Roger Glass Lecture

Building the Evidence for Rotavirus

Immunization

11th International Rotavirus Symposium

Delhi, India. 3-5 September, 2014

Duncan Steele

Bill & Melinda Gates Foundation

Building the EvidenceFor Rotavirus Immunization

2

1. The evidence of disease burden

2. The development of rotavirus vaccines

3. The public health impact of rotavirus vaccines

Building the Evidence 1 –

The Burden of Disease

3

Diarrhoeal diseases remain a major cause of Under5 child deaths

WHO CHERG 2012. Estimates for 193 countries for 2010.

Liu L, Johnson HL, Cousens S et al. Lancet 2012; 379: 2151-61

4

Electron microscopy identifies the major role of viruses in infantile gastroenteritis

Al Kapikian describes Norwalk virus in

stools - 1972

Ruth Bishop describes

rotavirus in duodenal biopsies

of young children -1973

5Kapikian AZ, Wyatt RG, Dolin R et al. J Virol 1972; 10: 1075-81

Bishop RF, Davidson GP, Holmes IH, Ruck BJ. Lancet 1973; ii: 1281-83

Rotavirus antigen detection – the key to evidence generation and the burden of disease

Rotavirus antigen ELISA developed in 1977

WHO Collaborating Centre, East Birmingham Hospital, UK

ELISA kits were constructed in the lab and mailed to

developing countries

Yolken RH, Wyatt RG, Kapikian AZ. Lancet 1977; ii: 819

Thomas Flewett

6

Rotavirus was rapidly identified as the most common cause of severe diarrhoea in young children

Ubiquitous virus infection globally

All children infected by the age of 2-3 years

First infections are generally symptomatic

and re-infections are common

Peak incidence of clinical disease among

children 6 –m 18 months

Natural immunity of ~75% is observed

Limited strains in circulation

Improvements in water and sanitation will

not prevent infection

7Parashar U et al. Emerg Infect Dis 1998 4(4) 561–570; Bresee JS, et al. Vaccine 1999; 17: 2207-22

Linhares AH & Bresee JS. Pan Amer J Public Health 2000 8(5) 305–330

WHO study to define aetiology of diarrhoeal disease in young children <36 months of age in 5 countries

Pathogen Cases Controls Pathogenicity

(n=3640) (n=3279) index

Rotavirus 16% 2% 8.0

ETEC 16% 5% 3.2

Shigella 11% 1% 11.0

C jejuni 11% 7% 1.6

EPEC 9% 6% 1.5

Enteric Ad 4% 2% 2.0

China, India, Mexico, Myanmar, Pakistan

Huilan S, Zhen LG, Mathan MM et al, Bull WHO 1991; 69: 549-558

Villous atrophy = malabsorptive diarrhoea

Saif L, Ward LA, Yuan L et al. Arch Virol 1996; 12:153-61

Histopathology of piglet intestine infected with rotavirus shows extensive damage to gut

Normal piglet villi Rotavirus infected

showing denuded

micro-villi

9

Creating the Tools for Evidence Generation

10

WHO-coordinated Global Rotavirus Surveillance Networks

11

Global Rotavirus Surveillance in 42 Member States 2012-2013

12

Rotavirus is identified as the most common cause of diarrhoeal death in young children

Tate JE, Burton AH, Boscho-Pinto C et al. Lancet Infect Dis 2012; 12: 136-41

10 countries account for ~85% of rotavirus associated

mortality

Global rotavirus surveillance:

36-40% of diarrhoeal

hospitalizations

13

36%

1st Asian Rotavirus Surveillance

Bangkok 1999

Vietnamese Rotavirus Group

Hanoi 2002

Where in the world is Roger?

Eastern Mediterranean Rotavirus Surveillance

Cairo 2005

15

African Rotavirus Surveillance

Accra 2002

Where in the world is Roger -2 ?

Understanding the Rotavirus structure and genome

VP2

VP4Neutralization

antigen

VP6Subgroupantigen

VP7Neutralization

antigen

Subcore

RNA

SegmentProtein

1

2

3

4

5

6

7

8

9

10

11

VP1

VP2

VP3

VP4

NSP1

VP6

NSP2

NSP3VP7

NSP4

NSP5

Modified from B.V. Venkataram Prasad, J Infect Dis 1996; 174: S37–S46 16

Rotavirus G and P genotypes determined by nested multiplex RT-PCR assays

Gouvea VP7 amplicons to identify

G-genotypes

Gentsch VP4 amplicons to identify

P-genotypes

500bp

Gouvea V, Glass R, Woods P et al. J Infect Dis 1990; 28: 276-82

Gentsch JR, Glass R, Woods P et al. J Infect Dis 1992; 30: 1365-72

18

P[8]G1

48%

P[4]G2

15%

P[8]G3

3%

P[8]G4

11%

P[6]G4

3%

other

7%

P[8]G9

7%

P[9]G6

6%

P[8]G3

other

P[8]G4

P[6]G9 P[6]G3

Rotavirus strains vary across the globe in the same time period

Brazil, 1982-94, N=130

Leite et al, 1996

Malawi, 1997-98,

N=100 Cunliffe et al,

1999

P[6]G8

42%

P[4]G8

9%

P[8]G5

10%

Hungary, 1995-99, N=284

Banyai et al, 2004

P[8]G1

P[4]G2

P[8]G3

P[8]G4

mixed

P[9]G3

P[6]G2

Gentsch JR, Laird AR, Bielfelt B et al. J Infect Dis 2005; 192: S146-5919

1995-1999

34%

25%

9%

17%

8%

0%

7%

2005-2009

29%

34%

2%

3%

13%

8%

11%

> = 1994

28%

26%14%

13%

7%

0%

12%

G1

G2

G3

G4

G9

G12

G Mixed

2000-2004

38%

20%1%

6%

9%

10%

16%

Rotavirus strain diversity over time in South East Asia (India, Pakistan and Bangladesh)

Miles MM, Lewis KDC, Steele AD. Vaccine 2012; 202: A131-39

20

Rotavirus in Africa Rotavirus in Asia

Rotavirus Vaccines

Evidence of the burden and

the impact of vaccines is

clearly demonstrated

Rotavirus is associated with moderate-to-severe diarrhoea in young Indian children

Annu

al M

SD C

ases

Per

100

Ch

ild Y

ears

Incidence of Moderate-to-Severe Diarrhea in Kolkata by Age and Cause

0

5

10

15

20

25

30

35

40

45

0-11 mo.

12-23 mo.

24-59 mo.

Kotloff KL, Nataro JP, Blackwelder WC et al. Lancet 2013; 382: 209-2222

24

Roger in Accra, Ghana

Roger in Geneva, Switzerland

25

Building the Evidence 2 –

Rotavirus Vaccine Development

26

Albert Z. Kapikian1930 - 2014

Father of viral gastroenteritis

“His seminal basic and clinical research contributions to the study of viruses and to vaccine development have had an enormous global impact”

Anthony Fauci, Director, NIAID

Natural infection with rotavirus offers protection against the disease

Bishop RF, Barnes GL, Cipriani E, Lund JS. Clinical immunity after neonatal

rotavirus infection. A prospective longitudinal study in young children. N

England J Med 1983; 309:72-76

Bhan MK, Lew JF, Sazawal S, et al. Protection conferred by neonatal

rotavirus infection against subsequent rotavirus diarrhea. J Infect Dis

1993; 168:282-287

Ward RL, Clemens JD, Knowlton DR, et al. Evidence that protection against

rotavirus diarrhea after natural infection is not dependent on

serotype-specific neutralizing antibody. J Infect Dis 1992; 166:1251-1257

Velaquez FR, Matson DO, Calva JJ, et al. Rotavirus infections in infant as

protection against subsequent re-infections. N Engl J Med 1996; 335: 1022-

1028

27

Lessons learnt from early clinical development with animal rotavirus strains

First clinical trial was conducted by Timo Vesikari with a bovine strain

(RIT4237) in 1983 in Finland

Series of clinical trials between 1984 and 1990 provided the basis of

our current vaccine strategies

– Discordant efficacy in various developing countries led to the “modified”

Jennerian approach pioneered by Al Kapikian at NIH

– Higher viral concentration had similar reactogenicity, but better immunogenicity

– Two doses gave better immune response than one

– Neutralizing antibody response was mostly homotypic

– Secondary immunization – even to the same serotype – gave a broadening of

the immune response

– >50% developed serum antibody responses

– Pre-existing ab levels correlated negatively with vaccine take

Vesikari T, Isolauri E, Delem A et al. Lancet 1983; ii: 807-11

Midthun K & Kapikian AZ, Clin Microbiol Rev 1996; 9:423-42

28

29

“Modified” Jennerian approach for Rhesus rotavirus reassortant vaccine

Animal strains are naturally

attenuated for humans

Belief that homotypic protection

was essential

Designed to include the VP7

gene coding the outer capsid

antigens of human rotaviruses

Rhesus strain was developed

and licensed as RotaShield

Midthun K, Greenberg HB, Hoshino Y & Kapikian AZ. J Virol 1985; 53: 949-54

Midthun K & Kapikian AZ. Clin Microbiol Rev 1996; 9:423-42

30

Lessons learnt from the Rhesus-human rotavirus reassortant vaccine trials

100% 97%

75%

100%

70% 73% 71%†

100%

69%

Dehydration Hospital admittance MD visits

US multi-centre

Finland

Venezuela

Rennels et al Pediatrics 1996;97:7-13. Santosham et al J Pediatr 1997;131:632-638.

Joensuu et al Lancet 1997;350:1205-1209. Pérez-Schael et al N Engl J Med 1997;337:1181-87

Tetravalent Rhesus-human rotavirus reassortant rotavirus vaccines & Intussusception

MMWR 1999; Patel M et al. Exp Rev Vaccines 2009; 8(11): 1555-64

RotaShield® licensed in USA in 1998 and immediately introduced into immunization programme

Associated with increased risk of intussusception– Relative risk of >30 in first week after dose 1

– Attributable risk: 1 in 10,000 vaccinees

ACIP recommendation for use was withdrawn and Wyeth withdrew vaccine from USA in 1999

31

Rhesus-human rotavirus reassortant vaccine clinical development continues…

RotaShield® clinical trials in

Africa/Asia in 1999

– Navrongo, Ghana

– Matlab, Bangladesh

– Ga-Rankuwa, South Africa

All trials were halted due to

intussusception in the USA

RRV-TV trial conducted in

Ghana in 2012, using a

neonatal dose schedule

Armah GE, Kapikian AZ, Vesikari T et al. J Infect Dis 2013; 208: 423-31 32

G1 G3

G2 G4

P[8]

Reassortant bovine-humanrotavirus strains

G1P[8]

Attenuated single human rotavirus strain

Rotarix™, GSK BioRotaTeq™, Merck

G6

P[5]

Ruiz-Palacios G, Perez-Schael I, Velazquez FR et al N Engl J Med 2006; 354: 1-11

Vesikari T, Matson DO, Dennehy p, et al, N Engl J Med 2006; 354: 12-23

33

Early clinical trial results led to two paradigms for Rotavirus Vaccines

SAGE recommends rotavirus vaccination of infants into all national immunization programmes

WHO. Weekly Epidemiological Record 2009; 84: 213-36

WHO strongly recommends the inclusion of rotavirus vaccines

into national immunization systems in all regions of the world

Countries where diarrhoeal deaths among children from

diarrhoeal disease account for >10% of Under-5 mortality

should prioritize rotavirus vaccine introduction

34

“Modified” Jennerian Approach – Construction of NIH bovine–human reassortant rotavirus vaccine

VP4

VP7

Midthun K et al. J Virol 1985; 53: 949-54; Midthun K et al. J Clin Microbiol 1986; 24: 822-26

Kapikian AZ et al. J Infect Dis. 2005; 192: 22-29

35

37

Serum Institute, Pune, India

Shantha Biotechnics, Hyderabad, India

Wuhan Institute, Wuhan, China

Butantan Institute, Sao Paulo, Brazil

Sources: http://www.gavialliance.org/resources/DOC__11e_AVI_Progress_Report.pdf

10th International Rotavirus Symposium, Bangkok, September 2012

Manufacturer Country Product Phase

Biofarma Indonesia Human monovalent Phase 2b

Butantan Institute Brazil Bovine reassortant Phase 1

Serum Institute of India India Bovine reassortant Phase 3

Shantha Biotechnics India Bovine reassortant Phase 2

Wuhan Inst of

Biological Products

China Bovine reassortant Preclinical

Medica International

Foundation

Germany Rhesus reassortant Phase 2b

Live attenuated, orally administered Rotavirus Vaccine Pipeline

38

Nationally Licensed Rotavirus Vaccines

Manufacturer,

Country

Product Specifications Date Licensed

Lanzhou Institute of

Biological Products

China

Lanzhou Lamb

Rotavirus (LLR)

Vaccine

Lamb monovalent

G10P[12]

2000 in China

Center for Research

and Production of

Vaccines (POLYVAC)

Vietnam

Rotavin-M1™ Live attenuated

human G1P[8]

2007 in Vietnam

Bharat Biotech

International Limited

India

ROTAVAC™ Monovalent, human-

bovine G9P[1]1

2014 in India

39

The US-Indo Vaccine Action Programa successful vaccine development partnership

40

Visiting Bharat Biotech facility,

Hyderabad

Clinical Trial team, Delhi

Non-replicating Rotavirus Vaccine Candidates:Lead candidate is P2-VP8* particle (NIH)

Considered to address the issue of

improved efficacy and safety

Developed by Taka Hoshino

and Al Kapikian, NIAID

Phase 1 safety study complete

– Safe and well tolerated

– Robust immune responses

Phase 2 immunogenicity and

age descending study ongoing

in South Africa

**

ΔVP8*

Fusion

domain

Hsc70

binding

site

41Wen X, Cao D, Jones RW, et al. Vaccine 2012; 30: 6121-26

Stan Cryz et al. 11th International Rotavirus Symposium, Delhi 2014

42

Cathy and Al Kapikian

with grandson

Building the Evidence 3 –

Public Health Impact of Rotavirus Vaccines

43

Ciro de Quadros

1940 - 2014

Public Health Hero of the Americas

May, 2014

Polio eradication in Brazil and in Latin America

“No single person has done more to extend the benefits of immunization to people throughout the Americas”

Carissa Etienne, Director, PAHO

44

Mexico declaration:6th International Rotavirus Symposium, Mexico City, 2004

Delivered by Dr Rosario Quiroga,

Vice Minister of Health, Bolivia

On behalf of 16 Latin America

countries

Calling on PAHO Revolving Fund,

GAVI and vaccine manufacturers

to facilitate introduction

Recognize the need for rotavirus

vaccines as a public good

45

Successful Introduction of Rotavirus Vaccines in the Americas – USA and Nicaragua in 2006

Rotavirus vaccine

introduced into

Nicaragua – 2006 and

many countries of

Latin America

Panama

0

10

20

30

40

50

60

70

Week of year

Perc

en

t o

f Tests

Ro

tavir

us P

osit

ive

Max

Median

Min

2007-8 Season

USA – impact seen between 2006 & 2008

MMWR 2008; 57:697-700; Patel et al, JAMA 2009; 301: 2245-51 46

Not GAVI-eligible [37]

GAVI-eligible [32]

Middle East

Bahrain

Iraq

Israel

Qatar

Saudi Arabia

UAE

Uzbekistan

Yemen

Western Pacific

Australia

Fiji

Marshall Islands

Micronesia

New Zealand

Palau

Europe

Armenia

Austria

Belgium

Estonia

Finland

Georgia

Germany

Luxembourg

Moldova

United Kingdom

*National introductions by geographic region as of 15 August 2014

Africa

Angola Madagascar

Botswana Malawi

Burkina Faso Mali

Burundi Morocco

Cameroon Niger

Congo, Rep. Rwanda

Djibouti Sierra Leone

Eritrea South Africa

Ethiopia Sudan

The Gambia Tanzania

Ghana Togo

Kenya Zambia

Libya Zimbabwe

National Rotavirus Vaccine Introductions by Geographic Region - 69 countries*

Americas

Bolivia

Brazil

Cayman Islands

Colombia

Dominican Republic

Ecuador

El Salvador

Guatemala

Guyana

Haiti

Honduras

Mexico

Nicaragua

Panama

Paraguay

Peru

United States

Venezuela

Asia

Philippines

47

Public health impact: Reduction in rotavirus hospitalizations

Belgium50-77%

RotaTeq & Rotarix

US66-86%RotaTeq

Bolivia70%

RotarixAustria 74-79%RotaTeq & Rotarix

Australia87%

RotaTeq & Rotarix

Patel MM, Glass R, Desai R, et al. Lancet Infect Dis 2012; 12(7): 561-570

Hospitalizations: documented reductions of 50% or more in

children 0-2 years old following rotavirus vaccination

Brazil

El Salvador

Mexico

Nicaragua

South Africa

48

Public health impact: Reduction in all-cause diarrhoea hospitalizations

Brazil17-48%Rotarix

El Salvador28-37%Rotarix

USA 29-52%RotaTeq Belgium

33% RotaTeq & Rotarix

Mexico40%

Rotarix

Hospitalizations: documented reductions of nearly 20% or more in

children 0-2 years old following rotavirus vaccination

Patel MM, Glass R, Desai R, et al. Lancet Infect Dis 2012; 12(7): 561-570

Australia

Nicaragua

South Africa

50

Richardson V, Pichardo JH, Solares MQ et al. NEJM; 2010: 362: 358-360

Reduction in deaths due to diarrhoeal disease in Mexico after the introduction of rotavirus vaccine

41% reduction

51

Public health impact: Herd immunity/indirect benefits of vaccination

Belgium65-80%

USA74-85%

Austria 76-79%

El Salvador79-86%

Belgium20-64%

USA41-80%

Austria 35%

El Salvador41-81%

Hospitalizations: documented

reductions of more than 50% in

children eligible for vaccination

Hospitalizations: documented

reductions of more than 20% in

children NOT eligible for vaccination

Patel MM, Glass R, Desai R, et al. Lancet Infect Dis 2012; 12(7): 561-57052

How would this efficacy translate into impact on a population level?

Estimates of cumulative impact of rotavirus vaccines, 2010-2025

0

500,000

1,000,000

1,500,000

2,000,000

2,500,000

30 40 50 60 70 80 90Efficacy

Liv

es

sa

ve

d

60%

efficacy

1.7 million lives

saved

Atherly DE, Dreibelbis R, Parashar UD et al. J Infect Dis 2009; 200: S28-3853

The Challenges Ahead for the Full Public Health Impact of Rotavirus Vaccines

Biological Challenges of the virus

and the host

Technical Challenges of rotavirus

vaccine development

Programmatic Challenges of

delivering the vaccines where

they are needed most

Funding Challenges to pay for

the vaccines

Safety Challenges of rotavirus

vaccines

Courtesy: Jan Holmgren, Goteborg University 54

55

Mathu Santosham & Ciro de Quadros

Roger Glass & Mathu Santosham

© 2014 Bill & Melinda Gates Foundation