Rotavirus Vaccines:

The impact of number of doses in

developing countries

10th International Rotavirus Symposium

Bangkok, Thailand

19-21 September, 2012

Duncan Steele

Bill & Melinda Gates Foundation

Determinants of responses to oral vaccines in developing countries

Experience with several oral vaccines have shown that the immune responses are not as robust or consistent when given to children in developing countries

• Host related issues:

• Nutrition – protein calorie deficiency / micronutrient deficiency

• Maternal antibody – transplacental antibody / breast milk

• Gut enteropathy or intestinal damage

• Bacterial small bowel overgrowth

• Interference from enteric microbes

• Vaccine characteristics: • Antigen composition and concentration

• Number and frequency of doses

• Age of administration

Sack DA et al. Ann Nestle 2008; 66: 71-79 2

To demonstrate that co-administering rotavirus vaccine with OPV

does not induce a significant decrease in poliovirus immune

response one month after the third dose of polio vaccine

Serendipitously was evaluated in a single study as two 2-dose

schedules – 6 and 10 weeks of age and 10 and 14 weeks of age

– Before rotavirus season

– After rotavirus season

RIX4414 (105.2 median CCID50)

3

Safety and immunogenicity of RIX4414 in healthy infants when co-administered with OPV

Steele AD, De Vos BV, Tumbo JM et al. Vaccine 2010; 28: 6542-48

Immunogenicity of RIX4414 with OPV or IPV in the EPI schedule in South African Infants

HRV5.2ffu + OPV HRV5.2ffu + IPV

Post-

dose 1 Post-

dose 2

Sero-conversion rates per groups

0

20

40

60

80

100

6, 10 weeks 10, 14 weeks

13% 36%

43% 60%

5 Steele AD, De Vos BV, Tumbo JM et al. Vaccine 2010; 28: 6542-48

To assess the immunogenicity of the vaccine in terms of sero-

conversion after 3 doses (administered at 6, 10 and 14 weeks of

age) versus 2 doses (administered at 10 and 14 weeks) of GSK

Biologicals’ HRV vaccine

RIX4414 (106.0 median CCID50)

6

Evaluation of 2 or 3 doses of RIX4414 in healthy infants when co-administered with OPV

Steele AD, Reynders J, Scholtz F et al, J Infect Dis 2010; 202: S93-100

Sero-conversion after 1st dose at 6 weeks of age – 19% sero-

conversion, showing similar low immune response as the 105.2

median CCID50 product

Sero-conversion 2 months after the last dose (i.e. ~20 weeks) was

similar in the 2-dose and the 3-dose arms (44% and 44%).

Vaccine shedding in the stools in the week after 1st dose was 3-fold

higher in the infants getting the 1st dose of vaccine at 10 weeks of

age as opposed to 6 weeks of age – this is an indication of higher

replication of the vaccine in the gut of the older infant.

7 Steele AD, Reynders J, Scholtz F et al, J Infect Dis 2010; 202: S93-100

Age of administration

– several studies indicate that the older the infant when they receive the first

dose of vaccine, the better the immune response in terms of sero-conversion

and GMCs

Maternal antibody

– this is linked to the titres of circulating maternal antibody in the infants.

Maternal antibody levels are inversely correlated with the immune response to

live, oral rotavirus vaccines (our own unpublished data from Bangladesh,

South Africa, Mexico and Finland).

OPV co-administration

– OPV co-administration with any rotavirus vaccine has a negative impact on

the immune response of the first rotavirus vaccine dose (lower sero-

conversion rates and reduced GMCs), although the responses are similar

after the second or third dose

Additional studies showed that these observations were linked to three specific factors

8

Immunogenicity of rotavirus vaccine is lower at younger ages

Countries Rotarix

Schedule

Anti-rotavirus IgA antibody

Seropositivity Rates

Vietnam

9, 13* 62.5 (54; 71)

13, 17* 81.1 (73; 88)

Philippines 6, 10 61.4 (53; 69)

10,14 72.9 (65; 80)

South Africa 6, 10 35.8** (23; 50)

10,14 60.5** (43; 76)

**sero-conversion *median age

9

GMC of transplacental rotavirus IgG in South African responders and non-responders

Group * Status N GMC

Before 2002

RV season

Responder 17 212.9 (117.0 – 387.2)

Non-Responder 32 819.5 (467.9 – 1435.5)

After 2002

RV season

Responder 21 504.3 (335.9 – 757.2)

Non-Responder 12 553.2 (233.3 – 1312.0)

* Response rate before 2002 RV season: 42.6%

Response rate after 2002 RV season: 55.6%

R Ward and D Steele (unpublished data) 11

Interference of OPV on rotavirus vaccine serum IgA antibody response at 1 month post-Dose 2

Treatment group N n Seroconversion rate %

(95% CI) P value

RIX4414 + OPV 69 39 57 (44; 68)

0.113

RIX4414 66 44 67 (54; 78)

Placebo + OPV 36 7 19 (8; 36)

Placebo 34 6 18 (7; 35)

Placebo - pooled 70 13 19 (10; 30)

Sero-conversion rate, cut-off ≤ 20U/ml

Zaman K et al. Vaccine 2009; 27: 1333-39 12

Study design for Rotarix™ efficacy study in Africa

• Routine EPI vaccines, including OPV, co-administered

• HIV-positive infants not excluded

• Breastfeeding not restricted

• Efficacy period: 2 weeks after last dose until one year of age

• Second year follow-up completed

Treatment group Dose 1

(6 wks)

Dose 2 (10

wks)

Dose 3 (14

wks)

3 doses RotarixTM RotarixTM RotarixTM

2 doses placebo RotarixTM RotarixTM

Placebo placebo placebo placebo

Madhi SA & Cunliffe NA et al. NEJM, 2010; 362: 346-57 13

Severe rotavirus gastroenteritis episodes prevented per 100 children vaccinated, Rotarix™

3 episodes prevented

2.5 episodes prevented

3.9 episodes prevented

Efficacy 61.2% 76.9% 49.5%

(44.0 – 73.2) (56.0 – 88.5) (19.2 – 68.3)

Madhi SA, Cunliffe NA, Steele AD et al. NEJM 2010; 362: 346-357

0

1

2

3

4

5

6

7

8

9

Africa South Africa Malawi Severe

ro

tavir

us G

E e

pis

od

es p

er

10

0

Placebo

Vaccine

14

What is the effect of number of doses on rotavirus vaccine efficacy?

Countries Africa South Africa Malawi

2 dose

(10,14 wks)

58.7

(35.7-74.0)

72.2

(40.4-88.3)

49.2

(11.1-71.7)

3 dose

(6,10,14 wks)

63.7

(42.4-77.8)

81.5

(55.1-93.7)

49.7

(11.3-72.2)

Pooled vaccine 61.2

(44.0-73.2)

76.9

(56.0-88.4)

49.4

(19.2-68.3)

Madhi SA & Cunliffe NA et al. NEJM 2010; 362:346-57. 15

What is the effect of the number of doses on immunogenicity to rotavirus vaccine?

South Africa Malawi

>=20 U/ML GMC >=20 U/ML GMC

2 dose

N=70/36

57.1

(48-69)

59.4

(37-94)

47.2

(30-64)

51.5

(26-102)

3 dose

N=66/49

66.7

(54-78)

94.3

(56-157)

57.1

(42-72)

63.0

(36-109)

Pooled

N=136/85

61.8

(53-70)

74

(53-104)

52.9

(42-64)

57.8

(38-88)

Placebo

N=69/42

11.6

(5-22)

<20 40.5

(25-57)

38.2

(21-68)

Madhi SA & Cunliffe NA et al. NEJM 2010; 362:346-57. 16

South Africa Malawi

67

83

85

57

72

32

Sero-conversion

Efficacy (1st year of

life) against severe

rotavirus diarrhea

Efficacy (2nd year

of life) against

severe rotavirus

diarrhea

57

49

47

18

Similar results

for 2 & 3-dose

(~49% VE)

Initial results show higher sero-conversion & 2-year efficacy with 3-dose course1

3-dose

2-dose

Madhi SA & Cunliffe NA et al. NEJM 2010; 362: 346-357; Cunliffe NA et al. Vaccine 2012; 30S: A36-43

Madhi SA et al. Vaccine 2012; 30S: A44-51

What is the effect of the number of doses on vaccine efficacy in the second year of life?

17

WHO SAGE Global Recommendation

WHO strongly recommends the inclusion of rotavirus vaccination into

the national immunization programmes of all regions of the world.

Countries where deaths among children due to diarrhoeal diseases

account for ≥10% of under-5 mortality rate should prioritize vaccine

introduction.

Weekly Epidemiological Record. 2009; 84 5 June. 18

Rotavirus vaccines in GAVI-eligible countries: actual, approved and forecast introductions

3 1 1 8 15

5

9 8

0

10

20

30

2009 2010 2011 2012 2013 2014 2015

Number of Countries per

year

Forecast

Introduced

Approved

Sudan

Nicaragua

Honduras

Guyana

Bolivia

Burundi

Djibouti

Zimbabwe

Zambia

Tanzania

S. Leone

Niger

Madagascar

Haiti

G-Bissau

Congo Republic

C A R

Cameroon

Angola

Togo Yemen

Rwanda

Ethiopia

19

Rotavirus Vaccines introduced in Africa

Ghana’s First Lady, Dr Ernestina Mills, vaccinates a

child with Rotarix - 27 April 2012

Permanent Secretary to the Rwanda MOH, Dr

Uzziel Ndagjimana, vaccinates a child with

RotaTeq - 25 May 2012

20

Acknowledgments

RAPID group – public private

partnership established in 2000

between WHO, GSK Bio,

PATH, USAID, NIH, SA MRC

Pieter Bos, George Armah,

Nicci Page (Medunsa)

Md Yunus, K Zaman, David

Sack (ICDDR,B)

Bernard Ivanoff, Ruth Frischer,

George Curlin, Julie Jacobson,

Roger Glass, Joe Bresee

21