sensitive) antigen, and the VP7 as the G antigen(glycosylated) (Estes, 2001; Kapikian et al., 2001; Mat-thijnssens et al., 2008b). The various G and P types tend to

Table 2

Distribution of group A rotavirus P genotypes across various animal species. Full

or that it has been described only in that species to date. Open circles indicate

Genotype species 1 2 3 4 5 6 7 8 9 10 11 12 13

Man * * � * � * � � � �Pig * * � � * * �Monkey * � �Cattle � * � �Goat/Sheep � * � * �Horse * * * �Dog �Cat � �Mouse

Rabbit

Birds

segregate according to species-specific patterns across thevarious animal species (Tables 1 and 2).

Genetically, rotaviruses are diverse, and different genesegments are peculiarly distributed across various animalspecies, suggesting existing host species barriers and hostrange restriction. However, a number of gene segments,mostly those encoding the neutralizing antigens (definingG and P types), have been identified repeatedly in humansin different parts of the world during surveillance studies(Santos and Hoshino, 2005; Gentsch et al., 2005), providingevidence that animals may act as a source of virus and/or ofgenetic material for diversification of human rotaviruses.These findings warrant rotaviruses to be handled aspotential zoonotic pathogens. As most data are relatedto a single rotavirus serogroup (group A) our review willfocus primarily on these viruses, unless otherwisespecified.

2. History

First records on rotaviruses date back to 1950s and1960s, when virus particles resembling reoviruses wereidentified in the intestinal tissue of mice and rectal swab ofcaptive monkeys by using electron microscopy. In 1969,viruses with similar morphology were identified in faecalsamples of diarrheic cattle and serial passage of this virusrevealed its etiologic role in diarrhea. First human caseswere diagnosed only in 1973, when intestinal mucosa andthen stool extracts of diarrheic children were examined byEM for viral pathogens (Bishop et al., 1973). Based on the

circles indicate that the P type is epidemiologically relevant for the species

sporadic description or low epidemiological relevance.

14 15 16 17 18 19 20 21 22 23 24 25 26 27

� * �� � � �

�* � * �* �

�

� �� �

�

V. Martella et al. / Veterinary Microbiology 140 (2010) 246–255248

characteristic wheel shaped virion morphology, therotavirus name was proposed in this same time period(Flewett et al., 1974).

Subsequent improvements in diagnostic assays, parti-cularly those that were based on direct antigen detectionfrom stool samples allowed rotaviruses to be characterizedas an important cause of gastroenteritis in infants andyoung children (Kapikian et al., 1996). Combined use ofelectron microscopy, genomic RNA analyses (electropher-otyping) and various antigen-based methods not onlyrevealed the potential impact of rotaviruses on humanhealth, but also allowed to gain some insight into thegenetic and antigenic composition of rotaviruses andrevealed that rotavirus strains circulating in humans andanimals share a common group antigen. Since late 1970s,however, several atypical rotavirus strains have beendescribed that shared the virion morphology but lackedthe common group antigen and/or displayed unusualgenomic RNA electropherotypes. These antigenicallydivergent strains represented various serogroups ofrotaviruses (Saif and Jiang, 1994).

To date, seven serogroups (A to G) of rotavirus havebeen determined (Saif and Jiang, 1994) (Table 3). Althougheach rotavirus serogroup has been associated withdiarrhea, their distribution, epidemiology and impactshows remarkable differences in various host species.GARVs have been shown to be important cause of diarrheain humans and a variety domesticated and captivemammals as well as poultry. Non-GARVs are relativelymore often detected in healthy animals but an associationwith disease has also been reported. Group B and Crotaviruses have been identified in some mammalian hostspecies, including humans, while group E rotaviruses havebeen detected only in pigs. Thus far, group D, F and Grotaviruses have been identified exclusively in poultry(Saif and Jiang, 1994). Representatives of a novel humannon-group A-C rotavirus have been recently described(Yang et al., 1998; Yang et al., 2004; Alam et al., 2007). Thequestion whether they represent a new serogroup orbelong to one of the known non-group A, -B, and -Crotaviruses is unclear, as no serologic data are available forthis new strain and no sequence data are available forcomparison for reference strains within serogroups D to G.

Table 3

Main features of rotavirus serogroups affecting humans.

Rotavirus serogroup

A B

Age distribution <5 years children Mainly adults

Seroprevalence Almost 100% antibody-prevalence

by 5 years of age

?

Typical setting Sporadic cases

(outbreaks in adults)

Outbreaks (m

sporadic case

Geography Worldwide East- and Sou

Seasonality Yes ?

Typical mode of

transmission

Faecal-oral route, air-borne? Water

Animal host Various species of

mammals and birds

Pig, Cattle, Sh

Evidence for zoonotic

transmission

Yes No

?, data non available.

3. Impact of rotaviruses on human health

GARV infections heavily impact on human health. Inhumans, GARVs are detected in up to 50–60% of allchildhood hospitalizations due to acute gastroenteritiseach year. They cause annually an estimated 130 millionprimary infections among children <5 years of age. Ofthese, every 5th and 65th cases require medical visit andhospital admission, respectively, and 1 in 293 cases is fatal(�611,000 per year). More than 80% of fatal rotavirusinfections occur in developing countries, where poorhygiene and sanitation, malnutrition, higher incidence ofinfections seriously affecting the immune status havedetrimental effect on the outcome of rotavirus infections(Parashar et al., 2003, 2006). The epidemiology of GARVs iscomplicated. As with other enteric infections, GARV aretransmitted mainly via faecal-oral route. The stability ofGARVs in the environment accounts for the possibility ofwater- or food-born outbreaks. GARVs show year-aroundactivity in tropical areas, but show marked seasonalactivity in countries with temperate climate, where virusactivity peaks during winter and spring. A gradual shift ofrotavirus peak activity from south-western to north andnorth-eastern direction has been described in NorthAmerica and Europe (LeBaron et al., 1990; Koopmansand Brown, 1999). Recent reviews of surveillance studiessummarized global distribution of G–P combinations for16,474 and 18,516 strains, respectively, drawing the mainconclusion that majority of medically important strains(90% or so) belong to five major surface G and P antigencombinations, including G1P[8], G2P[4], G3P[8], G4P[8],and G9P[8]. Other strains may be periodically and locallyimportant, such as G5P[8] strains in Brazil during the1990s (Santos and Hoshino, 2005; Gentsch et al., 2005).The strain prevalence usually changes year-by-year and aparticular genotype that is predominant in one season maybe less active or absent in the next season. Conversely,strains that are undetected in one year may becomeimportant in the next year (Banyai et al., 2005; Rahmanet al., 2005; De Grazia et al., 2007).

Non-GARVs are considered to have considerably lesspublic health importance. However, a large water-bornegastroenteritis outbreak in the 1980s in China having

C ADRV-N like strains

All age groups Mainly adults

50–60% seroprevalence

by age of 60 years

?

ore recently

s)

Outbreaks and sporadic cases Outbreaks?

th-Asia Worldwide East- and South-Asia

? ?

Faecal-oral route, food? ?

eep, Rat Pig, Cattle, Dog ?

Yes No

V. Martella et al. / Veterinary Microbiology 140 (2010) 246–255 249

affected �1 million people has been linked to infectionwith group B rotaviruses, affecting mainly adults (Hunget al., 1984). More recently, group B rotaviruses wereidentified from sporadic cases of infantile diarrhea outsideChina and these recent strains were genetically differentfrom the Chinese strain (Ahmed et al., 2004; Kelkar andZade, 2004), suggesting that various group B rotavirusstrains are circulating in humans, or, are transmissible tohumans. Group C rotaviruses are considered endemic inmost geographic areas and cause usually <5% of gastro-enteritis-associated hospitalizations in childhood (Banyaiet al., 2006). However, group C rotaviruses may also causeoutbreaks associated with consumption of contaminatedfood or water. The limited genetic variability of group Crotaviruses in humans contrasts with the diversitycurrently seen in pigs (Martella et al., 2007b). It is unclearwhether this low diversity among human strains reflects amore recent introduction of group C rotaviruses from ananimal reservoir and their subsequent global spread invarious populations or just a sort of genetic constraintsagainst diversification. Nonetheless, the interspecies bar-rier even for group C rotaviruses seems not to be absoluteas demonstrated by a recent report describing porcine-related group C rotavirus strains in Brazilian children(Gabbay et al., 2008). The source of strain ADRV-Nidentified in an outbreak of diarrhea in China or a relatedstrain reported from a sporadic adult case in Bangladesh(Alam et al., 2007) has not yet been determined.

4. Rotavirus disease in domestic animals

Infection by GARVs is considered the major cause of calfdiarrhea worldwide. Rotavirus infection usually affectscalves within the first 4 weeks of life, causing importanteconomic losses related to death treatment costs andreduction in weight gain of affected animals. The etiologyof the disease involves diverse infectious agents (virus,bacteria and protozoa) and is worsened by several factorsincluding herd management, environment, and hostnutritional and immunological conditions (Saif et al.,1994; Bendali et al., 1999).

Porcine GARVs are associated with weaning and post-weaning enteritis in piglets (Lecce and King, 1978; Willet al., 1994). GARVs are one of the most frequently detectedviral agents associated with diarrhea affecting pigletsbetween 1 and 8 weeks of age (Saif et al., 1994). GARV mayalso be detected in non-diarrheic piglets (Lecce and King,1978). GARV infection of pigs has been recognised in bothenzootic and epizootic forms of diarrhea resulting ineconomic losses in commercial piggeries (Saif andFernandez, 1996). Co-infections by other enteric patho-gens (viruses, bacteria or parasites) likely trigger mechan-isms of synergism, worsening the disease in piglets. About70.8% of 1–three months-old pigs form 12 porcine herdswith enteritis outbreaks were found to be positive forrotavirus but 50.7% of the GARV-positive animals were alsopositive for either calicivirus or group C rotavirus (Martellaet al., 2007a).

Equine GARVs are the main cause of diarrhea in foals upto 3 months of age, causing severe economic loss due tomorbidity and mortality in studs. Typically, GARV-induced

disease is manifested by profuse watery diarrhea, dehy-dration, anorexia, abdominal pain, and depression.Although the disease is self-limiting, dehydration maybe fatal, especially in young foals (Conner and Darligton,1980). Serological surveys have detected antibody in mostadult horses, suggesting that equine rotaviruses areubiquitous (Conner and Darligton, 1980, Pearson et al.,1982).

GARVs are not regarded as major enteric pathogens ofcats and dogs. Rotavirus-like particles have been detectedat low frequency from both symptomatic and asympto-matic domestic carnivores (Marshall et al., 1984, 1987).Diarrhea has been reproduced in neonatal gnotobiotic dogsinfected experimentally with a canine GARV (Johnsonet al., 1983).

Rotavirus infection has been seen in several avianspecies, including chickens, turkeys, guinea fowls, phea-sants, partridges and pigeons (Battilani et al., 2003;Legrottaglie et al., 1997). Signs include mild to severediarrhea, dehydration, poor weight gain, increased mor-tality. Asymptomatic infections may also occur. Avianrotaviruses appear genetically heterogeneous, as evi-denced by the broad diversity of e-types. Also, avianGARVs appear distantly related to mammalian GARVs (Itoet al., 2001; Matthijnssens et al., 2008b). In a 2005–2006large-scale survey in USA, GARVs were detected by RT-PCRin 46.5% of the chicken flocks and 69.7% of the turkey flockstested (Pantin-Jackwood et al., 2008).

5. Evidence for interspecies infections by GARVs

Although rotaviruses infect particular species prefer-entially for which they have been defined as thehomologous strains, heterologous rotavirus infectionsmay occur in both, natural and experimental conditions.Studies in the rabbit and mouse model have demonstratedthat only homologous viruses replicate efficiently andspread horizontally (Ciarlet et al., 2000; Feng et al., 1994).Based on a Jennerian approach, animal strains that arenaturally attenuated in humans have been exploited forthe construction of candidate rotavirus vaccines forhumans. In a number of field trials with such candidaterotavirus vaccines, the rhesus rotavirus (RRV) strainMMU18006 and the bovine strains NCDV, UK and WC3were shown to replicate to a lower extent in humans thanin their homologous hosts but to induce immuneresponses (Clark et al., 1996; Clements-Mann et al.,2001; Kapikian et al., 1996; Vesikari et al., 1984; Vesikari,1996).

Conversely, a number of studies have also proven thatunder experimental conditions, rotavirus strains can infectand/or induce diarrhea in a heterologous animal model.Human GARV strains have been shown to cause disease inseveral newborn animals (Kapikian et al., 2001). In thepiglet model, virulent human GARV strains induceddiarrhea and viraemia, while attenuated human GARVstrains did not (Azevedo et al., 2005). In the rabbit model,RRV has been shown to replicate efficiently and transmithorizontally (Ciarlet et al., 2000). Also, a pigeon rotavirusstrain (PO-13) was shown to infect and cause diarrhea inmice (Mori et al., 2001).

V. Martella et al. / Veterinary Microbiology 140 (2010) 246–255250

Genetic analysis by RNA–RNA hybridization and full-length genome sequencing of field animal and humanGARV strains has provided several examples of directinterspecies transmission under natural conditions.Complete genome sequence analyses has revealedthat the G3P[3] human strains Ro1845 and HCR3A areclosely related to the canine strains CU-1, K9 and A79-10

Table 4

Genetic relationships among group A rotavirus strains of human and animal ori

nomenclature was proposed: Gx-P[x]-Ix-Rx-Cx-Mx-Ax-Nx-Tx-Ex-Hx, representin

NSP4–NSP5 gene, respectively. The letter x indicates the number of the genotype

DS-1-like and AU-like gene segments, respectively. In addition, colors yellow, blu

segments, some typical porcine VP4, VP7, VP6 and NSP1 genotypes, and the S

2008b).

and to the feline strain Cat97 in all the genomesegments (Tsugawa and Hoshino, 2008). Also, theG3P[14] human strain B4106, detected from a childwith enteritis, has been shown to share a high degree ofgenetic conservation in all the genome segments withthe G3P[14] lapine strain 30/96 (Matthijnssens et al.,2006a) (Table 4).

gin. To designate the complete genetic make up of a virus, the schematic

g the genotypes of the VP7–VP4–VP6–VP1–VP2–VP3–NSP1–NSP2–NSP3–

. The colors green, red, and orange (see colors on web) represent Wa-like,

e, and purple (see colors on web) represent avian PO-13-like rotavirus gene

A-11-like gene segments, respectively (modified by Matthijnssens et al.,

V. Martella et al. / Veterinary Microbiology 140 (2010) 246–255 251

6. Reassortment and interspecies transmission maygenerate novel human GARVs

The mechanisms driving rotavirus diversificationinclude positive accumulation of single point mutations,inter-segmental recombination, rearrangement, and nota-bly reassortment (Estes, 2001). Reassortment of animalviruses with human strains may create chimeric virusesbearing dsRNA segments of both the parental viruses.Presumably, when rotaviruses cross the host speciesbarrier, they are not naturally able to efficiently infect orspread in a new host. By acquiring human GARV-deriveddsRNA segments, such chimeric viruses would gain morechances to efficiently infect and spread among thepopulation of the new host. Certain genome segmentsare more likely involved in rotavirus adaptation to newhosts under natural conditions than others.

Attempts to investigate the genetic relationshipsamong the various GARV strains have been made usingRNA–RNA hybridization analysis (Nakagomi et al., 1989).By extensive use of RNA–RNA hybridization, it has beenshown that rotaviruses recovered from the same animalspecies constitute a separate genogroup and usually sharea high degree of overall genome homology. At least threegenogroups have been identified for human GARVs,namely Wa-like, DS-1-like and AU-1-like (Nakagomiet al., 1989). RNA–RNA hybridization has providedmolecular evidence to show close interspecies relation-ships between human and some animal strains, or confirmthe existence of naturally occurring rotavirus reassortantstrains, but the extent of the relationship among thehuman and animal genogroups could not be completelyelucidated (Nakagomi et al., 1989; Nakagomi and Naka-gomi, 2002).

Animal-like GARVs, either as sporadic cases or as largeepidemics have been detected in several occasions. Thereis evidence that heterologous GARVs of porcine origin ornatural porcine-human GARV reassortants may haveoccurred and spread successfully throughout humanpopulations in more occasions. In Latin America, unusualG5 rotavirus strains have been detected in children inBrazil since the early 1980s and subsequently in Argentinaand Paraguay (Bok et al., 2001; Carmona et al., 2004;Coluchi et al., 2002; Gouvea et al., 1994; Mascarenhas et al.,2002; Santos et al., 1998), that were shown to be, by eitherRNA–RNA hybridization or sequence analysis, naturallyoccurring reassortants between Wa-like human andporcine viruses (Alfieri et al., 1996). In South East Asia,in the 1987–1988 season, an epidemic of infantilegastroenteritis by unusual strains was reported inManipur, India (Ghosh and Naik, 1989). Sequence analysisof one such strains, RMC321, revealed G9P[19] specifi-cities, with at least nine genome segments clearly ofporcine origin, including the VP4 gene (Varghese et al.,2004). In a subsequent epidemiological study (1989–1992), such strains were still circulating within the localpopulation at a low frequency (2.1%) (Krishnan et al.,1994). In the meantime, in 1989, the G9P[19] strainsMc323 and Mc345 were isolated in Chiang Mai, Thailand,and shown to be genetically more related to porcine thanto human rotaviruses by RNA–RNA hybridization and

sequence analysis (Okada et al., 2000; Urasawa et al.,1992), suggesting that G9P[19] strains spread throughoutSouthern Asia in those years. In Europe, human GARVsresembling porcine P[6] strains in the VP4 have beenidentified in a scattered fashion but continuously (Martellaet al., 2006; Banyai et al., 2004; Martella et al., 2008).Porcine-like P[6] strains have also been identified inAfrican and Asian children (Esona et al., 2009; Ahmed et al.,2007)

Bovine GARVs have also contributed to the generationof novel human strains in several occasions. Strains withbovine-like VP7 and VP4 specificities G6, G8 and G10 havebeen detected worldwide in conjunction with a variety of Ptypes, P[1], P[2], P[4], P[6], P[8], P[9], P[11] and P[14](Santos and Hoshino, 2005). The unusual African G8P[6]and G8P[8] GARV strains may have arisen through severalreassortment events involving human G2P[4] strains, DS-1-like, and strains carrying the G8, P[6] and P[8] genotypes(Matthijnssens et al., 2006b). The bovine-like strains,G10P[11], are regarded as common human entericpathogen in the Indian subcontinent, and a G10P[11]candidate vaccine has been developed (Ward et al., 2008).Such viruses were first identified in 1993 in Bangalore,India (Dunn et al., 1993) and have been detected frequentlyin subsequent epidemiological studies (Kelkar and Ayachit,2000; Iturriza-Gomara et al., 2004). The prototypeG10P[11] Indian strain I321 by RNA–RNA hybridisationand sequence analysis was shown to have the genesencoding NSP1 and NSP3 of human origin and the otherdsRNA segments derived from bovine strains (Dunn et al.,1993; Das et al., 1993).

Human rotaviruses emerging globally in the lastdecade, such as G9 and G12, are likely to have originatedfrom animal species by gene reassortment. In theseparticular cases, the major surface antigen, the VP7, isthought to have originated from animal GARVs, sinceGARVs with similar G9 and G12 VP7 specificities have beenobserved in piglets (Ghosh et al., 2006; Hoshino et al.,2005; Teodoroff et al., 2005). Although several geneticlineages of both antigens have been described, only a singlelineage from each was able to adapt and spread in varioushuman populations. These modern lineages of G9 and G12specificities are now circulating in all continents, andparticularly, the G9 strains were seen to completely changethe local strain prevalence (Matthijnssens et al., 2008c;Rahman et al., 2007).

Complete genome sequencing of GARV strains appearspivotal to better understand the genetic relationshipsamong the various strains, the role of each gene segment inhost range restriction and the mechanism of rotavirusevolution. To deal with the classification of the increasingamount of complete rotavirus genomic data, an extendedclassification and nomenclature system was developedrecently (Matthijnssens et al., 2008a). This classificationsystem was based on a nucleotide cut-off value for the ORFof each of the 11 gene segments, which resulted inappropriate genotypes for each of the 11 rotavirus genesegments. In line with the G- and P- genotypes for VP7 andVP4 respectively, a one-letter code was assigned for each ofthe gene segments, and successive numbers for thedifferent genotypes. To apply, maintain and update this

V. Martella et al. / Veterinary Microbiology 140 (2010) 246–255252

rotavirus classification system, a set of guidelines waspublished, and a Rotavirus Classification Working Group(RCWG) was formed (Matthijnssens et al., 2008b) (Table 4).This new classification system revealed a close evolu-tionary relationship between human Wa-like and porcinerotavirus strains, and between human DS-1-like andbovine rotavirus strains, suggesting that these two majorhuman genogroups might have an animal origin (Mat-thijnssens et al., 2008a). Further studies have shown thatan unusual human G6P[6] rotavirus strain, B1711, wasmost likely the result of a reassortment between a humanDS-1-like rotavirus and bovine rotaviruses (Matthijnssenset al., 2008d) and that human P[14] strains might be theresult of multiple interspecies transmissions and reassort-ment events from sheep or other ruminants to humans(Matthijnssens et al., 2009) (Table 4).

7. Rotavirus vaccines

Vaccines for prevention of rotavirus disease in calves,piglets and foals have been available since many years.Prevention of rotavirus disease in these animals is based onparenteral administration of either inactivated or attenu-ated vaccines. In order to provide a strong immunity ofmaternal origin, the vaccines are administered to themothers in the late stage of pregnancy. This immunizationstrategy requires proper assumption of colostrum by thenewborns in order to transfer adequate levels of passiveimmunity.

Although the development of human vaccines hasstarted decades ago, only in recent years vaccines ofprevention of rotavirus diarrhea in infants and childrenhave been released. Initial vaccine studies concentratedon the classical ‘‘Jennerian’’ approach because thisapproach has the advantage that animal virus strainsare often naturally attenuated in humans, or can beattenuated by relatively few tissue culture passages. Thisapproach has been applied using several animal virusstrains as vaccine candidates, including rotavirus strainRIT4237 (derived from the bovine rotavirus NCDVstrain), bovine rotavirus strain WC3, and the rhesusrotavirus (RRV)-derived strain MMU18006 (Ward et al.,2008). All of these candidate vaccines were welltolerated and provided some cross-protection againsthuman rotavirus strains; however, the protection againstsevere disease varied widely across studies (Offit et al.,2003; Heaton and Ciarlet, 2007). While commercialpursuit of the RIT4237 vaccine was abandoned, furtherresearch focused on the RRV and WC3 strains to developmultivalent vaccines, using a modified Jennerianapproach by taking advantage of the natural propertyof rotaviruses to reassort in cell culture, composed ofhuman-animal reassortants containing an animal rota-virus genetic background with human rotavirus surfaceVP4 and VP7 proteins representing the most common Gand/or P types worldwide (Offit et al., 2003; Heaton andCiarlet, 2007).

The first multivalent live-attenuated oral rotavirusvaccine produced was the rhesus-human reassortantvaccine, RotaShieldTM, which consisted of RRV (G3) andthree RRV-based reassortant (G1, G3, G4) strains (Offit

et al., 2003). The vaccine demonstrated 49–83% efficacyagainst all rotavirus gastroenteritis and 70–95% efficacyagainst severe disease (Heaton and Ciarlet, 2007; Wardet al., 2008). After more than 15 years of development andclinical trials, RotaShieldTM was licensed by the UnitedStates Food and Drug Administration and incorporatedinto the US infant immunization program in 1998. In July1999, the Centers for Disease Control recommendedpostponing any further administration of RotaShieldTM

due to the possible association of the vaccine withintussusception (a bowel obstruction in which onesegment of bowel becomes enfolded within anothersegment), and RotaShieldTM was removed from the marketin October 1999 (Ciarlet and Estes, 2001; Offit et al., 2003;Heaton and Ciarlet, 2007).

Despite the observation of intussusception with Rota-ShieldTM, two other oral rotavirus vaccine candidates,RotaTeqTM (Merck & Co., Inc. Whitehouse Station, NJ) andRotarixTM (GlaxoSmithKline [GSK], Rixensart, Belgium),were developed and are now licensed in several countriesworldwide. However, very large Phase III clinical trialswere required to show that these vaccines were safe, welltolerated, and that there was no association withintussusception (Vesikari et al., 2006; Ruiz-Palacioset al., 2006). RotaTeqTM is a pentavalent combinationvaccine of five live-attenuated human-bovine reassortantrotavirus strains (containing human serotypes G1, G2, G3,G4, and P1A[8] and bovine serotypes G6 and P7[5] (Heatonand Ciarlet, 2007). RotarixTM is based on the attenuatedhuman G1P1A[8] rotavirus strain (Ward et al., 2008). BothRotaTeqTM and RotarixTM have been shown to be highlyefficacious in developed countries and Latin America(Heaton and Ciarlet, 2007; Ruiz-Palacios et al., 2006;Vesikari et al., 2006; Ward et al., 2008)

Another oral rotavirus vaccine, the Lanzhou LambRotavirus (LLR) vaccine, is licensed in China since 2000. TheLLR vaccine was developed directly from an ovine animalstrain, Lp14 (G10P[15]) (Ciarlet et al., 2008). The LLRvaccine was shown to be efficacious; however, the datahave not been confirmed postlicensure (Ward et al., 2008).Several other live rotavirus vaccine candidates are underdevelopment: the bovine (UK strain)-human reassortantvaccine, the human neonatal RV-3 strain, and the naturalbovine-human reassortant neonatal 116E strain haveprogressed to different stages (Ward et al., 2008). Novelapproaches in the development of rotavirus vaccinesinclude, recombinant E. coli-expressed VP6 proteins,inactivated vaccines, and virus-like particles (VLPs) havebeen tested in several animal models but none have beenevaluated in humans (Ciarlet et al., 1998; Bertolotti-Ciarletet al., 2003; Ward et al., 2008).

8. Conclusions

Evidence for interspecies transmission and for geneticreassortment between human and animal rotaviruses hasbeen continuously accumulating in the literature and, inparticular, some animal species, cows, pigs, cats and dogs,appear to contribute frequently to the antigenic/geneticdiversity found in human rotaviruses, presumably becauseof the close interactions between humans and these

V. Martella et al. / Veterinary Microbiology 140 (2010) 246–255 253

animals driven either by cultural and/or economic forces.Reassortant GARV strains bearing mixed genome con-stellations (dsRNA segments derived from both human andanimal viruses) seem to be more successful than com-pletely heterologous GARV strains (with all the genomesegments derived from animal viruses). Improved adapta-tion to the new host, coupled with the lack of specific pre-existing population immunity against the new strain,might account for the quick spread of the new GARVstrains, and for their persistence in human populations.There is concern whether the introduction of rotavirusvaccines for children could alter the forces and balancesthat drive rotavirus evolution. However, the widespreademergence of the G9 (and G12) genotypes in humans in theabsence of a rotavirus vaccine indicates that these eventsmay occur with or without the introduction of a newrotavirus vaccine. Continuous epidemiological surveil-lance is critical for understanding the short- and long-term effects of the vaccines on rotavirus ecology andimplementing future vaccine strategies.

Conflict of interest statement

None.

Acknowledgments

This work was supported by grants from the projectMolecular and Antigenic Evolution of Rotavirus Strains ofHuman and Animal Origin (ISS-NIH 2004) and from theproject 60% 2006 ‘‘Studio di rotavirus atipici umani edanimali’’ from the project Ricerca Corrente 2007 ‘‘Zoonosi einfezioni virali esotiche: fronteggiare le emergenze attra-verso un approccio integrato fra medicina umana eveterinaria’’ and from the Hungarian Scientific ResearchFund (OTKA, PD76364).

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