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Rotavirus Strain Surveillance in the Vaccine Era: Why should we characterize
strains?
Jon Gentsch, Carl Kirkwood, George Armah, Jim Gray, Miren Iturriza-Gomara, Nicola Page, Duncan Steele,
Mathew Esona, May El Sherif and Roger Glass
Centers for Disease Control and Prevention, Atlanta, USA; Murdoch Childrens Research
Institute, Melbourne, Australia; NMIMR, University of Ghana, Legon; Health Protection Agency,
London, United Kingdom; Medical University of South Africa, Pretoria, South Africa
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Importance of Rotavirus Strain Surveillance and Molecular
Epidemiology
Vaccine Research- serotypes of vaccines- impact of vaccine on strains- reassortment of vaccine in vivo
Virus Evolution- origin of new strains- animal rotavirus role- reassortment between strains- genetic variation in RV genes
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Rotavirus Surveillance Studies
• Lessons learned in pre-vaccine era• Goals of surveillance during vaccine
program implementation • Reference lab activities supporting
surveillance programs
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Rotavirus StructureRNA
Segment Protein
1234
5
6
78
9
10
11
VP1VP2VP3VP4
NSP1
VP6
NSP2
NSP3
VP7
NSP4
NSP5
VP2
VP4 Neutralization
antigen
VP6Subgroupantigen
VP7Neutralization
antigen
Subcore
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P[8]G47.5%
P[8]G152.2%
other18.2%
P[8]G32.8%
P[4]G211.5%
Lessons from Surveillance: 1. Limited Number of Globally Common Strains
N=21,256 (1993-2003)Gentsch et al, JID, 2005
Rare or regionally common strains (25 strainstotal): P[4]G1 (1.3%), P[6]G2 (0.8%), P[6]G1 (0.6%), P[6]G8 (0.6%), P[4], G3 (0.5%)
5.5%
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Lessons from Surveillance: 2. Large Variation in Strain Incidence between Developed and
Developing Regions
P[6]G1 or G24%
P[6]G210%
P[8]G119%
other28%
P[8]G42%
P[8]G38%
P[4]G23%
P[8]G96%
P[6]G810%
P[8]G91% P[4]G1
1%
other15%
P[8]G412%
P[8]G32%
P[4]G29% P[8]G1
60%
Europe Africa
N=6328
Gentsch et al, JID, 2005
N=1147
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6[1]
US58512
Mc35I32110
Mc323116EUS1205
WI619
HAL1166
69MMW023MW3338
PA169PA1516
Br10545
ST-3Hochi4
157CHCR3AU-1McN13107E1BP3
1076DS-12
K8AU19M37AU64Wa1
12[19]11[14]8[11]5A[3]4[10]3[9]2C[6]2A[6]1B[4]1A[8]G type
Lessons from Surveillance: 3. Extensive Serotype Diversity and Reassortment
P serotype [genotype]
Globally Common UncommonRegionally Common Neonates Gentsch et al, JID, 2005
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Genotypic Properties (gene segment):
G type P type (4) Subgroup (6) PAGE pattern (11)
No of strains
9 8 II Long 1
9 6 I Short 32
9 6 I, II Long 5
9 8 I Short 9
9 0 ND Short 6
9 0 ND Long 3
Distribution of natural RV G9 reassortants in Bangladesh
Unicomb, et al. 1999
Reassortment in Multiple Gene Segments
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Lessons from Surveillance: 4. Emergence of Serotype G9 (1995-2005)
First reports, mid 1980sG9 reports - late 1980s through 2005
Philadelphia, 83 Osaka, 85
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Surveillance goals during and after implementation of vaccine programs?
• Breakthrough strains that appear after vaccination
• Changes in serotype incidence and the emergence of novel strains with distinct G and P serotypes
• Circulation of vaccine strains in children• Reassortment with wild-type human
rotaviruses, yielding new strains or changes in virulence
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What kind of breakthrough strains might occur after Vaccination with Rotarix and
Rotateq?
G1P1A[8]
G1 G3
G2 G4
P1A[8]
Human rotavirus
Bovine rotavirus with single human rotavirus gene
substitution
GSK Bio(Rotarix)
Merck(Rotateq)
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HighHighP[8], G4HighHighP[8], G9HighReducedP[4], G2
HighHighP[8], G3HighHighP[8], G1
Rotateq**(P[8], G1-G4)
Rotarix (P[8]G1)Infecting strain
Efficacy
**Only G types of infecting strains reported
Adapted from Vesikari et al and Ruiz-Palacios et al, N Engl J Med: 354, 2006
Efficacy of Licensed Rotavirus Vaccines
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Other Strains with Reduced Efficacy or Failure?
1
111098765432
111098765432
P[8]G1 P[8]G3 P[8]G4 P[8]G9 P[4]G2 P[6]G9Rotarix
VP4 (P)
VP6
VP7 (G)NSP4
P[8]G1
High efficacyReducedEfficacy
Wa genogroupDS-1 genogroup
Within genogroups - high genetic homology and antigenic relatednessBetween genogroups – lower genetic homology and antigenic relatedness
Efficacy?
P[6]G12
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Potential Breakthrough Strains with Rotateq
P[6]G9 P[6]G12
Wa HRV genogroupDS-1 HRV genogroupAU-1 HRV genogroup
P[8]
G1 G2 G3 G4
Bovine genogroup
Strains from the United StatesP[9]G6
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Circulation of Vaccine Strains and Reassortment with HRV
• Rotarix – expect reassortment with natural RV (P[8]G1, P[8]G9,etc) during mixed infections– Reassortment in all 11 genes likely
• Rotateq?• Potential to produce new strains with
altered virulence – important surveillance issue
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123
45678
91011
Genogroup Specificity
WaDS1
Segments
High Throughput Techniques are neededTo Study Reassortment in all Genes:Gene Segment Typing by Microarray
ab c d e f g h i j
Wa WaDS1 DS1
B223/Bov
Strain 116e
P[8]G1
P[4]G2
Strain 116e
P[8]G1
P[4]G2
Strain 116e
B223/BovVP4
VP7 B223/Bov
NSNS
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Rotavirus Reference Centersand Collaborating Centers
• Supported by WHO and PATH• Set up to support surveillance networks• Provide training, protocols, reagents and
assistance• Prepared a unified lab manual of rotavirus
characterization protocols
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Rotavirus Reference Centersand Collaborating Centers
WHO Collaborating CenterCDC, Atlanta
WHO Collaborating CenterMurdoch Childrens Research InstituteMelbourne
South African Reference CenterMEDUNSAPretoria
West African Reference CenterNMIMR, Univ. of GhanaLegon
United Kingdom Reference CenterHealth Protection AgencyLondon
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MANUAL OF ROTAVIRUS CHARACTERIZATION METHODS
Draft Version
This document was produced by the Laboratory Directors of the European, West African, and South African Rotavirus Reference Laboratories, and the WHO Rotavirus Collaborating Centers in Melbourne, Australia, and
Atlanta, Georgia, United States
Copies may be requested from:
Jim GrayHealth Protection AgencyLondon, United [email protected]
George ArmahWest African Reference CenterNMIMR, Univ. of [email protected]
Nicola PageSouth African Reference [email protected]
Carl KirkwoodWHO Collaborating CenterMurdoch Childrens Research [email protected]
Jon GentschWHO Collaborating CenterCDC, [email protected]
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Summary• Rotavirus strain surveillance and
characterization studies have played key role in defining serotypes important for vaccines and understanding strain diversity and mechanisms of evolution
• During and after vaccine programs are implemented surveillance will be crucial to monitor changes in serotypes and vaccine effectiveness