Global distribution of rotavirus serotypes/genotypes and its implication for the development and...

Rev. Med. Virol. 2005; 15: 29–56.Published online 14 October 2004 in Wiley InterScience (www.interscience.wiley.com).

Reviews in Medical Virology DOI: 10.1002/rmv.448

Global distribution of rotavirus serotypes/genotypes and its implication for thedevelopment and implementation of aneffective rotavirus vaccineNorma Santos1* and Yasutaka Hoshino2

1Departamento de Virologia, Instituto de Microbiologia, Universidade Federal do Rio de Janeiro,Rio de Janeiro, RJ, 21.941-590, Brazil2Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases,National Institutes of Health, Bethesda, Maryland 20892, USA

SUMMARY

A safe and effective rotavirus vaccine is urgently needed, particularly in developing countries. Critical to vaccinedevelopment and implementation is a knowledge base concerning the epidemiology of rotavirus G and P serotypes/genotypes throughout the world. The temporal and geographical distribution of human rotavirus G and P types wasreviewed by analysing a total of 45571 strains collected globally from 124 studies reported from 52 countries on fivecontinents published between 1989 and 2004. Four common G types (G1, G2, G3 and G4) in conjunction with P[8] orP[4] represented over 88% of the strains analysed worldwide. In addition, serotype G9 viruses associated with P[8] orP[6] were shown to have emerged as the fourth globally important G type with the relative frequency of 4.1%. Whenthe global G and/or P type distributions were divided into five continents/subcontinents, several characteristicfeatures emerged. For example, the P[8]G1 represented over 70% of rotavirus infections in North America, Europeand Australia, but only about 30% of the infections in South America and Asia, and 23% in Africa. In addition, inAfrica (i) the relative frequency of G8 was as high as that of the globally common G3 or G4, (ii) P[6] representedalmost one-third of all P types identified and (iii) 27% of the infections were associated with rotavirus strains bearingunusual combinations such as P[6]G8 or P[4]G8. Furthermore, in South America, uncommon G5 virus appearedto increase its epidemiological importance among children with diarrhea. Such findings have (i) confirmed theimportance of continued active rotavirus strain surveillance in a variety of geographical settings and (ii) providedimportant considerations for the development and implementation of an effective rotavirus vaccine (e.g. ageographical P-G type adjustment in the formulation of next generation multivalent vaccines). Copyright # 2004

John Wiley & Sons, Ltd.

Received: 22 April 2004; Revised: 3 August 2004; Accepted: 3 August 2004

INTRODUCTIONInfectious acute diarrhea is a significant cause ofmorbidity and mortality of infants in developingcountries and an important cause of morbidity inthe same age group in developed countries. It isestimated that in developing countries in Africa,Asia and Latin America 744 million to 1 billioncases of diarrhea and 2.4 to 3.3 million deathsoccur annually among children under 5 years ofage, corresponding to 6600 to 9000 deaths per

day [1]. In developed countries, the mortality ratescaused by diarrhea are significantly lower.

Rotaviruses, which form a genus of the Reoviridaefamily, are classified into seven groups (A–G).Since their first detection three decades ago, groupA rotaviruses have been established as the singlemost important cause of severe acute gastroenter-itis in infants and young children in both devel-oped and developing countries and are estimatedto cause each year, 111 million episodes of diarrhearequiring only home care, 25 million clinic visits,2 million hospitalisations and 325 000–592 000deaths (median 440 000 deaths) in children of< 5 years [2]. Because of this enormous burdenof rotavirus disease among children worldwide,

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Copyright # 2004 John Wiley & Sons, Ltd.

*Corresponding author: N. Santos, Departamento de Virologia, Insti-tuto de Microbiologia, Universidade Federal do Rio de Janeiro, CidadeUniversitaria, CCS-Bl. I, Ilha do Fundao, Rio de Janeiro, RJ, 21.941-590, Brazil.E-mail: [email protected] or [email protected]

various candidate rotavirus vaccines have beendeveloped or are being developed [for reviewssee references 3,4,5]. Group B and C rotavirusesdetected in humans do not appear to be of epide-miological importance outside China wheregroup B rotaviruses were associated with severallarge outbreaks of severe diarrhea, predominantlyin adults [6,7].

An infectious rotavirus particle (¼ virion) pos-sesses 11 double-stranded RNA segments sur-rounded by three concentric protein layers. Theouter capsid consists of VP7 and VP4 thatcarry independent neutralisation and protectiveantigens: antibodies to either protein can conferresistance to virulent rotavirus in a type-specificmanner in experimental animals [for reviews, seereference 7]. Thus, a binary system of rotavirusclassification to designate the neutralisation speci-ficity of both VP7 and VP4 proteins was estab-lished [7,8]. The VP7 serotype is designated as G(because VP7 is a glycoprotein) serotype, where-as the VP4 serotype is designated as P (becauseVP4 is protease-sensitive) serotype. Fourteen Gserotypes have been established and the designa-tions for G serotypes (types determined by neutra-lisation assay) and G genotypes (types determinedby a non-serological assay) are identical. Ten Gtypes have been recovered from humans (G1–G6,G8–G10 and G12). Recently, a new G genotype(G genotype 15) was described for strain Hg18isolated from a single cattle farm near Bangalore,India, however, such a strain has not been testedby neutralisation assay for serotype determinationyet [7,9]. In contrast, the numbers assigned for Pserotypes and genotypes are different, therefore,the P serotype is designated as P followed byassigned number and the P genotype is designatedby a P followed by assigned number in brackets,e.g. P1A[8]. So far, 14 P serotypes have beendescribed, nine of which have been recoveredfrom humans (P1, P2A, P3, P4, P5A, P7, P8, P11and P12). Twenty three P genotypes have beendescribed ten of which have been recovered fromhumans (P[3]–P[6], P[8]–P[11], P[14] and P[19])[7,10,11]. Because the genes encoding the G andP antigens segregate independently, various P-Gcombinations have been observed.

In 1998, the US Food and Drug Administra-tion licensed a rhesus rotavirus (RRV)-basedquadrivalent vaccine (RotaShieldTM) that was desi-gned to cover four epidemiologically important G

serotypes, G1–G4. Whilst after administration ofapproximately 1.5 million doses, the vaccine waswithdrawn from the market by the manufacturerbecause of an association with intussusception[12–17], the recommendation for universal use ofthis vaccine in US infants by the Advisory Com-mittee on Immunization Practices and subsequentimplementation in routine childhood immunisa-tion of RotaShield has emphasised the need forcontinued surveillance of rotavirus serotypes/genotypes throughout the world. Indeed, in theUSA and Australia, National Rotavirus StrainSurveillance programs were established and havebeen conducting rotavirus G and P serotype/gen-otype surveillance since 1996 (USA) and 1993(Australia), respectively [18,19]. More recently,regional rotavirus strain surveillance groups havebeen established in Africa (African Rotavirus Net-work) and South East Asia (Asian Rotavirus Sur-veillance Network) to monitor the antigenicdiversity of circulating rotavirus strains [20,21].In Brazil, rotavirus strain surveillance has beenconducted consecutively in various locations since1982 [22–29]. It is interesting to note that the totalnumber of papers (34) used in this analysis thatwere published during a 10 year period (1989–1998) before the licensure of RotaShield is smallerthan that published (39) between 1999 and 2000alone. This reflects the efforts of worldwide sur-veillance groups to generate a rotavirus genotypereference database that could be used after theimplementation of a rotavirus vaccine to evaluatethe impact of such a vaccine on rotavirus fieldstrains bearing the same genotypes as the vaccinestrains and those bearing different genotypes. Inaddition to the identification of G and P sero-type/genotype of rotavirus field isolates, thedetermination of subgroup specificity, which ismediated by inner capsid protein VP6, is carriedout in some but not all rotavirus strain surveillancestudies. This is performed by subgroup specificmonoclonal antibody-based ELISA [30] or anamplification of a 379 bp cDNA of the VP6 geneby RT-PCR followed by sequencing or restrictionfragment length polymorphism analysis of theamplicon [31,32]. Since the VP6 gene segregatesindependently of the VP7 or VP4 gene, the deter-mination of subgroup specificity is useful in char-acterising individual rotavirus strains.

Previously, several review articles presentedexcellent overviews concerning the genetic and

3030 N. Santos and Y. HoshinoN. Santos and Y. Hoshino

Copyright # 2004 John Wiley & Sons, Ltd. Rev. Med. Virol. 2005; 15: 29–56.

antigenic diversity of rotavirus strains [33–35]. Theobjective of this article is to review the relative dis-tribution of rotavirus G and P serotypes/geno-types derived from globally collected databetween 1973 and 2003. In addition, studies onrotavirus VP4 and VP7 gene polymorphism arebriefly reviewed, since the comprehensive analysisof both genetic and antigenic diversity of rotavirusstrains may have significant implications for thedevelopment and implementation of an effectivenext generation rotavirus vaccine.

REVIEW OF GLOBAL EPIDEMIOLOGICALDATA OF ROTAVIRUS G AND P TYPESA total of 45571 rotavirus strains collected between1973 and 2003 included by reviewing 124 studiespublished between 1989 and 2004 from 52 coun-tries on five continents, were analysed for the rela-tive frequencies of various rotavirus serotypes/genotypes (Table 1, and references therein). A totalof 45571 rotavirus strains were characterised forthe G specificity; 17966 strains were characterisedfor P specificity; and 16474 strains were charac-terised for both antigens. Both non-typeable rota-virus strains and mixed rotavirus infections wereexcluded from the general analysis, however, theiroccurrence and importance in the context of rota-virus natural history are discussed. The reportsincluded in this analysis were selected based onthe availability of the manuscripts via MedLinesearch. To avoid potential duplicate reports ofsamples, samples reported from the same countrywere cross-referenced in light of a locality and atime period of sample collection.

Global distribution of human rotavirusG and P combinations detectedbetween 1973 and 2003As shown in Figure 1, rotavirus strains of fourglobally common rotavirus P-G combinationsP[8]G1, P[4]G2, P[8]G3 and P[8]G4 were responsi-ble for 88.5% of the rotavirus diarrhea amongchildren worldwide. When such global P-G combi-nation data were broken down by continent/subcontinent, it became clear that the distributionof various P-G combinations vary drastically fromone continent to another (Figure 2). For instance,the four major combinations, P[8]G1, P[4]G2,P[8]G3 and P[8]G4 represented over 90% of therotavirus infections in North America, Europe

and Australia. However, in South America andAsia they represented only 68%, and in Africa50%. The P[8]G1 combination alone representedover 70% of rotavirus infections in North America,Australia and Europe, whereas it representedabout 30% of infections in South America andAsia and only about 23% in Africa. It should benoted that in Australia the incidence of G9 strainshas increased considerably in the past 4 years,which could change the distribution of P-G combi-nations in that country shown in Figure 2. How-ever, because the Australian National RotavirusReference Center published only the results of Ggenotyping analysis during 1999–2002, such dataare not included in Figure 2.

Strains of other P-G combinations that are con-sidered unusual have also been described allover the world (Table 2) and represented 4.9% ofall isolates (Figures 1 and 2). The percentages ofsuch unusual strains were much higher in Africa(27%), Asia (14%) and South America (11%) thanin North America, Europe and Australia (5%,1.4% and 0.1%, respectively). Rotavirus strains car-rying P[4]G1 [27,36,37], P[8]G2 [36,38,39], P[4]G3[27,40–42], P[9]G4 [42], P[4]G4 [37,43], P[4]G9[22,44], P[10]G9 [44], P[6]G12 [45,46] or P[9]G12[47] specificity may represent naturally occurringreassortants among various human rotavirus gen-otypes [43]. On the other hand, unusual strainssuch as P[11]G3 [48], P[1]G4 [49], P[11]G4 [50],P[6]G5 [39], P[8]G5 [51], P[6]G6 [52], P[9]G6[19,53,54], P[14]G6 [53–56], P[1]G8 [57,58], P[2]G8[42], P[4]G8 [41,59–61], P[6]G8 [62], P[8]G8 [63],P[11]G9 [48] and P[19]G9 [64] are likely to repre-sent reassortants between human and animalrotavirus strains or even a direct transmissionfrom animal to human as in the case of rotavirusstrains with P[11]G10 specificity [65], since theycarry both P and G specificities generally regardedas animal types. Unusual P-G combinations couldemerge as the result of mixed rotavirus infections[43,66]. Actually, based on the data reviewed, mixedrotavirus infections have been detected in SouthAmerica, Asia, Africa, North America, Australiaand Europe, in an average of approximately 15%,12%, 10%, 4.8%, 2.3% and 1.8%, respectively. It isnoteworthy that in Bangladesh nationwide floodsbrought by the 1988 monsoon increased signifi-cantly the frequency of rotavirus mixed infectionfrom 8.1% (before the flooding) to 22.7% (afterthe flooding) [67]. The impact of those unusual

Rotavirus vaccineRotavirus vaccine 3131


Table 1. List of countries from which epidemiological data were obtained

References

Year(s) of sample P typesContinent Country collection G types onlya only P and G types

Americas Argentina 1996–1999 100,103,140,199Brazil 1982–2003 23,28,29,155,200 38 22,24–27,39,51,101,102,201Canada 1984, 1997–1998 155,202Chile 1985–1993 203Mexico 1986–1991, 73,204 72,89,205,206

1994–2001Nicaragua 1994 207Paraguay 1999–2000 49Peru 1983, 1986 73,155United States 1987–1989, 1996–1999, 73 19,37,45,112,132

2001Venezuela 1988–1993 208

Asia Bangladesh 1985–1997 209 117China 1982–1986, 1994–2000 73,210,211 131India 1984, 1986–2001 108,155,212 46,48,50,58,65,104,109,

118,144,213Indonesia 1978–1979 214Israel 1987, 1991–1994 73 138Japan 1982–2000 33,116,215 216 139,217Malaysia 1997–1998 218Myanmar 1986 155(Burma)Pakistan 1985, 1990–1997 155,219Philippines 1987–1988 220 145Korea 1988, 1998–2000 73,146 221Saudi Arabia 1995–1996 222,223Sri Lanka 1987 155Thailand 1982–1997 224 47,64,217Taiwan 1991–1997 225 226Vietnam 1998–2000 227 36,228,229

Africa Botswana 1999–2001 230Central Africa 1983–1985 156RepublicEgypt 1992–1993, 1995–1996 75,231Gambia 1982–1984 156Ghana 1998–2001 40,44,80Guinea-Bissau 1996–1998 42,61Kenya 1982–1994 156 60Malawi 1997–2000 41,59,62Nigeria 1989, 1999–2000 156 57South Africa 1978, 1984–1989 73 92 153,156Tunisia 1995–1999 74

Continues



strains on rotavirus evolution is yet to be deter-mined, however, such strains could provide theopportunity for introduction of novel P or G genesinto human population via reassortment events

[68]. Of note is the finding that some of the unu-sual P-G combinations, such as P[4]G1, P[8]G2,P[4]G3 and P[4]G4 have been detected at relativelyhigh frequency in different parts of the world(Table 2) which may suggest their genetic stabilityand potential capability of spreading among thepopulations.

Occurrence of non-typeable rotavirus strains hasbeen reported in almost every epidemiologicalsurvey around the world regardless of the metho-dology employed. Because rotaviruses have beendemonstrated to undergo constant genetic varia-tion via sequential point mutations or ‘antigenicdrift’, genetic reassortment or ‘antigenic shift’,genomic rearrangement or intragenic recombina-tion [43,66,69,70], the emergence of strains thatcannot be typed by the currently available meth-odologies is not unexpected [71]. The rates ofnon-typeable samples reported in studies thatemployed only the EIA ranged from 8% to 46.2%[72–76]. This could be due to the existence ofmutant strains that escape the recognition by

Table 1. Continued

References

Year(s) of sample P typesContinent Country collection G types onlya only P and G types

Europe Albania 2000 124Austria 1997–1998 232Estonia 1989–1992 233Finland 1984, 1986–1990, 157

1993–1995France 1995–1998 234 120,235Germany 1997–1998 236Hungary 1984–1992, 1994–2000 141,157 54,152Ireland 1995–1998 79,105Italy 1981–1994 157 53,121,122,134Spain 1989–2002 123,237,238 239Sweden 1983, 1985 155,157Switzerland 1998 240Netherlands 1990 157 133United 1995–1998 155,157 63,119Kingdom

Australia/ Australia 1973–1974, 76,82–84 55,81,126Oceania 1977–1989,

1993–1996,1999–2002

aG type only (or P type only or G and P types) analysed in indicated reference(s).

Figure 1. The global distribution of human group A rotavirus P-

G types (n¼ 16 474) reviewed from 124 studies from 52 countries

on five continents published between 1989 and 2004



monoclonal antibodies [77,78] or due to the pre-sence of unusual serotypes (e.g. G5, G6, G8, G10or G12) that are undetectable by the monoclonalantibodies regularly used in the EIA for humanrotavirus characterisation. The development andapplication of RT-PCR assays for rotavirus geno-typing have reduced the rates of non-typeablestrains, however, such assays also suffer frominherent shortcomings; strains containing a spon-taneous mutation(s) at the primer binding site(s)cannot be typed. The detection rates of non-type-able strains reported in selected studies in whichonly the RT-PCR was used ranged from 16% to65% [22,42,50,57,79,80]. In some studies a combina-tion of EIA, RT-PCR and probe hybridisation wasused, however, 7.8% to 26.6% of strains remainednon-typeable [81–84] probably due to rotavirusgenetic variation [85–88]. In some studies VP4-

and/or VP7-encoding genes of the selected non-typeable strains were sequenced and demon-strated to belong to common P or G genotypes[59,89], however, the non-typeable strains couldrepresent unusual or even new rotavirus geno-types [46–48,51–53,55,56,90–93]. Studies to investi-gate such non-typeable strains would provide amore accurate knowledge on rotavirus epidemiol-ogy and evolution. Recently, in order to overcomeinherent shortcomings of traditional rotavirustyping assays such as EIA and RT-PCR, severalnew methodologies have been developed whichinclude (i) an oligonucleotide microarray hybridi-sation [94,95] and (ii) a PCR-ELISA [96]. Bothassays are rapid, reliable and highly sensitive. Inaddition, since both assays employ multipletype- specific probes/G or P type, which providea high redundancy of test results, they can

Figure 2. Continental/subcontinental distribution of human group A rotavirus P-G combinations



reduce erroneous or ambiguous typing resultstremendously.

Continental/subcontinental variation inthe distribution of human rotavirusG and P types from 1973 to 2003In each of the five continents/subcontinents G1was the predominant G type. In Asia, NorthAmerica and Europe G1–G4 strains accountedfor over 97.5% of all rotavirus infections analysed,whereas in South America, Africa and Australiathe relative frequency of G1–G4 strains was 89%,83.5% and 90.4%, respectively (Figure 3). In Africa,

strains bearing type G8 specificity have beendetected at high frequency since the mid-1990srepresenting the fourth most common genotype(12.8%), whereas outside of Africa G8 strainshave seldom been detected (Figure 3). So far,rotavirus type G5 has been detected in humansonly in South America, more precisely in Brazil,Argentina and Paraguay except for one singleisolate in Cameroon (Africa) [97]. It has notreached North America yet as of 2002. In Australiabetween 1973 and 2002, rotavirus G9 accounted for9.6% of rotavirus infections, a higher frequencythan globally common G3 or G4 types. In South

Table 2. Continental variation in the distribution of unusual P-G combinations of humanrotaviruses between 1973 and 2003

SouthP-G combinations America Africa Asia North America Europe Australia Total

P[4]G1 33a 1 63 51 59 1 208P[8]G2 19 12 8 10 49P[3]G3 1 1 2P[4]G3 18 37 3 4 62P[11]G3 2 2P[14]G3 1 1P[1]G4 1 1P[4]G4 2 21 14 8 45P[9]G4 1 1P[11]G4 5 5P[8]G5 56 56P[6]G5 1 1P[6]G6 1 1P[9]G6 1 16 17P[14]G6 2 3 5P[1]G8 1 2 3P[4]G8 1 47 48P[6]G8 189 189P[8]G8 1 1 2 4P[14]G8 2 2 4P[4]G9 3 1 2 1 7P[10]G9 2 2P[11]G9 53 53P[19]G9 2 2P[9]G10 1 1P[11]G10 44 44P[14]G10 1 1P[6]G12 2 1 3P[9]G12 3 3Total 135 284 215 80 100 6 820

aValues indicate the number of strains reported.



America G9 genotype was more prevalent (8.6%)than genotype G3 (4.4%), being the fourth mostcommon genotype in the continent, almost thesame frequency as the third most common geno-type G4 (8.8%). Interestingly, the distribution oftypes G1–G4 in North and South Americas wasconsiderably different. The percentage distributionof such G types in South America was similar tothat in Africa and Asia whereas the relative fre-quencies of types G1–G4 in North America weresimilar to those in Europe and Australia (Figure 3).

With respect to P types, in each continent/sub-continent, (i) P[8] was the predominant type and(ii) types P[8] and P[4] accounted for over 90% ofall rotavirus diarrheal cases except for Africawhere its unique P type distribution pattern was

demonstrated: the relative frequency of such Ptypes was only 70.0% (Figure 4). P[6] typesaccounted for almost one-third of all P typesdetected which was second only to P[8] in fre-quency in that continent. These findings couldhave important implications for rotavirus vaccina-tion campaigns in these locations.

CLINICALLY IMPORTANT G TYPESOTHER THAN G1–G4

G5 rotavirus strainsType G5 rotavirus is an important and com-monly detected pathogen of swine and has alsobeen identified in equine [7]. In 1994 Gouvea and

Figure 3. Continental variation in the distribution of human group A rotavirus G types (n¼ 45 571) ascertained by analysis of strains

collected between 1973–2003



colleagues first demonstrated the occurrence ofrotavirus genotype G5 among Brazilian childrenwith diarrhea in a nationwide survey and showedthat such strains have been circulating in Brazilsince 1982 (IAL-28-P[8]G5, the prototype strain)[51,98]. The wide circulation of G5 type virusesin Brazil was later confirmed by others [23,24,39]to be exclusively in association with P[8] genotype,subgroup II specificity (and long electrophero-type), with the exception of one single strain bear-ing P[6]G5 genotype specificity [39]. Southernblot hybridisation, RNA-RNA hybridisation andsequence analysis of two Brazilian P[8]G5 isolateshave indicated that these strains are likely to benaturally occurring reassortants between human(P[8], Wa-like) and animal (G5, OSU-like) strains

[99]. The detection of rotavirus G5 among childrenwith diarrhea has also been reported in Argentinaand Paraguay, indicating the spread of this virusacross South America [49,100]. However, its inci-dence in Brazil appears to be decreasing lately[22,26,39,101,102]. For instance, in the city of Rio deJaneiro, where a surveillance program has beenconducted since 1982, the incidence of rotavirusG5 strains has ranged from 5.6% (1982–1994),57% (1996), 14.3% (1997) to 0% (1998–2003) (Figure5A) [22–24,26,51] indicating a periodic fluctuationin incidence as has been described for other Gtypes [19,79,103–105]. Recently, the detection ofone single rotavirus P[8]G5 isolate was reportedin Cameroon, Africa, with subgroup I specificity(and short electropherotype) [97]. Phylogenetic

Figure 4. Continental variation in the distribution of human group A rotavirus P types (n¼ 17 966) ascertained by analysis of strains

collected between 1982–2003



analysis of the VP7 gene of this isolate showedthat it was more closely related to porcine rota-virus G5 strains than human G5 strains, suggest-ing that the Cameroonian G5 strain was alsolikely to represent a reassortant between humanand porcine strains.

G8 rotavirus strainsSerotype G8 virus, which can be found in cows atrelatively high frequency [7], was first isolated in astudy performed between 1979 and 1981, fromstool specimens collected from children withdiarrhea in Jakarta and Medan, Indonesia in asso-ciation with P[10] genotype (prototype strain 69M)[106]. Such G8 strains demonstrated a distinctRNA electrophoretic migration pattern called‘super short’. Since then very few reports of sucha G serotype have been published [63,81,107,108],except for some countries in Africa where it hasbeen detected in an increasing frequency since1997–1998 [41,80,88,90]. For instance, G8 strainsrepresented 34.1% of the rotavirus single infec-tions between 1997 and 1999 in Blantyre, Malawi[59] and 27.7% of the rotavirus single infectionsin Nigeria between 1999 and 2000 [57]. Interest-ingly, the majority of these G8 human strains arenot associated with the P[10] type, but present agreat diversity of P-G combinations such asP[8]G8, P[4]G8, P[6]G8, P[1]G8, P[2]G8 andP[14]G8 [41,42,53,57–62,80,88,90,107,109], which issimilar to those found in G9 type. Because of thesegmented nature of the rotavirus genome, indivi-dual gene segments reassort at relatively high fre-quency following co-infection in vivo or in vitro.

This enormous diversity of P-G combinationsmay have resulted from genetic reassortmentbetween two different human rotaviruses orhuman and animal rotaviruses.

G9 rotavirus strainsThe relative frequency of genotype G9 strains,usually detected in association with P[8] or P[6],appears to be increasing recently, and these strainsalready represent 4.1% of global rotavirus infec-tions, a rate higher than P[8]G3 strains (3.4%)that used to be the fourth most prevalent strains(Figure 1). Rotavirus G9 strains were initiallydetected in Philadelphia, PA, USA, during 1983–1984 in 9.2% of infants with rotaviral disease[110], became undetectable for about one decadeand then reemerged in the same city with an inci-dence of 50% of rotavirus diarrhea in 1995–1996[111]. Since then G9 strains have been detected ata lower frequency in other US cities as well[19,112]. They were also detected sporadically inchildren with diarrhea in Japan and Thailand inthe 1980s [113–116]. However, G9 type wasreported to be the most prevalent serotype inTokyo and Sapporo, Japan, from 1998 to 1999with a high prevalence rate of 52.9% and 71.4%,respectively [116]. In Australia serotype G9 wasidentified for the first time in the season of 1999–2000, although retrospective analysis showed thepresence of three G9 virus isolates in the countryin 1997 [82]. In the seasons 1999–2000 and 2000–2001, it was the second most common G typeresponsible for 10% and 18.1%, respectively, ofthe infections in the country [82,83]. In the season

Figure 5. Temporal distribution of rotavirus type G5 in Rio de Janeiro, Brazil (1982–2003) (A) and type G9 in Alice Springs and

Melbourne, Australia (1993–1996, 1999–2001) (B). Data were taken from references [22–25,51,81–84]



2001–2002 G9 was the most important infectingrotavirus serotype in the country representing40.4% of the isolates [84]. In the city of AliceSprings the incidence of G9 was 0%, 21.8%, 57%and 80.5% in the 1993–1996, 1999–2000, 2000–2001 and 2001–2002 seasons, respectively; in Mel-bourne during the same period the incidencewas 0%, 11%, 23.3% and 13.3%, respectively (Fig-ure 5B) [76,81–84]. In 1995 rotavirus G9 genotypeemerged in Bangladesh and became predominantin 1996 and 1997 [117]; in India it has beenreported since 1993 as a common serotype[48,50,118]; in Africa the circulation of rotavirusG9 has been demonstrated across the continentsince 1997–1998 [20,41,44]. It has also beendetected in the UK since 1995–1996 [63,119], inFrance since 1997–1998 [120], in Italy since 1990–1994 [121,122], in Brazil since 1997 [26,27,102], inArgentina since 1996–1998 [100,103], in Hungarysince 1997–1998 [54], in Spain since 1998–1999[123], in Paraguay since 1999–2000 [49] and inAlbania since 2000 [124] (Figure 6).

Sequence analysis of the VP7 gene of various G9isolates has demonstrated the existence of at leastthree phylogenetic lineages [85]: lineage 1 (G9strains isolated in the 1980s in the USA and Japan),lineage 2 (G9 strains isolated in India only, thusfar), and lineage 3 (contemporary G9 strains pre-vailing throughout the world). A number of minorlineages also exist [125]. A great diversity has also

been demonstrated for some of the other genesamong rotavirus G9 isolates (Table 3). As depictedin Figure 6, in the past decade, the number ofcountries that reported the detection of rotavirusG9 strains has increased dramatically whichclearly indicates the efficient spreading of suchstrains throughout the world. Thus, type G9 hasestablished itself as a globally common rotavirusG serotype of clinical importance [19,26,41,44,100,102,112,116,118–120,126]. Besides humans, G9

Figure 6. Temporal spreading of rotavirus serotype G9 around

the world since 1983. Countries included in this figure: United

States, Japan, India, Thailand, Italy, Bangladesh, UK, Argentina,

Brazil, Australia, Spain, France, Malawi, Ireland, The Nether-

lands, Paraguay, Ghana, China, Hungary, Libya, Kenya, Cuba,

Albania and Mexico. Arrows indicate the emergence of lineages

1 , 2—", and 3— G9 strains, respectively

Table 3. Genomic and antigenic diversity of selected genotype G9 rotavirus strains

VP7 geneVP6 gene VP4 gene

(G type)a Lineage (Subgroup)a (P type)a E-typeb Representative strains [ref.]

G9 1 II P[8] L WI61[110]G9 2 II P[11] L 116E[48]G9 3 II P[8] L US1212[112]G9 3 ?c P[9] L R44 [102]G9 3 I P[8] S BD431[117], US1343[112]G9 3 I P[6] S US1205[112], US1206[112]G9 3 II P[6] L INL1[160], INL16[160]G9 3 I P[4] S R178c[85], Italian isolate[134]G9 3 ? P[4] L Brazilian isolate[26]G9 3 I P[19] L Mc323[64]

aAntigenic specificity carried by indicated protein.bElectropherotype, L, long; S, short.cSubgroup specificity unknown.



rotavirus strains have been detected in pigs andsheep [7].

CLINICALLY IMPORTANT P TYPESOTHER THAN P[8] AND P[4]

P[6] rotavirus strainsInitially rotavirus strains bearing genotype P[6]in association with each of the four major Gtypes (G1–G4) were detected in asymptomaticallyinfected neonates in hospital nurseries in Australia,Sweden, Venezuela and England [127,128]. Morerecently, studies conducted in other countriesamong hospitalised children without diarrhealsymptoms have demonstrated the circulation ofstrains bearing P[6]G8 or P[6]G9 specificities[48,62]. Because those so-called nursery strainsshare the same VP4 specificity distinct from thatof so-called virulent strains and were characteristi-cally associated with endemic and predominantlysymptom-free infections in newborn babies, theywere considered to be naturally attenuated andthus two of these P[6] strains have been developedas a candidate vaccine (Table 4). However, itshould be noted that in the United States andSouth Africa rotavirus strains were isolated inthe 1980s from diarrheic children that carried theVP4 gene of the nursery strains [129,130]. Morerecently, rotavirus strains bearing the same P[6]allele have been detected from an increasing num-ber of children with diarrhea, hospitalised or not,worldwide [19,25,26,41,74,100,112,118,120, 131–133]. Two studies in Brazil among children withdiarrhea reported the detection of rotavirusesbearing P[6] specificity in 6% and 13% of the sam-ples, respectively [25,26]. In Argentina, 18% of allrotavirus strains associated with diarrhea between1998 and 1999 were demonstrated to bear P[6]G9specificity [103]. One study among hospitalisedchildren with acute diarrhea in India, in 1993,reported the incidence of 43% of P[6] strains[118]; and another study among hospitalised chil-dren in Eastern India between 1998 and 2000reported the occurrence of P[6] strains in 6% ofthe isolates [104]. In Blantyre, Malawi, 1997–1999,P[6] strains were detected in 32% of the rotavirusisolates [41]. Rotavirus P[6] strains represented17% of all strains analysed in Bangladesh in 1995[117]. Strains with P[6] specificity have also beendetected among children with diarrhea in France[120], China [131], USA [19,112], Tunisia [74],

Ghana [44], Italy [134], the UK [63,119] and theNetherlands [133]. Genotype P[6] has also beendetected in pigs [7].

P[9] rotavirus strainsGenotype P[9] is frequently detected in cats [7].The first P[9] human rotavirus, strain K8, in asso-ciation with G1 specificity was isolated from aschoolboy of 14 years of age, in Hokkaido, Japanin 1977 [135]. The second P[9] strain, named AU-1, was recovered from an infant with diarrhea inAkita, Japan in 1982 [136] which bore G3 specifi-city. The AU-1 strain displays a long and distinctRNA pattern as demonstrated by polyacrylamidegel electrophoresis, subgroup I specificity andhas been shown by RNA-RNA hybridisation tobe most closely related to feline rotavirus strainssuggesting the occurrence of a possible inter-species transmission from cat to human [137].Thus far, all the P[9] strains (all sporadic cases)have been shown to carry G1 or G3 specificity[19,24, 40,53,54,102, 138], except for a few isolatesidentified in the USA, Italy and Hungary with a G6specificity [45,53,54], in Thailand, Japan andArgentina with G12 specificity [47,139,140], anotherone detected in Guinea-Bissau with G4 specificity[42] and two isolates detected in Brazil withP[9]G9 and P[9]G10 specificities [85, Santos et al.,unpublished data]. However, in 1997 for the firsttime, a small outbreak of diarrhea among childrenassociated with P[9] strains was described in Riode Janeiro, Brazil [102].

SELECTED HUMAN ROTAVIRUS STRAINSWITH UNCOMMON G OR P TYPES

G6 rotavirus strainsSerotype G6 is the commonest rotavirus G typefound in cows and at low frequency in sheepand goats [7]. In a study conducted in Italy during1987–1988, two rotavirus strains with P[9]G6(PA151 strain) or P[14]G6 (PA169 strain) were iso-lated from hospitalised children with acute gastro-enteritis [53]. Since then rotavirus G6 strains havebeen detected sporadically in humans in Australiain association with P[14] specificity [55,56], India(with unknown P specificity) [108], the USA (inconjunction with P[9] specificity) [45] and Belgium(in association with P[6] specificity) [52]. A recentstudy in Hungary reported the circulation of rota-virus G6 strains in conjunction with P[9] or P[14]with a prevalence of 1.3% since 1995–1996 [54,141].



Table 4. Past and present rotavirus candidate vaccines

Serotype Company orVaccine Concept and formulation [Genotype] producer Status

Jennerian approachRIT 4237 Monovalent live oral bovine P[1]G6 Smith Kline Beecham Discontinued

NCDV strain (Belgium)WC3 Monovalent live oral bovine P[5]G6 Merck (USA) Discontinued

WC3 strainRRV Monovalent live oral rhesus P[3]G3 DynCorp (USA) Discontinued

MMU 18006 strainLLR Monovalent live oral lamb P[12]G10 Lanzhou Institute of Active.

LLR strain Biological LicensedProducts (China) (China 2000)

Modified Jennerian approachWa�UK Monovalent live oral human P[8]G6 DynCorp (USA) Active.

(Wa)-bovine (UK) reassortant Phase IWaxDS-1�UK Monovalent live oral human P[8]G2 DynCorp (USA) Active.

(Wa and DS-1)-bovine (UK) Phase Ireassortant

RotaShield Quadrivalent live oral P[3]G1, G2, Wyeth Ayerst Licensedhuman-rhesus (RRV) G3, and G4 (USA) (USA 1998)reassortants Withdrawn

1999RotaTeq Pentavalent live oral P[5] G1, G2, Merck (USA) Active.

human-bovine (WC3) G3, G4, Phase IIIreassortants and P[8]G6

UK-based Quadrivalent live oral P[5]G1, G2, NIH (USA) Active.reassortants human-bovine (UK) G3, and G4 Phase III

reassortantsNon-Jennerian approachM37 Monovalent live oral human P[6]G1 DynCorp (USA) Discontinued

neonatal M37 strainRotarix Monovalent live oral P[8]G1 GlaxoSmithKline Active.

human 89-12 strain (Belgium) Phase IIIRV3 Monovalent live oral human P[6]G3 DynCorp (USA) Active.

neonatal RV3 strain Phase I-II116E Monovalent live oral human P[11]G9 Bharat Biotech Active.

neonatal 116E strain (India) Phase II321 Monovalent live oral human P[11]G10 Bharat Biotech Active.

neonatal I321 strain (India) Phase IBIRVI Monovalent inactivated P[4]G1 Biken (Japan) Under

human AU64 strain developmentVirus like particles approachVLPs Simian (SA11) virus VP2/6 Lederle/Green Under

like particle Cross (Korea) development



G10 rotavirus strainsRotavirus strains bearing G10 specificity aredetected frequently among cattle and infrequentlyamong horses, pigs and lambs [7]. The first isola-tion of such a virus from humans was reportedin 1992 from an immunocompromised child withchronic diarrhea in the UK [142]. In 1993, a studyconducted in Bangalore, India, reported the circu-lation of G10 rotavirus strains among asymptoma-tically infected neonates [143]. The prototypestrain I321 obtained from such a study possessesa combination of P[11]G10 specificity. By RNA-RNA hybridisation and sequence analysis theI321 strain was shown to have a high level ofgenetic relatedness to the bovine strain B233(P[11]G10) [65,143]. Recent epidemiological sur-veys of rotavirus strains reported that strains bear-ing this same P-G combination (P[11]G10) wererecovered from an increasing number of infantsand young children with diarrhea in some partsof India [108,144]. Detection of genotype G10viruses, albeit at low frequency, has also beenreported from Thailand in association withP[14] [114], Paraguay in conjunction with P[8][49], and P[9] in Brazil [Santos et al., unpublisheddata].

G12 rotavirus strainsRotavirus serotype G12 was first detected in stoolspecimens collected from 20 children of < 2 yearsof age with diarrhea between 1987 and 1988 in thePhilippines, and the reference strain (L26) wasreported to bear P[4]G12 specificity [145]. Afterthis description, no reports describing the detec-tion of such G type were published until 2002when few such isolates were reported: one strainwas isolated from an 11 month old child with diar-rhea in Thailand in 1998–1999 which bore P[9] spe-cificity [47]. Another G12 isolate was reported inthe USA in 1998–1999 in conjunction with P[6] spe-cificity [45]. Three other G12 strains were recentlydetected in India, two with P[6] specificity and thethird with unknown P specificity [46]. TwoP[9]G12 strains were detected in Japan in a surveybetween 1999 and 2002 [139]. Four G12 strainswith unknown P specificity were detected inKorea [146]. In a surveillance study conducted inArgentina between 1999 and 2003, 6% of the rota-virus strains exhibited a P[9]G12 specificity [140].Thus far, G12 has not been detected in animalsother than humans.

P[3] rotavirus strainsGenotype P[3] is commonly detected in dogs andless often in cats [7]. In 1984 during a rotavirusvaccine trial conducted in Philadelphia, PA,USA, an unusual strain named HCR3 was isolatedfrom the stool of a healthy infant. By sequence andserological analyses this strain was shown to beara P[3]G3 specificity and to be closely related tocanine and feline rotavirus strains [147,148].Another strain (Ro1845) with such P-G specificitywas isolated from a child with diarrhea in Israelin 1985 [149]. In 1986, a third strain with thesame P-G specificity was recovered from thestool of another healthy child, under similar condi-tions in Philadelphia [150]. These strains presentseveral characteristics that are unusual for rota-viruses of human origin but are common to strainsrecovered from animal species, such as growth tohigh titers in cell cultures, haemagglutinationactivity and a long electropherotype with sub-group I specificity, which strongly suggest a directtransmission of such viruses from animal tohuman.

P[11] rotavirus strainsGenotype P[11] is a common P type found in cattleand is found infrequently in horses, pigs andlambs [7]. A study conducted among healthy new-born infants from various hospitals and clinics inBangalore, India, between 1988 and 1991 reportedthe existence of rotavirus strains having subgroupI specificity and long RNA patterns [151]. Selectedstrains adapted to growth in cell cultures werefound to belong to genotype P[11] by sequenceanalysis. As stated above, the prototype strain(I321) bearing a P[11]G10 specificity was reportedto be highly homologous to the bovine strain B223(P[11]G10) genetically [143]. Soon thereafter, P[11]rotavirus strains were detected in character-istically asymptomatic newborns in New Delhi,India, in conjunction with G3 or G9 specificity[48]. In another study conducted at several loca-tions in India between 1996 and 1998, rotavirusstrains with P[11]G4 or P[11]G9 specificity wererecovered from children with diarrhea [50].Recently, the emergence of P[11]G10 strains asso-ciated with severe diarrheal disease in neonatesin Southern India was reported [144]. So far,rotavirus strains bearing the P[11] specificityhave not been detected in humans outside ofIndia.



P[14] rotavirus strainsType P[14] is commonly found in rabbits andinfrequently in goats [7]. Detection in humans ofrotavirus strains bearing P[14] specificity was firstreported in a survey carried out in 1987–1988 [53]:one from Palermo, Italy (in conjunction with G6specificity) and the other from Finland (in associa-tion with G8 specificity) both of which were iso-lated from diarrheic children. Later rotavirusstrains bearing the same P specificity were recov-ered from a child with diarrhea in Thailand(in conjunction with G10 specificity) [91], threechildren in Australia and one in Hungary (in asso-ciation with G6 specificity) [54–56,152], sixchildren with diarrhea in South Africa (inconjunction with G1 specificity) [92,153], two diar-rheic children in Egypt (in conjunction withG8 specificity) [90], again from another childwith diarrhea in Italy (in association with G6 spe-cificity) [93], and one child in Belgium with G3specificity [154].

TEMPORAL FLUCTUATION OF ROTAVIRUSG OR P TYPE DISTRIBUTIONExtensive global epidemiological surveys employ-ing G serotyping and/or G and P genotypingassays have generated, in addition to the datadescribed above, information such as (i) the inci-dence of individual serotypes in the same regioncan show a yearly fluctuation; (ii) the incidenceof rotavirus serotypes in different regions withinthe same country can differ during the sameyear; and (iii) multiple G and P types can co-circulate within the same region [reviewed inreferences 7,33,63,81,117,155–157]. For example,a consecutive 10-year (1987–1997) survey inBangladesh showed a typical yearly fluctuationpattern of the distribution of rotavirus G1–G4,and G9 serotypes (Figure 7A). During the first 3years rotavirus G2 was the most common serotypedetected, followed by G1 and G4 strains, respec-tively. By the fourth year the G4 strains becamethe most frequent and remained predominantuntil 1995; in 1995 the G9 strains emerged andthe incidence of serotype G4 declined consider-ably. In 1996 and 1997 rotavirus G9 was the mostcommon serotype detected in the country (34.4%and 53.0%, respectively). The incidence of G4strains during the same period was 19.7% and3.1%, respectively. Serotypes G1, G2, G3 and G4co-circulated throughout the study period [117].

Ten years of rotavirus surveillance in the UnitedKingdom, from 1983 to 1988 and 1995 to 1998,have also demonstrated an annual variation onthe distribution of G serotypes (Figure 7B). Overall

Figure 7. Temporal fluctuation of the prevalence of rotavirus G

serotypes in (A) Bangladesh (1987–1997), (B) United Kingdom

(1983–1988, 1995–1998), and (C) Australia (1974–1974, 1977–1989,

1993–1996, 1999–2002). Data were taken from references [63,76,81–

84,117,126,155]. Figures 7A–7C do not include mixed or untyped

infections. Mixed infections made up 23% (1987–1997) and

untyped infections ranged from 7.8% (2000–2001) to 26.6% (1999–

2000) in Bangladesh; in the UK mixed infections ranged from

0.3% (1997–1998) to 5% (1996–1997) and untyped infections ranged

from 0% (1985, 1987 and 1988) to 9% (1984); and in Australia mixed

infections ranged from 0.9% (1999–2000) to 3.4% (2001–2002) and

untyped infections ranged from 11.1% (1987) to 45.1% (1981)



serotype G1 was the most prevalent serotype,however, in 1984 G2 was the second most preva-lent serotype and in 1988 it became the most pre-valent serotype. In 1986 G4 emerged as the secondmost prevalent serotype. In the 1995–1996 seasonserotype G9 was detected in the UK for the firsttime and in the 1997–1998 season it was the fourthmost prevalent serotype. Serotypes G1, G2 and G3co-circulated during most of the surveillance peri-ods [63,155].

A survey on rotavirus serotypes has been per-formed in Australia for at least 22 years (1973–1974, 1977–1989, 1993–1996, 1999–2002) (Figure 7C).It provides a reliable database for analysis of theyearly fluctuation of serotype prevalence. Over a28-year period (1973–2001) G1 serotype was themost prevalent strain in the country, except duringthe period of 1977–1979 and 1988–1989 when G2and G4 strains, respectively, were the most pre-dominant serotypes; serotypes G3 and G4 weredetected intermittently. Serotype G9 emerged in1999–2000 and became predominant nationwide in2001–2002. Of interest was the finding that as thedetection rate of G9 increased since 1999–2000,that of G1 decreased [76,82–84].

ROTAVIRUS VP7 AND VP4 GENEPOLYMORPHISM AND ITS POSSIBLEIMPLICATION IN VACCINE DEVELOPMENTGenomic point mutations and accumulations havebeen proposed to be one of three mechanisms ofrotavirus evolution in nature, besides genome rear-rangements and genetic reassortments [158]. Genet-ic and antigenic variation have both been reportedfor human rotavirus neutralisation antigens VP7and VP4, in particular among the six most commontypes G1–G4, G9 and P[8] which are major targetsfor vaccine development [85–89,117,122,125,159–177]. For example, the presence of four phylogeneticVP7 gene lineages and their worldwide distributionhave been reported for the most prevalent rotavirusserotype G1 [163–165]. In addition, antigenic analy-sis of selected G1 strains with a panel of neutralisingmonoclonal antibodies (NMAbs) has demonstratedthe existence of antigenic subtypes or monotypes[163,171]. Furthermore, VP7 gene lineages I and IIwere reported to correlate with monotypes G1band G1a, respectively [163]. Similarly, the existenceof distinct VP7 gene phylogenetic lineages andrelated monotypes or subtypes has been reportedfor selected serotype G2 [166,170,172], G3 [168],

G4 [167,169,173–176] or G9 [85,160, 161,176] virusstrains. Thus, these studies have shown that subtledifferences in the antigenic composition of the VP7protein may exist among different phylogeneticlineages within a given G type. However, thequantitative and qualitative nature of antibodiesdirected against VP7 proteins of different lineageshas not been well investigated.

Jin et al. [165] compared post-vaccination neutra-lising antibody titers of infants that received reas-sortant rhesus rotavirus vaccine against a G1strain that was recovered from vaccinees whoexperienced diarrheal episodes. Post-immunisationneutralising antibody titers directed towards theG1 vaccine strain were significantly greater thanthose directed towards the circulating G1 strain.However, this difference did not correlate with pro-tection against diarrhea since infants who experi-enced asymptomatic or no rotavirus infectionpresented similar differences in antibody titer.Comparison of the VP7 gene sequence of vaccineand circulating G1 strains indicated that theybelong to different phylogenetic lineages. Althoughthis study did not prove that antigenic drifts couldbe responsible for vaccine failures, it suggested thepresence of VP7 antigenic differences between thecirculating G1 strain and the vaccine G1 strain.

More recently, Hoshino et al. [178] analysed byneutralisation selected G9 viruses with VP7 phylo-genetic lineage 1 (three strains), 2 (one strain) or 3(five strains) specificity and reported that (i) anti-sera to lineage 1 viruses neutralised lineage 2and 3 strains efficiently and (ii) antisera to lineage3 viruses neutralised lineage 1 viruses poorly.These findings may have important implicationsfor the development of G9 or G1 rotavirus vaccinecandidates as the strain with the broadest reactiv-ity would certainly be the ideal strain for inclusionin a vaccine.

Genetic and antigenic variation of another pro-tective antigen, VP4, has not been well studiedyet. However, a certain degree of polymorphismappears to exist within the major P[8] type. Analy-sis of selected P[8] rotavirus strains from Brazil,USA or Japan differentiated the P[8] genes intotwo distinct phylogenetic lineages [162]. Anotherstudy in Italy reported the existence of three P[8]phylogenetic lineages: Malawian-like, Japanese-like and American-like [122]. However, therelationship between these three P[8] lineagesand the two P[8] lineages described previously



[162] is not clear. The existence of antigenic diver-sity among selected P[8] strains has been sug-gested [72], however, further clarification may berequired. Likewise, two distinct phylogeneticVP4 gene sequence lineages among P[6] strainshas also been suggested [179]. Because the nextgeneration of rotavirus vaccines may incorporatea VP4 component in the formulation, knowledgeof the genetic and antigenic diversity of epidemio-logically important VP4s may be important.

Both natural and experimental rotavirus infec-tions evoke immune responses that provide pro-tection against disease caused by subsequentrotavirus infection. However, the mechanismsunderlying such protection are not well under-stood. In various animal models, antibodies torotavirus outer capsid proteins VP4 and VP7have been demonstrated to provide protectionagainst disease in a type-specific manner uponchallenge with virulent viruses [180–182]. Itappears that there is a positive correlation betweenrotavirus-specific IgA and protective immunityagainst rotavirus infection/disease in pigs andchildren [183–186]. However, in some casesrotavirus-specific IgG appears to play some pro-tective role against rotavirus infection/disease inchildren [187,188]. Thus, the effector functionsthat best predict protection against rotavirus dis-ease is still under discussion [for reviews, seereferences 183, 186,188,189].

ROTAVIRUS VACCINE DEVELOPMENTAND ROTAVIRUS EPIDEMIOLOGYVarious candidate rotavirus vaccines that weredeveloped have been or are being evaluated indifferent populations in various parts of theworld [for reviews see references 3–5,7,190].Initially, based on a Jennerian approach to vaccina-tion, various live monovalent animal rotavirusvaccines were evaluated in humans including abovine rotavirus NCDV strain (RIT4237) withP[1]G6 specificity, a bovine rotavirus WC3 strainwith P7[5]G6 specificity, and a rhesus rotavirusMMU18006 strain with P[3]G3 specificity (Table 4).Since the protective efficacy of such vaccines wasvariable, the strategy was modified to achievebroader antigenic coverage in which the VP7 orVP4 gene of an animal strain was replaced withthe corresponding gene of human rotavirusstrain of epidemiologic importance. Based onsuch a modified Jennerian approach, various

monovalent as well as multivalent candidate vac-cines were developed to achieve optimal protec-tion (Table 4). Such vaccines are designed toprovide antigenic coverage for G1, G2, G3, G4,G8, G9 as well as P[8] and P[4]. Various monova-lent human rotavirus vaccines have also beendeveloped including M37 strain (P[6]G1]), 89-12strain (P[8]G1), RV3 strain (P[6]G3), 116E strain(P[11]G9), I321 strain (P[11]G10) and AU64 strain(P[4]G1) (Table 4).

The importance of serotype-specific protectionagainst rotavirus disease is still under discussion.Some studies have suggested that the vaccineinduced a type specific protection [7,191,192],whereas other studies found no correlationbetween protection and serotype-specific antibo-dies [7,193]. It is worth noting that a majority ofcurrently available vaccines or vaccines underdevelopment are designed to provide antigeniccoverage for globally or regionally important Gand/or P types (Table 4). Given the complexityof rotavirus epidemiology as multiple G and P ser-otypes can circulate simultaneously in a givenpopulation, the ability of a rotavirus vaccine togenerate heterotypic immunity is critical.

CONCLUSIONRotavirus diarrhea is a serious and potentially life-threatening disease that affects mostly infants andyoung children throughout the world. The avail-ability of a safe and effective rotavirus vaccinewould thus represent a global public health break-through. In this review, rotavirus G and P sero-type/genotype epidemiology was highlighted byanalysing a total of 45571 rotavirus strains derivedfrom 124 studies from 52 countries on five conti-nents published between 1989 and 2004. Strainsbearing serotypes/genotypes G1, G3 and G4 inconjunction with P[8], and G2 associated withP[4] were shown to be responsible for over 88%of all rotavirus infections worldwide. Thus, if ser-otype-specific immunity plays an important role inprotection against rotavirus disease, the currentlyavailable candidate vaccines such as RRV-basedor UK-based quadrivalent vaccine or WC3-basedpentavalent vaccine would provide serotype-specific protection against diarrhea caused byapproximately 88% strains worldwide. However,as shown in this review, since the distribution ofrotavirus P-G combinations can show a temporaland geographical fluctuation, (i) serotype-specific



protection provided by such vaccines would varyfrom population to population and (ii) a geogra-phical P-G type adjustment in the formulation ofnext generation multivalent vaccine would benecessary. In addition, this global review hasrevealed that certain G serotypes have emergedas globally important types. For example, serotypeG9, which has been detected in every continentwith an overall percentage of 4.1%, represented10.6% of all rotavirus isolates between 1982–2003in the Americas, 21.9% between 1986–2001 in India

and the most prevalent G type nationally (40.4%)during the 2001–2002 season in Australia.

Furthermore, this review has indicated that insome geographic settings G types other than G1–G4 may be of epidemiological importance, whichincludes serotype G8 in some regions of Africaand serotype G5 in Brazil. Thus, it appears thatthe formulation of future rotavirus vaccines islikely to be adjusted considering the geographicalvariation of the distribution of various G types[194]. Although the distribution of P types appears

Table 5. Rotavirus strains, which are suspected to have arisen in the human populationthrough interspecies transmission or animal-human rotavirus reassortment

VP7 gene VP4 gene VP6 geneStrain Country (G type)a (P type)a (Subgroup)a E-typeb References

GR67/91, GR475/87 South Africa G1 P[14] II L 153HCR3, Ro1845 US, Israel G3 P[3] I L 147–149Indian isolate India G3 P[11] ?c ?d 48B4106 Belgium G3 P[14] ? SS 154Paraguayan isolate Paraguay G4 P[1] ? ? 49Indian isolates India G4 P[11] ? ? 50IAL-28 Brazil G5 P[8] II L 98MRC3105 Cameroon G5 P[8] I S 97PA151, Se584, Hun 3 Italy, US, Hungary, G6 P[9] I L 45,53,54,152B1711 Belgium G6 P[6] ? ? 52PA169, Hun 5, MG6.01, Italy, Hungary, G6 P[14] I L 53,54,56,152aG6.01 AustraliaBritish strain UK G8 P[8] ? ? 631322, 1345, 1363 Kenya G8 P[4] I S 60MW23 Malawi G8 P[6] I S 59HAL1166 Finland G8 P[14] ? L 241EGY1850, EGY2295, Egypt, Australia G8 P[14] I L 56,90BG8.01, mG8.01MP409, MP480 India G8 P[1] I L 58HMG035 Nigeria G8 P[1] ? L 57Guinean isolate Guinea-Bissau G8 P[2] ? ? 42116E India G9 P[11] II L 48Mc323 Thailand G9 P[19] I L 64Mc345 Thailand G9 P[19] I ?e 64R239 Brazil G10 P[9] ? L UnpublishedI321 India G10 P[11] I L 14399-D/228, 00-KD/399 India G10 P[11] I ? 144Mc35 Thailand G10 P[14] I L 91

aAntigenic specificity carried by indicated protein.bElectropherotype, L, long; S, short; SS, super short.cSubgroup specificity unknown.dE-type unknown.eE-type anomalous.



to be more conservative than that of G types withtype P[8] being predominant around the world, itis noteworthy that in Africa approximately one-third of all P types analysed in this review wereof P[6] specificity. Since antibodies to VP4 havebeen demonstrated to be protective [reviewedin reference 7], the next generation rotavirusvaccines may include not only G componentsbut also P components to further increase theireffectiveness against severe rotavirus disease[195,196]. The extent of antigenic variationwithin a given G or P types requires furtherexploration.

Because of the complexity and flexibility ofrotavirus epidemiology particularly in developingregions of the world where a rotavirus vaccine ismost urgently needed, it is important that contin-ued longitudinal rotavirus strain surveillanceprograms are conducted throughout the world.In addition, evidence for (i) reassortment betweenhuman and animal rotaviruses during mixedinfections and (ii) interspecies transmission ofanimal rotaviruses to humans becomes more andmore compelling [for reviews see references197,198]. An increasing number of rotavirusstrains bearing animal rotavirus characteristicshave been recovered from humans (Table 5).Although interspecies transmission of animal rota-virus to humans appears to be a very rare event(e.g. strains HCR3 and AU1), the introduction ofcertain animal rotavirus genes into human rota-viruses through genetic reassortment appears tobe common. Some of such possible animal–humanrotavirus reassortants are well established invarious human populations as in the case ofP[11]G10 rotavirus strains in India, P[8]G5 strainsin Brazil and the P[6]G8 strains in Africa [51,62,144]. Therefore, it would be prudent to extendthe surveillance programs to animal rotavirusstrains as well. Such a concerted effort would pro-duce a substantial regional as well as global data-base on the spatial and temporal dynamics ofrotavirus epidemiology including the emergence,frequency and distribution of rotavirus G and Ptypes which is essential for the development andimplementation of an effective next generationrotavirus vaccine.

ACKNOWLEDGEMENTSThis work was partially supported by CNPq,FAPERJ, CAPES, Brazil and TWAS, Italy.

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