Simposio Subregional de Nuevas Vacunas:

Neumococo, Rotavirus y HPV

Caracas, Venezuela

29-30 Enero 2008

La Carga Global del Rotavirus

Daniel C. Payne, PhD, MSPHUS Centers for Disease Control and Prevention

Epidemiology of rotavirus

• Diarrheal disease in young childrenVirtually all children infected by age 5 years‘Democratic’ virusHighest rates of disease between 6-24 monthsLess common before 3 months

• 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 (US)

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)

Why is rotavirus mortality not dropping as fast as with other diseases?

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

• Antibiotics ineffective against rotavirus

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

2007 research - rotavirus often spreads beyond the intestines into the blood

stream

Rotavirus causes systemic viremia in 90% of infected children

(Blutt et al.)

And, rotavirus is more than a diarrheal disease

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

US rotavirus hospital rates are highest for children 12-<24 months (NVSN, 2006)

0

10

20

30

40

50

60

70

< 6 6 - < 12 12 - < 18 18 - < 24 24 - < 30 30 - < 36

Age (Months)

Hos

pita

lizat

ion

rate

per

10,

000

child

ren

< 3

yrs

Rotavirus Non-Rotavirus

Payne, et al. Pediatrics, 2008

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 Asian countries and United States

J Bresee EIDJ 2005

United States

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

Population-based rotavirus strains(NVSN sites in USA, 2006)

P[6], G9 -- 0.4%

P[6], G1 --1.8%

P[8], G12 -- 0.4%

P[8], G2 -- 0.4%

P[6], G12 -- 3.6%

P[4], G1 -- 0.4%

P[4], G2 -- 4.9%

Mixed -- 4.0%P[8], G184.0%

M ixed infections include:P[8], G1, G2 (0.4%)P[4], P[6], G2 (0.4%)P[4], P[8], G1 (2.7%)P[4], P[6], P[8], G1 (0.4%)

Circulating rotavirus s trains , 2006New Vaccine Surveillance Network

Note: RotaTeq® (M erck and Co., West Point, PA) includes G1, G2, G3, G4, and P[8] strains

Payne, et al. Pediatrics, 2008

G1, P8: 84%

Strain monitoring

Diversity of strains by regionDiversity of strains by region

Gentsch et al, JID, 2005

RotaTeq (Merck): G1, G2, G3, G4, P[8]

Rotarix (GSK): G1, P[8]+ Cross-protection?

Safety of RotaTeq in US

• Observed intussusception rates following vaccination are not greater than expected

• CDC continues to monitor rotavirus vaccine for safety

• CDC continues to support the ACIP recommendation for routine immunization of all U.S. infants with three doses of RotaTeq

Volume 354 January 5, 2006 Number 1

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

Volume 354 January 5, 2006 Number 1

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

WHO 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

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

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

Introduction of subsidized vaccine to GAVI-eligible countries

PATH: RVP

Europe, Latin America

Africa, Asia

First rotavirus immunizations in Panama by President Martin Torrijos and his wife, Vivien de Torrijos

March 14, 2006

GRACIAS!

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

Linhares AC, Bresee JS. Rotavirus vaccines and vaccination in Latin America. Rev Panam Salud Publica 2000; 8:305-331.

“Data from a large catchment trial in Venezuela with a higher RRV-TV dose, of 4 x 10(5) PFU/dose, indicated an efficacy rate of 48% against all rotavirus diarrhea and 88% against severe rotavirus diarrhea. It appears that breast-feeding does not compromise the efficacy of RRV-TV if three doses of the vaccine are administered. Similarly, possible interference of oral poliovirus vaccine with the "take" of the rotavirus vaccine can be overcome by giving three doses of the rotavirus vaccine or by using a higher-titer formulation of it. Wild enteroviruses, however, may cause primary rotavirus vaccine failure in developing countries. Studies in Peru with RRV-TV have shown a trend towards higher vaccine efficacy rates against "pure" (rotavirus-only) diarrheal episodes.”

Strain diversity and trends

Kang et al JID, 2005

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

Site % RV+Past studies, range % RV+ Difference

China 46 26, 13, 41 +5 to +33Taiwan 44 15, 27, 41, 43 +1 to +29Hong Kong 30 26, 29, 34, 35 -5 to +4

Vietnam 54 22 +32Myanmar 56 22 +34Thailand 43 17, 17, 20, 25, 30,

33, 38, 55-12 to +26

Malaysia 49 28 +21Indonesia

MEDIAN

54

45

38

29

+16

+16

Updated rotavirus mortality estimate

Study Year DD Deaths (millions)

Study Year RV deaths

Snyder 1982 4.6

IOM 1986 3.5 870,000

Martines 1990 3.2

Bern 1992 3.3

WDR 1993 2.5

Murray 1998 2.4 – 2.9

CHERG 2003 1.56 39%608,000

25%

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

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%

GSK Rotarix® licensure (92 countries –2007):

WHO Region Countries that have licensed Rotarix®

Americas 22 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

Africa 19 Benin, Burkina Faso, Cameroun, Central African Republic, Congo, DRCongo, Gabon, Guinea, Ivory Coast, Kenya, Madagascar, Malawi, Mali, Mauritania, Mauritius, Nigeria, Senegal, South Africa, Togo

Europe 31 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

Middle East 10 Bahrain, Egypt, Jordan, Morocco, Oman, Pakistan, Qatar, Saudi Arabia, UAE, Yemen

Southeast Asia 3 Bangladesh, Sri Lanka, Thailand

Western Pacific 7 Australia, Hong Kong, Malaysia, New Zealand, Philippines, Singapore, Taiwan

Courtesy Dr Robin Biellik

Merck RotaTeq™ licensure(47 countries –2007):

WHO Region Countries that have licensed RotaTeq®Americas 12 Argentina, Canada, Curação, Ecuador, El Salvador,

Guatemala, Honduras, Mexico, Nicaragua, Perú, Puerto Rico, USA

Africa 6 DRCongo, Guinea, Kenya, Niger, Rwanda, Togo

Europe 26 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

Middle East 0Southeast Asia

0

Western Pacific

3 Australia, Hong Kong, Taiwan

Courtesy Dr Robin Biellik

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

immunization of all US 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