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
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
Rotavirus Surveillance Studies • Lessons learned in pre-vaccine era • Goals of surveillance during vaccine program implementation • Reference lab activities supporting surveillance programs
Rotavirus Structure RNA Segment Protein VP2 1 VP1 2 VP2 VP4 3 VP3 Neutralization VP4 4 antigen 5 NSP1 VP6 VP6 6 Subgroup antigen NSP2 7 NSP3 8 VP7 VP7 9 Neutralization antigen 10 NSP4 Subcore 11 NSP5
Lessons from Surveillance: 1. Limited Number of Globally Common Strains P[4]G2 P[8]G4 11.5% 7.5% P[8]G1 P[8]G3 52.2% 2.8% other 18.2% 5.5% Rare or regionally common strains (25 strains total): P[4]G1 (1.3%), P[6]G2 (0.8%), N=21,256 (1993-2003) P[6]G1 (0.6%), P[6]G8 (0.6%), P[4], G3 (0.5%) Gentsch et al, JID, 2005
Lessons from Surveillance: 2. Large Variation in Strain Incidence between Developed and Developing Regions Europe Africa other P[8]G9 P[8]G9 15% P[8]G3 6% P[8]G4 1% P[4]G1 8% P[6]G8 P[8]G4 1% 2% 10% 12% P[4]G2 3% P[6]G2 10% P[8]G3 P[8]G1 P[6]G1 or 2% 19% P[4]G2 G2 9% 4% other P[8]G1 28% 60% N=6328 N=1147 Gentsch et al, JID, 2005
Lessons from Surveillance: 3. Extensive Serotype Diversity and Reassortment P serotype [genotype] G type 1A[8] 1B[4] 2A[6] 2C[6] 3[9] 4[10] 5A[3] 6[1] 8[11] 11[14] 12[19] 1 Wa AU64 M37 AU19 K8 2 DS-1 1076 3 P 107E1B McN13 AU-1 HCR3 157C 4 Hochi ST-3 5 Br1054 6 PA151 PA169 8 MW333 MW023 69M HAL116 6 9 WI61 US120 116E Mc323 5 10 I321 Mc35 12 US585 Globally Common Uncommon Regionally Common Neonates Gentsch et al, JID, 2005
Reassortment in Multiple Gene Segments Distribution of natural RV G9 reassortants in Bangladesh Genotypic Properties (gene segment): G type P type (4) Subgroup (6) PAGE pattern No of strains (11) 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 Unicomb, et al. 1999
Lessons from Surveillance: 4. Emergence of Serotype G9 (1995-2005) Philadelphia, 83 Osaka, 85 First reports, mid 1980s G9 reports - late 1980s through 2005
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
What kind of breakthrough strains might occur after Vaccination with Rotarix and Rotateq? Bovine rotavirus with single human rotavirus gene substitution Human rotavirus G1 G3 G1P1A[8] P1A[8] G2 G4 GSK Bio Merck (Rotarix) (Rotateq)
Efficacy of Licensed Rotavirus Vaccines Efficacy Rotarix Rotateq ** (P[8]G1) Infecting strain (P[8], G1-G4) P[8], G1 High High P[8], G3 High High P[8], G4 High High P[8], G9 High High P[4], G2 Reduced High ** Only G types of infecting strains reported Adapted from Vesikari et al and Ruiz-Palacios et al, N Engl J Med: 354, 2006
Other Strains with Reduced Efficacy or Failure? Reduced High efficacy Efficacy? Efficacy Rotarix P[4]G2 P[6]G9 P[6]G12 P[8]G1 P[8]G3 P[8]G4 P[8]G9 P[8]G1 1 2 2 3 3 VP4 (P) 4 4 5 5 VP6 6 6 7 7 8 8 9 9 VP7 (G) 10 10 NSP4 11 11 Wa genogroup DS-1 genogroup Within genogroups - high genetic homology and antigenic relatedness Between genogroups – lower genetic homology and antigenic relatedness
Potential Breakthrough Strains with Rotateq Strains from the United States P[6]G12 P[9]G6 P[6]G9 P[8] G1 G2 G3 G4 Bovine genogroup Wa HRV genogroup DS-1 HRV genogroup AU-1 HRV genogroup
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
High Throughput Techniques are needed To Study Reassortment in all Genes: Gene Segment Typing by Microarray Segments Genogroup Specificity V 1 Wa P 2 B223/Bov Wa Wa B223/Bov 4 3 DS1 4 DS1 DS1 5 V 6 P NS 7 7 NS 8 9 10 11 a b Strain 116e c d P[8]G1 e P[4]G2 Strain 116e f g P[8]G1 h P[4]G2 Strain 116e i B223/Bov j
Rotavirus Reference Centers and 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
Rotavirus Reference Centers and Collaborating Centers United Kingdom Reference Center Health Protection Agency London WHO Collaborating Center CDC, Atlanta West African Reference Center NMIMR, Univ. of Ghana Legon South African Reference Center WHO Collaborating Center MEDUNSA Murdoch Childrens Research Institute Pretoria Melbourne
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 Gray George Armah Nicola Page Health Protection Agency West African Reference Center South African Reference Center London, United Kingdom NMIMR, Univ. of Ghana MEDUNSA Jim.Gray@HPA.org.uk Legon Pretoria GArmah@noguchi.mimcom.net pagenic@medunsa.ac.za Carl Kirkwood Jon Gentsch WHO Collaborating Center WHO Collaborating Center Murdoch Childrens Research Institute CDC, Atlanta Melbourne jgentsch@cdc.gov carl.kirkwood@mcri.edu.au
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
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