The ever-changing landscape of rotavirus serotypes.

Abstract

Rotavirus is a double-stranded RNA virus that is characterized by substantial genetic diversity. The various serotypes of rotavirus have been determined by the presence of neutralizing epitopes on the outer capsid of the protein shell. At present, 5 rotavirus serotypes (G1, G2, G3, G4, G9) are the predominant circulating strains, accounting for approximately 95% of strains worldwide, although there is considerable geographic variability. Incidence rates for various serotypes also vary temporally with seasonal and year-to-year fluctuations. Unusual serotypes are generally uncommon, but new serotypes can emerge. In particular, G9[P8], a reassortment virus, was first identified in 1983 and in the last 10 to 15 years has become widely distributed worldwide. Indeed, G9[P8] has become highly prevalent in many countries in Europe and Australia, with somewhat lower incidence rates in South America, Africa, and Asia. The heterogeneity and ever-changing epidemiology of rotavirus underscores the need for continued surveillance to ensure that vaccination programs provide optimal protection.

Full text

Page 1

SUPPLEMENT
The Ever-Changing Landscape of Rotavirus Serotypes
Miguel O’Ryan, MD
Abstract: Rotavirus is a double-stranded RNA virus that is characterized
by substantial genetic diversity. The various serotypes of rotavirus have
been determined by the presence of neutralizing epitopes on the outer
capsid of the protein shell. At present, 5 rotavirus serotypes (G1, G2, G3,
G4, G9) are the predominant circulating strains, accounting for approxi-
mately 95% of strains worldwide, although there is considerable geo-
graphic variability. Incidence rates for various serotypes also vary tempo-
rally with seasonal and year-to-year fluctuations. Unusual serotypes are
generally uncommon, but new serotypes can emerge. In particular, G9?P8?,
a reassortment virus, was first identified in 1983 and in the last 10 to 15
years has become widely distributed worldwide. Indeed, G9?P8? has
become highly prevalent in many countries in Europe and Australia, with
somewhat lower incidence rates in South America, Africa, and Asia. The
heterogeneity and ever-changing epidemiology of rotavirus underscores
the need for continued surveillance to ensure that vaccination programs
provide optimal protection.
Key Words: rotavirus, gastroenteritis, serotype, ribose nucleic acid
virus, epidemiology
(Pediatr Infect Dis J 2009;28: S60–S62)
R
capsid, (2) an inner capsid, and (3) an internal core that surrounds
segments of double-stranded RNA.2There are 7 rotavirus groups
(A through G) that are determined by the antigenic specificities of
proteins encased in the triple-layer capsid.1Of these, Group A is
responsible for most endemic human disease.3There are also various
subgroups and serotypes with serotyping based on the presence of
neutralizing epitopes on outer capsid proteins (ie, VP4 and VP7).3
VP4 is designated as the P antigenic protein because it is cleaved by
the protease trypsin at the intestinal level and VP7 is designated as the
G antigenic protein because it is a glycosylated structure.2,3These
proteins have been considered relevant for the development of a
rotavirus vaccine because in vitro and animal-based studies indi-
cate that they are targets for neutralizing antibodies that provide
serotype-specific and, in some cases, cross-reactive protection.2
otavirus is a double-stranded RNA virus from the Reoviridae
family.1The virus is composed of 3 protein shells: (1) an outer
EPIDEMIOLOGY OF COMMON CIRCULATING
SEROTYPES
Rotaviruses are characterized by substantial diversity; there
are at least 42 different G/P strains with different serotype com-
binations.2However, 5 serotypes (G1?P8?, G2?P4?, G3?P8?,
G4?P8?, and G9?P8?) are the predominant circulating rotavirus G/P
serotypes.2,4,5However, there is substantial temporal and geo-
graphic variability in the epidemiology of rotavirus serotypes, and
multiple serotypes can cocirculate within the same region.2,5
Serotypes can also vary in different regions, even within the same
country. Further, the incidence of serotypes can fluctuate from year
to year within the same region. For example, Clark et al6followed
the prevalence of rotavirus strains in Philadelphia between 1994
and 1999. As shown in Figure 1,6the predominant circulating
strain varied significantly over the 5 seasons. In 1994 to 1995,
G3?P8? strains predominated. G9?P8? comprised more than 50% of
cases during a G9 outbreak in the 1995 to 1996 rotavirus season.
In 1996 to 1997 and 1997 to 1998 most disease was caused by
G1?P8?, and in 1998 to 1999 G1?P8? and G2?P4? were each
responsible for approximately 50% of infections.6
Rotavirus also exhibits a distinct seasonality, particularly in
temperate climates. In the United States, activity usually peaks in
the Southwest in November/December, spreading north and east
and reaching the northeastern states by April and May.4,7Figure 2
summarizes the distribution of rotavirus serotypes according to
continents during a prolonged surveillance period of approxi-
mately 15 years.5The distribution describes the global distribution
of human group A rotavirus G and P types from 1989 through
2004, based on the results of 124 studies from 52 countries.
Although the 5 most common rotavirus serotypes (G1–G4 and G9)
were responsible for approximately 95% of infections worldwide,
there are substantial geographic differences. For example, G1?P8?
was responsible for more than 70% of infections in North America,
Australia, and Europe but ?30% of infections in South America,
Asia, and Africa. G2?P4? was common in South America (23%)
and Asia (13%), whereas G3?P8? was common in Africa (21%).5
EMERGING SEROTYPES
Unusual serotypes rise and fall in many parts of the world
during limited time periods, but because trends could change, they
require continued monitoring. Overall, strains that are considered
unusual represent only 4.9% of isolates.5These unusual P–G combi-
nations likely represent naturally occurring reassortments of the var-
ious human rotavirus genotypes, reassortments between human and
animal strains, or direct transmission from animals to human. Nota-
bly, unusual serotypes were more common in Africa (27%), Asia
(14%), and South America (11%) compared with North America,
Europe, and Australia (5%, 1.4%, 0.1%, respectively). For example,
G8 strains—mainly G8?P4? and G8?P6?—have been increasingly
reported in Africa since the mid-1990s, accounting for approxi-
mately 13% of infections. However, to date, these strains have
rarely been reported outside of Africa. Similarly, G5?P8? has
been reported almost exclusively in South America.5G12
strains with both P8 and P6 VP4 antigenicity are being increas-
ingly recognized worldwide, including in the United States.8
The relatively high frequency of unusual serotypes in some
geographic regions suggests that these serotypes may have genetic
stabilityandthepotentialtospreadamongthepopulation;butwhether
they will sustain in a given population over time—indicating that they
are fit for human intestinal cell receptors—requires further monitor-
ing. In addition, most epidemiologic surveys have noted the occur-
rence of nontypeable rotavirus strains. This is likely due to the ability
of the virus to undergo constant genetic variation via sequential point
mutations (ie, antigenic drift), genetic reassortment (ie, antigenic
From the Institute of Biomedical Sciences, Faculty of Medicine, University of
Chile, Santiago, Chile.
Disclosure: Dr. O’Ryan has received honorarium and grant support from
GlaxoSmithKline, and consultant fees from Merck.
Address for correspondence: Miguel O’Ryan, MD, Institute of Biomedical
Sciences, Faculty of Medicine, University of Chile, Avda Independencia
1027, Santiago, Chile. E-mail: moryan@med.uchile.cl.
Copyright © 2009 by Lippincott Williams & Wilkins
ISSN: 0891-3668/09/2803-0060
DOI: 10.1097/INF.0b013e3181967c29
The Pediatric Infectious Disease Journal • Volume 28, Number 3, March 2009
S60

Page 2

shift), genomic rearrangement, or intragenic recombination. The in-
cidence rate of nontypeable strains in various surveys is dependent on
the type of assay used with the use of enzyme immunoassay generally
associated with higher rates of nontypeable strains compared with
studies that use reverse transcription polymerase chain reaction (RT-
PCR) assays. Nevertheless, even studies that use enzyme immunoas-
say, RT-PCR, and probe hybridization in combination report rates of
8% to 27% for nontypeable strains. Again, if these strains will prevail
in a given population, it will depend on their capacity to adapt to
human intestinal cell receptors.5
THE EMERGING G9 SEROTYPE
The G9 strain, usually in combination with P8 or P6, is
the only “new” serotype that has gained epidemiological rele-
vance in the past years. G9 as a cause of diarrhea was first
identified in Philadelphia, Pennsylvania, in 1983 and was rela-
tively rare until the last 10 to 15 years.6,9,10The G9 serotype
has subsequently become ubiquitous in the United States and
other countries and is now the fourth most common strain
worldwide, accounting for 4.1% of infections.5,6G9 strains
have been documented in a number of epidemiologic studies
conducted in the past 10 years. G9 has been identified in
Australia,11–16Ireland,17Spain,18Sweden,19Hungary,20,21
Bulgaria,22Slovenia,23Italy,24,25North America,26South Amer-
ica,27,28Africa,29,30Saudi Arabia,31and Asia.10,32Rates of G9 in
any given year can fluctuate widely.6,11–16,33This is illustrated in
Table 1,11–16,34,35which presents rates reported in Australia, a coun-
trythathasconductedextensiverotavirussurveillanceformanyyears.
FIGURE 1. Prevalence of rotavirus strains in Philadelphia from 1995 to 1999. Reprinted with permission.6
FIGURE 2. Geographical distribution of rotavirus serotypes. Reprinted with permission.5
The Pediatric Infectious Disease Journal • Volume 28, Number 3, March 2009Varying Epidemiology of Rotavirus Serotypes
© 2009 Lippincott Williams & Wilkins
S61

Page 3

SUMMARY AND CONCLUSIONS
Rotavirus is a common gastrointestinal pathogen that pro-
duces considerable morbidity and mortality. Currently, 5 serotypes
(G1–G4, G9) predominate, accounting for almost 95% of strains
worldwide. Circulating strains vary both regionally and tempo-
rally, with substantial year-to-year, seasonal, and geographic vari-
ability. In addition, reassortments of the various human rotavirus
genotypes can potentially allow new serotypes to emerge, although
new serotypes would have to be fit for human intestinal receptors
to prevail over time. The ever-changing epidemiology of rotavirus
may represent a substantial challenge to the development of
effective vaccines. This emphasizes the need for long-term rota-
virus surveillance to judge effectiveness of vaccines on circulating
strains.
REFERENCES
1. Bass ES, Pappano DA, Humiston SG. Rotavirus. Pediatr Rev. 2007;28:
183–191.
2. Dennehy PH. Rotavirus vaccines: an overview. Clin Microbiol Rev. 2008;
21:198–208.
3. Bernstein DI, Ward RL. Rotaviruses. In: Feigin RD, Cherry JD, eds.
Textbook of Pediatric Infectious Diseases. 5th ed. Volume 2. Philadelphia,
PA: Saunders; 2004:2110–2133.
4. Centers for Disease Control and Prevention. Prevention of rotavirus
gastroenteritis among infants and children. Recommendations of the
Advisory Committee on Immunization Practices (ACIP). MMWR. 2006;
55(RR-12):1–16.
5. Santos N, Hoshino Y. Global distribution of rotavirus serotypes/genotypes
and its implication for the development and implementation of an effective
rotavirus vaccine. Rev Med Virol. 2005;15:29–56.
6. Clark HF, Lawley DA, Schaffer A, et al. Assessment of the epidemic
potential of a new strain of rotavirus associated with the novel G9 serotype
which caused an outbreak in the United States for the first time in the
1995–1996 season. J Clin Microbiol. 2004;42:1434–1438.
7. Parashar UD, Bresee JS, Gentsch JR, et al. Rotavirus. Emerg Infect Dis.
1998;4:561–570.
8. Payne DC, Staat MA, Edwards KM, et al. Active, population-based sur-
veillance for severe rotavirus gastroenteritis in children in the United States.
Pediatrics. 2008;122:1235–1243.
9. Ramachandran M, Gentsch JR, Parashar UD, et al. Detection and charac-
terization of novel rotavirus strains in the United States. J Clin Microbiol.
1998;36:3223–3229.
10. Laird AR, Gentsch JR, Nakagomi T, et al. Characterization of serotype G9
rotavirus strains isolated in the United States and India from 1993 to 2001.
J Clin Microbiol. 2003;41:3100–3111.
11. Kirkwood CD, Bogdanovic-Sakran N, Clark R, et al. Report of the Aus-
tralian Rotavirus Surveillance Program 2001–2002. Commun Dis Intell.
2002;26:537–540.
12. Kirkwood CD, Bogdanovic-Sakran N, Bishop R, et al; National Rotavirus
Surveillance Group. Report of the Australian Rotavirus Surveillance Pro-
gram, 2003–2004. Commun Dis Intell. 2004;28:481–485.
13. Kirkwood CD, Bogdanovic-Sakran N, Clark R, et al. Report of the Aus-
tralian Rotavirus Surveillance Program 2002–2003. Commun Dis Intell.
2003;27:492–494.
14. Kirkwood CD, Bogdanovic-Sakran N, Clark R, et al. National Rotavirus
Surveillance Program annual report, 2004–2005. Commun Dis Intell.
2006a;30:133–136.
15. Kirkwood CD, Cannan D, Bogdanovic-Sakran N, et al; National Rotavirus
Surveillance Group. National Rotavirus Surveillance Program annual re-
port, 2005–2006. Commun Dis Intell. 2006b;30:434–438.
16. Kirkwood CD, Cannan D, Bogdanovic-Sakran N, et al; National Rotavirus
Surveillance Group. Australian Rotavirus Surveillance Program: annual
report, 2006–2007. Commun Dis Intell. 2007;31:375–379.
17. Lennon G, Reidy N, Cryan B, et al. Changing profile of rotavirus in Ireland:
predominance of P?8? and emergence of P?6? and P?9? in mixed infections.
J Med Virol. 2008;80:524–530.
18. Sa ´nchez-Fauquier A, Montero V, Moreno S, et al. Human rotavirus G9 and
G3 as major cause of diarrhea in hospitalized children, Spain. Emerg Infect
Dis. 2006;12:1536–1541.
19. Rubilar-Abreu E, Hedlund KO, Svensson L, et al. Serotype G9 rotavirus
infections in adults in Sweden. J Clin Microbiol. 2005;43:1374–1376.
20. Ba ´nyai K, Gentsch JR, Schipp R, et al. Dominating prevalence of P?8?,G1
and P?8?,G9 rotavirus strains among children admitted to hospital between
2000 and 2003 in Budapest, Hungary. J Med Virol. 2005;76:414–423.
21. Ba ´nyi K, Gents JR, Glass RI, et al. Eight-year survey of human rotavirus
strains demonstrates circulation of unusual G and P types in Hungary.
J Clin Microbiol. 2004;42:393–397.
22. Tcheremenskaia O, Marucci G, De Petris S, et al; Rotavirus Study Group.
Molecular epidemiology of rotavirus in Central and Southeastern Europe.
J Clin Microbiol. 2007;45:2197–2204.
23. Steyer A, Poljsak-Prijatelj M, Bufon TL, et al. Rotavirus genotypes in
Slovenia: unexpected detection of G8P?8? and G12P?8? genotypes. J Med
Virol. 2007;79:626–632.
24. De Grazia S, Ramirez S, Giammanco GM, et al. Diversity of human
rotaviruses detected in Sicily, Italy, over a 5-year period (2001–2005). Arch
Virol. 2007;152:833–837.
25. Martella V, Terio V, Del Gaudio G, et al. Detection of the emerging
rotavirus G9 serotype at high frequency in Italy. J Clin Microbiol. 2003;
41:3960–3963.
26. Griffin DD, Nakagomi T, Hoshino Y, et al. National Rotavirus Surveillance
Program. Characterization of nontypeable rotavirus strains from the United
States: identification of a new rotavirus reassortment (P2a?6?, G12) and rare
P3?9? strains related to bovine rotaviruses. Virology. 2002;294:256–269.
27. Barril PA, Martinez LC, Giordano MO, et al. Detection of group a human
rotavirus G9 genotype circulating in Co ´rdoba, Argentina, as early as 1980.
J Med Virol. 2006;78:1113–1118.
28. Stupka JA, Parra GI, Go ´mez J, et al. Detection of human rotavirus G9?8?
strains circulating in Argentina: phylogenetic analysis of VP7 and NSP4
genes. J Med Virol. 2007;79:838–842.
29. Chouikha A, Fodha I, Noomen S, et al. Group A rotavirus strains circulating
in the eastern center of Tunisia during a 10-year period (1995–2004). J Med
Virol. 2007;79:1002–1008.
30. Cunliffe NA, Dove W, Bunn JE, et al. Expanding global distribution of
rotavirus serotype G9: detection in Libya, Kenya, and Cuba. Emerg Infect
Dis. 2001;7:890–892.
31. Kheyami AM, Nakagomi T, Nakagomi O, et al. Molecular epidemiology of
rotavirus diarrhea among children in Saudi Arabia: first detection of G9 and
G12 strains. J Clin Microbiol. 2008;46:1185–1191.
32. Kang JO, Kilgore P, Kim JS, et al. Molecular epidemiological profile of
rotavirus in South Korea, July 2002 through June 2003: emergence of
G4P?6? and G9P?8? strains. J Infect Dis. 2005;192(Suppl 1):S57–S63.
33. Rahman M, Sultana R, Ahmed G, et al. Prevalence of G2P?4? and G12P?6?
rotavirus, Bangladesh. Emerg Infect Dis. 2007;13:18–24.
34. Masendycz P, Bogdanovic-Sakran N, Palombo E, et al. Annual report of the
Rotavirus Surveillance Programme, 1999/2000. Commun Dis Intell. 2000;
24:195–198.
35. Masendycz P, Bogdanovic-Sakran N, Kirkwood C, et al. Report of the
Australian Rotavirus Surveillance Program, 2000/2001. Commun Dis Intell.
2001;25:143–146.
TABLE 1.
Serotypes in Australia From 1999 to 200711–16,34,35
Nationwide Incidence of Rotavirus
Time Frame
Serotype*
G1 G2G3 G4G9
1999–2000
2000–2001
2001–2002
2002–2003
2003–2004
2004–2005
2005–2006
2006–2007
58%
50%
39%
11%
40%
48%
40%
37%
2%
13%
2%
1%
17%
48%
1%
?5%
?1%
?1%
0
2%
26%
1%
15%
23%
2%
10%
2%
?1%
?1%
37%
23%
0
10%
18%
40%
75%
12%
7%
15%
31%
*Percentages do not equal 100% because some serotypes could not be assigned and
some were mixed reactions.
O’Ryan
The Pediatric Infectious Disease Journal • Volume 28, Number 3, March 2009
© 2009 Lippincott Williams & Wilkins
S62