sabin vaccine institute - global rotavirus (rv) surveillance in the … jon... · 2014. 9. 18. ·...

Global Rotavirus (RV) Surveillance in the

Vaccine Era: Insights from Molecular

Characterization of Strains

Jon Gentsch, Ph.D.Gastroenteritis and Respiratory Viruses Laboratory Branch (GRVLB)

Division of Viral Diseases (DVD), NCIRD

Centers for Disease Control and Prevention

Atlanta, Georgia U.S.A.

Division of Viral Diseases

National Center for Immunization & Respiratory Diseases

Overview

• Global strain prevalence before/after

vaccine introduction

• Strain monitoring in vaccine era

Prevalence changes post introduction

• Molecular studies



Post-licensure Strain Surveillance Issues

• Cross-protection to heterotypic RV strains

Common or rare serotypes

• Long term Impact of vaccine selection

pressure:

Changes in strain prevalence

Emergence of vaccine escape mutants

Antigenic drift in G-P antigens common RV

Antigenic shift (rare G-P types)

Zoonotic strains by reassortment or

interspecies transmission



Review of Global Strain Diversity

Global Strain Prevalence, 1996-

2007 and 2007-2012

1996-2007 2007-2012

Adapted from Banyai et al, Vaccine (2012),

Doro et al, Infection Genetics and Evolution,

in Press

Human Rotavirus G-P Genotypes Identified Through 2007

Banyai et al, Vaccine (2012)

Temporal and Geographic G Genotype Variation in WHO Regions, 1996-2007

Banyai et al Vaccine 2012

G9

G4

G3

G2

G1

G8 G8

G12

Changes in Prevalent Rotavirus

Strains Post Introduction



Monitoring Rotavirus Strains Post Vaccine Introduction

Rotarix introduced, 2006

Adapted from

L. Oliveira, PAHO

Rotarix – Human Rotavirus,

G1P[8]

No program

RotaTeq – Bovine Rotavirus, G1,

G2, G3, G4, G6, P[5], P[8]

RotaTeq introduced,

2006

Rotarix introduced,

2008

•Population-based surveillance of acute gastroenteritis (AGE) set up to assess vaccine impact on rotavirus disease in children less than 3 years of age of known vaccination status

•Estimates vaccine effectiveness each year

•Hospitalization trends

•Estimates serotype-specific vaccine effectiveness

NVSN

Seven sites:

-University of Rochester

-Cincinnati Children’s Hospital

-Vanderbilt University

-Houston

-Kansas City

-Seattle

-Oakland, CA



Rotavirus Genotyping Results from NVSN 2006 to 2008

G1 P[8]84.0%

G1 P[M]3.1%

G1 P[6]1.8%

G1 P[4]0.4%

G2 P[4]4.9%

G2 P[8]0.4%

G9 P[6]0.4%

G12 P[8]0.4%

G12 P[6]3.6%

GM P[8]0.9%

Strain Prevalence: 2006 (n=225)

G1 P[8]44.7% G1 P[M]

0.4%

G1 P[NT]1.1%

G2 P[4]10.3%

G2 P[6]0.7%

G2 P[8]7.7%

G2 P[M]1.1%

G3 P[8]2.2%

G4 P[8]0.4%

G9 P[8]0.4%

G12 P[8]27.5%

G12 P[M]0.4%

GM P[8]1.5%

GM P[M]0.4%

GNT P[8]1.1% GNT P[NT]

0.4%

Strain Prevalence: 2006-2007 (n=273)G1

P[8]82.1%

G3 P[8]

10.7%

GNT P[NT]7.1%

Strain Prevalence: 2007-2008 (n=28)

Slide courtesy of Dr Mike Bowen

Genotype Prevalence USA, NVSN 2008-2012

2008-2009 2009-2010

2010-2011 2011-2012

n=145


NVSN 2012-13, All Sites

RV positive AGE cases only

N = 532

94 RV negative AGE cases not included in chart

GENOTYPE PREVALENCE USA, NVSN 2012-2013

DEPARTMENT OF HEALTH AND HUMAN SERVICES

VE and 95% CI by Rotavirus Genotype for full courses of

RotaTeq and Rotarix NVSN – 2009-2011

89% 87% 87% 74% 83%0

10

20

30

40

50

60

70

80

90

100

G1P[8] G2P[4] G3P[8] G3P[8] G12P[8]

RotaTeq RotaTeq RotaTeq Rotarix RotaTeq

Va

ccin

e E

ffec

tiv

enes

s (%

)

Payne et al, Clin Infect Dis. 2013

15

*Gurgel et al EID 13(10):1571; 2007

*Nakagomi et al, Arch Vir 153(3); 2008

El Salvador

Rotarix, 2006

Guatemala

(no vaccine)

Honduras

(no vaccine)

Adapted from Patel et al, 2008

2005 2006 2007

P[8]G996%

P[8]G994%

P[8]G940%

P[4]G281%

P[4]G272%

P[4]G268%

P[8]G191%

P[8]G190%

P[8G168%



Age groups VE (95% CI)

6-11 months of age 77 (42 to 91)

> 12 months of age -24 ( -190 to 47)

RV1 Effectiveness Against Severe G2P[4]

Rotavirus Diarrhea in Recife, Brazil, by

Age*

Correia et al, J Infect Dis. 2010

* Results shown for rotavirus test negative controls

Prevalence of Rotavirus Strains in Brazil

0

10

20

30

40

50

60

70

80

90

100

110

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013

Year

Ra

te o

f R

VA

ge

no

typ

es

de

tec

tio

n (

%)

G1 G2 G3 G4 G5 G9

0

10

20

30

40

50

60

70

80

90

100

110

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013

Year

Ra

te o

f R

VA

ge

no

typ

es

de

tec

tio

n (

%)

P4 P6 P8

Carvalho-Costa et al, manuscript in preparation

Summary

• Changes in genotype prevalence after RV1

and RV5 introduction

– Not associated with reduced VE

– Associated with increased proportion G2P[4] of

hospitalized cases RV AGE(Belgium)

– Differences in genotype distribution depending on

vaccine used (Australia – RV1 vs RV5 states)

– Transient (natural variation or vaccine driven?)

• Heterotypic protection vs variety non-vaccine

genotypes

• Need for longterm surveillance in different

settings

Detection of Vaccine Strains in

Rotavirus Surveillance Specimens



Payne et al. (2010) Pediatrics 125:e438-441



G1

RotaTeq G1

Vanderbilt

2009726981

• Genotyped by RT-PCR as a G1P[8]

• VP4 and VP7 sequences were 100% identical to sequences found in RotaTeq


Reassortment in vivo between RotaTeq Vaccine Strains

• G1P[8] RotaTeq reassortant causes gastroenteritis, indicating it may

be more virulent than 5 parental strains

P[5]G1 P[5]G2 P[5]G3 P[5]G4 P[8]G6

G1 VP7 gene P[8] VP4 gene

Reassortant strain:

G1P[8]

9 genes of WC3 parent



Association of RotaTeq Strains with Gastroenteritis

• NVSN, Tennessee- Transmission of RotaTeq from vaccinee

to older sibling who developed severe gastroenteritis (Payne

et al., 2010)

o G1P[8] reassortant identified

• Australia- 16 gastroenteritis cases associated with RotaTeq

vaccine strains (Donato et al., 2012)

o 6/16 (38%) cases associated with G1P[8] reassortant

• Finland - RotaTeq vaccine strains detected in 5 gastroenteritis

cases (Hemming et al., 2012)

o 3 cases associated with G1P[8] reassortant

• Nicaragua - RotaTeq NSP2 gene detected in 2 wild-type

G1P[8] strains (Bucardo et al., 2012)

o Clinical significance yet to be determined



Reports of Rotarix Strain Associated with Gastroenteritis

• Brazil – introduction of Rotarix genes into

circulating human rotaviruses and introduction of

human rotavirus gene into Rotarix vaccine strain in

vivo (Rose et al, 2013)

Vaccine Failure-Matched Control Whole Genome Sequencing Study

Goal – sequence full rotavirus genomes of vaccine

failure cases and matched controls and analyze data for

genetic markers of vaccine escape

NVSN Controls matched by rotavirus genotype, year, site, age,

inpatient vs. ED

3-dose vaccine failures (RotaTeq) and matched controls

identified (2009-2011)

Vaccine failure samples and controls from Atlanta EIP study also

included (mostly Rotarix) 2010-2011

(G1P[8],G3P[8], G9P[8], G12P[8], G2P[4] (~125 strains)

Preliminary analysis G3P[8] VF-matched controls

SIA Products

Amplicons quantitated then sent to HudsonAlpha

Institute for QC, library preparation, and paired-end 150

sequencing using the Illumina MiSeq

Purified SIA products RNA after DNase treatment and

LiCl precipitation

9626

9641

1235

1311

9541

9576

2020 (

c)

M

9626

9641

1235

1311

9541

9576

202

0 (

c)

M


VP4 2010722020-MC

2010722043-VF

2010722113-MC

2010722158-MC

2010749198-MC

2010749200-VF

2010749274-MC

2010749389-VF

2010749399-VF

2010749401-VF

2010749441-VF

2010749457-VF

2010749498-VF

2010749539-VF

2010749561-VF

2010749235-MC

2010749571-VF

2010749584-MC

2010749339-VF

2011729071-VF

2010722082-VF

2010721976-MC

2010721597-VF

2010721581-VF

2010721586-MC

HM773714

JN258360

HM773747

HM773758

HM773659

JN258371

HM773582

HM534675

HM773593

HM773615

HM773604

HM773626

HM773637

JN258393

HM773835

HM773846

AF183870/TF101/Lin-III

HM773824

JN258340

2011742230-VF

2011782521-MC

2011782519-VF

2011782546-VF

2011782522-MC

HM773725

JN258404

2011728655-VF

HM773648

HM773670

HM773681

HM773692

HM773703

2011729127-VF

2011799773-VF

2011728989-VF

2011729006-MC

2011782365-VF

2011782366-MC

HM773736

2011728833-MC

2011742381-MC

2011783244-VF

2011783304-MC

2011783289-VF

2011783330-MC

2011852053-VF

2011729938-VF

2011783333-MC

2011728857-VF

2011729214-VF

2011729197-VF

2011729020-MC

2011783290-VF

2011783348-MC

EU045220/Py99371/Lin-III

2011729010-VF

2011728953-VF

2011728965-MC

JN258349

U30716/F45/Lin-II

AF052450/L5/Lin-II

AJ302146/MW670/Lin-IV

AJ302152/OP530/Lin-IV

AB008280/ITO/Lin-I

L34161ref

M96825/Wa/Lin-I

Rotarix VP4

HM773780

HM773791

HM773802

HM773813

JN258383

HM773769

89

87

99

71

99

96

95

100

73

94

9597

95

95

100

80

96

97

97

97

78

86

96

93

99

73

94

95

94

88

99

96

96

99

39

82

99

53

99

99

95

99

100

97

99

78

87

84

100

99

69

98

81

0.02

VP7 2010721586-MC

2010721597-VF

2010721976-MC

2010722043-VF

2010722113-MC

2010722158-MC

2010749198-MC

2010749200-VF

2010749235-MC

2010749274-MC

2010749339-VF

2010749389-VF

2010749399-VF

2010749401-VF

2010749441-VF

2010749457-VF

2010749498-VF

2010749539-VF

2010749561-VF

2010749571-VF

2010722082-VF

2010749584-MC

2011729071-VF

2010722020-MC

2010721581-VF

HM773664

EF088831/4643/Lin-I

HM773730

2011782546-VF

2011782522-MC

2011782521-MC

2011742230-VF

2011782519-VF

AY707794/CMH054/Lin-I

2011728655-VF

HM773708

HM773697

HM773653

HM773675

HM773686

2011728833-MC

HM773741

2011742381-MC

2011782365-VF

2011782366-MC

2011729006-MC

2011728989-VF

2011729127-VF

2011799773-VF

2011728953-VF

2011728965-MC

2011729010-VF

2011783333-MC

2011852053-VF

2011783289-VF

2011783290-VF

2011783330-MC

2011783348-MC

2011783244-VF

2011783304-MC

HM773719

2011729938-VF

2011729020-MC

2011728857-VF

2011729197-VF

2011729214-VF

D86271ref

GU565079Rotateq

AJ311738/CC425/Lin-I

D86264/02/92/Lin-I

AF295303/RRV/Lin-II

AY707792/CMH222/Lin-II

AB046465/JE29/Lin-V

AY750921/4616G11/Lin-V

AF271089/RV198/95/Lin-III

AF528204/30/96/Lin-IV

AY740736/B4106/Lin-IV

K02033ref

94

57

91

91

84

92

90

96

98

79

79

92

92

88

76

91

95

91

85

74

99

0

98

70

96

98

89

96

0.05

Matched Control

Vaccine Failure

Slide courtesy of Dr Sunando Roy

Antigenic Region A B C F

1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2

8 8 8 9 9 9 9 9 9 9 9 9 9 0 4 4 4 4 4 4 4 5 0 0 1 1 1 1 1 1 1 1 1 1 2 2 3 3 3 3 3 4 4 4

7 8 9 0 1 2 3 4 5 6 7 8 9 0 3 4 5 6 7 8 9 0 8 9 0 1 2 3 4 5 6 7 8 9 0 1 5 6 7 8 9 0 1 2

RotaTeq-WI78-8/G3P75 T E A A T E I N D N S W K D K Y D A T L Q L L T T D A N T F E E V A T A H K L K V T T D

2010721581-VF . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2010721586-MC . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2010721597-VF . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2010721976-MC . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2010722020-MC . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2010722043-VF . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2010722082-VF . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2010722113-MC . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2010722158-MC . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2010749198-MC . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2010749200-VF . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2010749235-MC . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2010749274-MC . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2010749339-VF . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2010749389-VF . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2010749399-VF . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2010749401-VF . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2010749441-VF . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . I . . . . N . . . N

2010749457-VF . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2010749498-VF . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2010749539-VF . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2010749561-VF . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . S . . . N . . . N

2010749571-VF . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2010749584-MC . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2011728655-VF . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . I . . . . . . N . . . N

2011728833-MC . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2011728857-VF N . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2011728953-VF . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2011728965-MC . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2011728989-VF . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2011729006-MC . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2011729010-VF . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2011729020-MC N . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2011729071-VF . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2011729127-VF . . . . . . . . . . . . . . . . N . . . . . . . . . T . . . . . . . . . . . . N . . . N

2011729197-VF N . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2011729214-VF N . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2011729938-VF . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . Y . . N . . . N

2011742230-VF . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2011742381-MC . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2011782365-VF . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . S . . . N . . . N

2011782366-MC . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . S . . . N . . . N

2011782519-VF . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2011782521-MC . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2011782522-MC . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2011782546-VF . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2011783244-VF . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2011783289-VF . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2011783290-VF . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2011783304-MC . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2011783330-MC . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2011783333-MC . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2011783348-MC . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2011799773-VF . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

2011852053-VF . . . . . . . . . . . . . . . . . . . . . . . . . . T . . . . . . . . . . . . N . . . N

Antigenic Region Amino Acid Sequences of G3P[8] VF Strains and Matched Controls

Compared to RotaTeq G3 VP7


Vaccine Failures Matched Controls

Dash City VP7 VP4 VP6 VP1 VP2 VP3 NSP1 NSP2 NSP3 NSP4 NSP5 Dash City VP7 VP4 VP6 VP1 VP2 VP3 NSP1 NSP2 NSP3 NSP4 NSP5

2010721581 Houston 2010722113 Houston

2010721597 Houston 2010749235 Houston

2010722043 Houston 2010749198 Houston

2010722082 Houston 2010722020 Houston

2010749200 Houston 2010721586 Houston

2010749339 Houston 2010721586 Houston

2010749389 Houston 2010721586 Houston

2010749399 Houston 2010721586 Houston

2010749401 Houston 2010722020 Houston

2010749441 Houston 2010749274 Houston

2010749457 Houston 2010722020 Houston

2010749498 Houston 2010722020 Houston

2010749539 Houston 2010722158 Houston

2010749561 Houston 2010722158 Houston

2010749571 Houston 2010721976 Houston

2010749584 Houston 2010722158 Houston

2011728655 Houston

2011728857 Houston 2011728965 Houston

2011728953 Houston 2011728833 Houston

2011728989 Houston 2011729020 Houston

2011729010 Houston

2011729071 Houston 2011729006 Houston

2011729127 Houston

2011729197 Houston 2011728833 Houston

2011729214 Houston 2011728833 Houston

2011729938 Houston 2011729020 Houston

2011742230 Cincinnati

2011782365 Rochester 2011782366 Rochester

2011782519 Cincinnati 2011782521 Cincinnati


2011783244 Kansas City 2011783304 Kansas City



2011799773 Oakland

2011852053 Nashville



2011783348 Kansas City

2010

2011


Conclusions

• Rotavirus vaccines Rotarix and RotaTeq have made a

significant impact on rotavirus disease where used in

national immunization programs

• Changes in strain prevalence seen in countries post

introduction are difficult to distinguish from natural

variation

• Long term surveillance needed to monitor vaccine

effectiveness and impact on strain epidemiology



I Would Like to Thank:

•Margaret Cortese

•Jazmin Duque

•Eyal Leshem

•Umesh Parashar

•Manish Patel

•Daniel Payne

•Jackie Tate

•Mary Wikswo

•Catherine Yen

•Mike Bowen

•Mathew Esona

•Molly Freeman

•Rashi Gautam

•Tara Kerin

•Jamie Lewis

•Freda Lyde

•Sharla McDonald

•Osbourne Quaye

•Sunando Roy

•Kunchala Rungsrisuriyachai

•Slavica M. Rustempasic

•Michele Sturgeon

•Ka Ian Tam

•Elizabeth Teel

CDC RV Lab Surveillance CDC RV Vaccines

•Jennifer Hull

•Baoming Jiang

•Sung-Sil Moon

•Yuhuan Wang

CDC Epidemiology

NIH

New Vaccine Surveillance

Network Collaborators

Hungarian Academy of

Sciences•Krisztian Banyai

•Renáta Dóró

•Brigitta László

Chinese University of Hong Kong

•Roger Glass

•Tony Nelson

Bill and Melinda Gates Foundation

•Duncan Steele

Program for Appropriate Technolgy

In Health

University of Bari,Italy

•Vito Martella

Questions?

Thank you!

The findings and conclusions in this report are those of the author(s) and do not necessarily represent the

official position of the Centers for Disease Control and Prevention.

sabin vaccine institute - global rotavirus (rv) surveillance in the … jon... · 2014. 9. 18. ·...

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