La Carga Global del Rotavirus...All children will get at least one rotavirus infection early in life...

Simposio Subregional de Nuevas Vacunas: neumococo y rotavirus

San JoseCosta Rica

20-21 agosto 2007

Marc-Alain WiddowsonCenters for Disease Control and Prevention

La Carga Global del Rotavirus

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Epidemiology of rotavirus• Disease in young children

§ Virtually all children infected and ill by age five years§ Democratic virus§ Highest rates of disease between 6-24 mos.§ Uncommon before 3 months

• Single clinical syndrome – gastroenteritis§ Mild to very severe

• Natural infection confers protection against subsequent infection§ Higher protection against severe disease

• Worldwide distribution



All children will get at least one rotavirus infection early in life

Reproduced with permission from Velázquez et al. N Engl J Med. 1996;335:1022-1028.

1.00.90.80.70.60.50.40.30.20.1

3 6 9 12 15 18 21 24

Prob

abili

ty o

f rot

aviru

s in

fect

ion

Age (months)

1st infection

2nd infection

3rd infection

4th infection

5th infection



Annual disease burden of rotavirus in the United States

3.5 - 4.0 millones1:1

500,0001:7

55-70,0001:72

20-40<1:100,000

Riesgo a 5 anos Eventos

Muertes

Hospitalizaciones

Casos de diarrea

Consultas



La carga global del RotavirusLa carga global del Rotavirus

527,000 (475,000 – 580,000)

2.3 millones

24 millones

114 millones

1 : 285

1 : 58

1 : 5

1 : 1

Riesgo a 5 anos Eventos

WHO estimates, 2004

Muertes

Hospitalizaciones

Casos de diarrea

Consultas

5% of all deaths in children < 5are due to rotavirus



1 dot = 1000 deaths

Estimated global distribution of the 527,000 annual deaths caused by rotavirus

Estimated global distribution of the 527,000 annual deaths caused by rotavirus

14,751(11-17,000)



Estimated rate of rotavirus deaths per 100,000 population under five years of age.

Estimated rate of rotavirus deaths per 100,000 population under five years of age.



0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 12 24 36 48

Age (months)

Cum

ulat

ive

% R

V po

sitiv

e

60

India

Myanmar

China

Vietnam

Thailand

Indonesia

Japan

TaiwanHong Kong

Malaysia

Korea

Age distribution of rotavirus hospitalizations in ARSN sites and United States

J Bresee EIDJ 2005

United States



Differences in rotavirus epidemiology between developed and developing countries

DevelopedCountries9-15 mo.

65%Winter

4-5 commonUncommonUncommon

DevelopingCountries

6-9 mo.80%

Year-roundDiverse

CommonHIV, Malnutrition

Age - median- % <1year

SeasonalityRv StrainsCo-infectionsCo-morbidity



Causes of severe acute gastroenteritis among children <5 years

OtherOther

Bacterial Bacterial

Rotavirus

Developed Countries Developing Countries

Unknown Unknown Rotavirus

A. Kapikian Fields Virology 2003



WHO’s Generic Protocol• Hospital-based surveillance• Simple data collection• Outcomes:

» Rates of rotavirus hospitalizations

» % Rv positive• Guidelines for strain typing• Platform for measuring

other outcomes» Outpatient visits» Costs» intussusception



Global Rotavirus Surveillance

CDC, Atlanta

Murdoch Childrens Research InstituteMelbourne, Australia

MEDUNSAPretoria, S Africa

NMIMR, Univ. of GhanaLegon, Ghana

Health Protection AgencyLondon, UK

Reference Laboratory

PAHO (10)

SEARO/WPRO/EURO (14)

EMRO (10)

EURO (4)

AFRO (6)

Surveillance activities are scheduled to begin in 2006-2007

LEGEND

>40 countries



Rotavirus hospitalizations in the Asian Rotavirus Surveillance Network, 2001-3

Median = 45%

Vietnam: 54%

Bresee, Nelson, Hummelman, Glass, JID, 2005

China: 46%

Korea: 73%

Malaysia: 49%Indonesia: 54%

Myanmar: 56%

Hong Kong: 30%

Taiwan: 44%

Thailand: 43%



Proportion of hospitalizations attributable to rotavirus, Aug 2001 – July 2002, Asia

+16

+16

+21

-12 to +26+34+32

-5 to +4+1 to +29+5 to +33

DifferencePast studies, range % RV+ % RV+Site

38

29

54

45

Indonesia

MEDIAN

2849Malaysia

17, 17, 20, 25, 30, 33, 38, 55

43Thailand2256Myanmar2254Vietnam

26, 29, 34, 3530Hong Kong15, 27, 41, 4344Taiwan

26, 13, 4146China



Updated rotavirus mortality estimate

2.4 – 2.91998Murray

2.51993WDR

1.562003CHERG

3.31992Bern

3.21990Martines

870,0003.51986IOM

4.61982Snyder

RV deathsYearStudyDD Deaths (millions)

YearStudy

39%608,000

25%



Why is rotavirus mortality not dropping as fast?

• Sanitation, safe water and hygiene improvements will prevent bacterial & parasitic infections but less so rotavirus

• Antibiotics ineffective against rotavirus

• ORS may be less effective for rotavirus because of frequent vomiting



P[8]G47.5%

P[8]G152.2%

P[6] or P[8], G9

2%

other18.2%

P[8]G32.8%

P[4]G211.5%

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%



Rotavirus strainsRotavirus strains

Gentsch et al, JID, 2005



Number 1January 5, 2006Volume 354

Safety and Efficacy of an Attenuated Vaccine against Severe Rotavirus Gastroenteritis

Guillermo M. Ruiz-Palacios, M.D., Irene Pérez-Schael, M.Sc., F. Raúl Velázquez, M.D., Hector Abate, M.D., Thomas Breuer, M.D., SueAnn Costa Clemens, M.D., Brigitte Cheuvart, Ph.D., Felix Espinoza, M.D., Paul Gillard, M.D., Bruce L. Innis, M.D., Yolanda Cervantes, M.D., Alexandre C. Linhares, M.D., Pío López, M.D., Mercedes Macías-Parra, M.D., Eduardo Ortega-Barría, M.D.,

Vesta Richardson, M.D., Doris Maribel Rivera-Medina, M.D., Luis Rivera, M.D., Belén Salinas, M.D., Noris Pavía-Ruz, M.D., Jorge Salmerón, M.D., Ricardo Rüttimann, M.D., Juan Carlos Tinoco, M.D.,

Pilar Rubio, M.D., Ernesto Nuñez, M.D., M. Lourdes Guerrero, M.D., Juan Pablo Yarzábal, M.D., Silvia Damaso, M.Sc., Nadia Tornieporth, M.D., Xavier Sáez-Llorens, M.D., Rodrigo F. Vergara,

M.D., Timo Vesikari, M.D., Alain Bouckenooghe, M.D., Ralf Clemens, M.D., Ph.D., Béatrice De Vos, M.D., Miguel O'Ryan, M.D., for the Human Rotavirus Vaccine Study Group



Number 1January 5, 2006Volume 354

Safety and Efficacy of a Pentavalent Human–Bovine (WC3) Reassortant Rotavirus Vaccine

Timo Vesikari, M.D., David O. Matson, M.D., Ph.D., Penelope Dennehy, M.D., Pierre Van Damme, M.D., Ph.D., Mathuram Santosham, M.D., M.P.H., Zoe

Rodriguez, M.D., Michael J. Dallas, Ph.D., Joseph F. Heyse, Ph.D., Michelle G. Goveia, M.D., M.P.H., Steven B. Black, M.D., Henry R. Shinefield, M.D., Celia D.C.

Christie, M.D., M.P.H., Samuli Ylitalo, M.D., Robbin F. Itzler, Ph.D., Michele L. Coia, B.A., Matthew T. Onorato, B.S., Ben A. Adeyi, M.P.H., Gary S. Marshall,

M.D., Leif Gothefors, M.D., Dirk Campens, M.D., Aino Karvonen, M.D., James P. Watt, M.D., M.P.H., Katherine L. O'Brien, M.D., M.P.H., Mark J. DiNubile, M.D., H Fred Clark, D.V.M., Ph.D., John W. Boslego, M.D., Paul A. Offit, M.D., Penny M.

Heaton, M.D., for the Rotavirus Efficacy and Safety Trial (REST) Study Team PDF created with FinePrint pdfFactory trial version http://www.pdffactory.com


1. US FDA licenses RotaTeq2. ACIP recommends RotaTeq for routine

immunization of all American children3. EMEA licenses Rotarix4. Brazil, Panama, Venezuela, Mexico,

Nicaragua, El Salvador begin programs of routine childhood immunization

5. GAVI approved investment case for Phase 1

2006 – momentum builds



Introduction of subsidized vaccine to GAVI-eligible countries

PATH: RVP

Europe, Latin America

Africa, Asia



GSK Rotarix® licensure (92 countries – 31 May, 2007):

Bahrain, Egypt, Jordan, Morocco, Oman, Pakistan, Qatar, SaudiArabia, UAE, Yemen

10Middle East

Bangladesh, Sri Lanka, Thailand3Southeast Asia

Austria, Belgium, Bulgaria, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Romania, Slovakia, Slovenia, Spain, Sweden, Switzerland, Turkey, UK

31Europe

Australia, Hong Kong, Malaysia, New Zealand, Philippines, Singapore, Taiwan

7Western Pacific

Benin, Burkina Faso, Cameroun, Central African Republic, Congo, DRCongo, Gabon, Guinea, Ivory Coast, Kenya, Madagascar, Malawi, Mali, Mauritania, Mauritius, Nigeria, Senegal, South Africa, Togo

19Africa

Argentina, Aruba, Bolivia, Brazil, Chile, Colombia, Costa Rica, Curaçao, Dominican Republic, Ecuador, El Salvador, Guatemala, Honduras, Jamaica, Mexico, Nicaragua, Panama, Paraguay, Peru, Suriname, Trinidad/Tobago, Venezuela

22Americas

Countries that have licensed Rotarix®WHO Region

Courtesy Dr Robin BiellikPDF created with FinePrint pdfFactory trial version http://www.pdffactory.com


Merck RotaTeq™ licensure (47 countries – March 1, 2007):

0SoutheastAsia

0Middle East

Austria, Belgium, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Poland, Portugal, Slovakia, Slovenia, Spain, Sweden, Turkey, UK

26Europe

Australia, Hong Kong, Taiwan3WesternPacific

DRCongo, Guinea, Kenya, Niger, Rwanda, Togo6Africa

Argentina, Canada, Curação, Ecuador, El Salvador, Guatemala, Honduras, Mexico, Nicaragua, Perú, Puerto Rico, USA

12AmericasCountries that have licensed RotaTeq®WHO Region

Courtesy Dr Robin Biellik



First rotavirus immunizations in Panama, Inaugurated by President Martin Torrijos and his wife, Vivien de Torrijos, March 14, 2006



http://www.who.int/immunization_monitoring/burden/rotavirus_estimates/en/index.html

GRACIAS



http://www.who.int/immunization_monitoring/burden/rotavirus_estimates/en/index.html



Strain diversity and trends

Kang et al JID, 2005



P[4]G2

P[8]G3

P[8]G4

otherP[6]G1

P[8]G1

P[8]G3

other

P[8]G4

P[6]G9P[6]G3

P[8]G1

P[4]G2P[8]G3

P[8]G4

mixed

P[9]G3

P[6]G2

P[8]G1

P[4]G2

P[8]G3P[8]G4

other

U.S., N=348 India, N=133

Examples of Unusual Strain Prevalence

Brazil, N=130 Malawi, N=100

P[6]G842%

P[4]G8 9%

P[8]G510%

P[8]G9P[6]G9

7.2% P[6]G917%

} P[6]G1, P[6]G2,P[6]G3, P[6]G4

J. Gentsch



Detection rate of rotavirus in hospitalized diarrhea cases, 1986-1999 vs. 2000-2004

0

10

20

30

40

50

60

70

80

100 1000 10000 100000

GNP Per Capita

% R

V Po

sitiv

e

2000-2004 1986-1999

Low incomeLow-middle

incomeHigh-middle

income High income

Parashar EIDJ, 2006



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La Carga Global del Rotavirus...All children will get at least one rotavirus infection early in life...

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