Can we improve the performance of live oral rotavirus vaccines?

Transcription

1 Can we improve the performance of live oral rotavirus vaccines? Duncan Steele 9 th International Rotavirus Symposium 2 & 3 August 2010, Johannesburg, South Africa

2 Vaccine efficacy against severe rotavirus GE in the first year of life, by region Region Vaccine Countries VE 95% CI Africa 1 Rotarix TM Malawi, South Africa Africa 2 RotaTeq Ghana, Kenya, Mali Asia 3 RotaTeq Bangladesh, Vietnam , , , Madhi & Cunliffe et al. NEJM 2010; 362: ; 2 Armah et al. Lancet 2010 Aug6 epub; 3 Zaman et al. Lancet 2010 Aug6 epub

3 Lives saved How does this efficacy translate into impact on a population level? 2,500,000 Estimates of cumulative impact of rotavirus vaccines, ,000,000 60% efficacy 1,500,000 1,000, ,000 0 Conservative estimates including vaccine efficacy; immunization coverage; graduated uptake by countries Efficacy 3 Source: GAVI Investment Case, 2006; Atherly D et al. J Infect Dis 2009.

4 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. Nutrition protein calorie deficiency / micronutrient deficiency Maternal antibody transplacental antibody / breast milk Gut enteropathy or intestinal damage Bacterial small bowel overgrowth Intestinal parasitic infections Interference from enteric microbes Vaccine characteristics antigenicity vs. reactogenicity; # doses; age of administration, etc. 4 Source: Sack DA et al. Ann Nestle 2008; 66: 71-79

5 Does maternal antibody play a role? Higher background levels of maternal antibody adversely affects immune response to rotavirus vaccines An inverse correlation was observed in three studies of maternal antibody levels and the vaccine sero-response Maternal antibody levels vary according to rotavirus season Maternal antibody wanes over time 5

6 GMC of Transplacental Rotavirus IgG in Mexico in Responders and Non-Responders Sero-response rate was 65.4% Status N GMC Responder ( ) Non-Responder ( ) 6 R Ward and G Ruiz-Palacios (unpublished data)

7 GMC of Transplacental Rotavirus IgG in South Africa in Responders and Non-Responders Group * Status N GMC Before 2002 RV season Responder ( ) Non-Responder ( ) After 2002 Responder ( ) RV season Non-Responder ( ) * Response rate before 2002 RV season: 42.6% Response rate after 2002 RV season: 55.6% 7 R Ward and D Steele (unpublished data)

8 8 Maternal antibody probably plays a role in the poor immune response seen in infants in developing countries, but programmatic solutions are unlikely

9 What do we know of the role of breast milk? Breast milk contains anti-rotavirus antibodies Breast milk can neutralize rotavirus titre in vitro Breast milk contains other anti-rotavirus factors eg. lactadherins Studies are ongoing to evaluate the effect of delaying breast feeding at the time and point of vaccination Exclusive breastfeeding is advocated by WHO may be difficult to implement programmatically 9 Moon SS et al. P Infect Dis J 2010; Newbury DS et al. Lancet 1998

10 Effects of the dose regimen and number of doses Current WHO recommendations: 2-dose vaccine at DPT1 and DPT2 Last dose of vaccine by 32 weeks of age 10

11 What is the effect of the number of doses on immunogenicity? South Africa Malawi >=20 U/ML GMC >=20 U/ML GMC 2 dose N=70/36 (48-69) (37-94) (30-64) (26-102) 3 dose N=66/49 (54-78) (56-157) (42-72) (36-109) Pooled N=136/85 (53-70) (53-104) (42-64) (38-88) Placebo 11.6 < N=69/42 (5-22) (25-57) (21-68) 11 Madhi & Cunliffe et al. NEJM 2010; 362:

12 What is the effect of number of doses on rotavirus vaccine efficacy? Countries Africa South Africa Malawi 2 dose (10,14 wks) ( ) ( ) ( ) 3 dose (6,10,14 wks) ( ) ( ) ( ) Pooled vaccine 61.2 ( ) 76.9 ( ) 49.4 ( ) 12 Madhi & Cunliffe et al. NEJM 2010; 362:

13 Immunogenicity of rotavirus vaccine is lower at younger ages Countries Rotarix Schedule Anti-rotavirus IgA antibody Seropositivity Rates Vietnam Philippines South Africa 9, 13* 62.5 (54; 71) 13, 17* 81.1 (73; 88) 6, (53; 69) 10, (65; 80) 6, ** (23; 50) 10, ** (43; 76) *median age **sero-conversion 13 Steele AD et al. Vaccine 2008

14 Coverage What is effect of age of administration on rotavirus vaccines? wk 12 wk 70% 57% 24 wk 36 % 8 m 54% DTP1 DTP Age in months Clark A et al. Lancet WHO recommends the last dose of rotavirus vaccine by 32 weeks of age WHO / UNICEF advocates on time immunization so it is counter-productive to hope for delayed vaccination in the infants most in need

15 Should we think of a booster dose of rotavirus vaccine? Waning of protection was observed with both vaccines in the second year of life in developing country populations Should we consider a booster dose of vaccine with measles at 9 months of age? Safety of co-administration with measles vaccine Evaluate non-interference with measles vaccine immune response Lower disease burden in second year of life Safety concerns for intussusception and age of administration at 9 months? 15

16 Supplementation with micronutrients and / or probiotics Rhesus Rotavirus Vaccine immunogenicity study. Lactobacillus casei GG given at vaccine administration at 4 months of age; then 2x daily for 5 days at home IgA sero-conversion was more frequent in probiotic group compared with placebo group IgA, IgM and IgG GMT were all (non-significantly) higher. OPV trial in adults with 2 different Lactobaccilus spp. Neutralizing antibody levels were higher in the probiotic groups 16 Source: Isolauri E et al. Vaccine 1995; De Vreese M et al. Euro J Nutr 2005

17 Rotavirus Research Agenda AVI TAC Special Studies Ongoing studies: 17 Effectiveness studies in Nicaragua, Bolivia and South Africa Post-marketing studies for vaccine safety in Latin America Modeling of transmission dynamics of rotavirus Population effectiveness of vaccination in Bangladesh Evaluation of an additional dose of Rotarix in Pakistan Evaluation of withholding of breastfeeding in Pakistan Strain diversity and molecular evolution analysis Planned studies: Age of administration of Rotarix Booster dose with measles

18 Lives saved Introduction of rotavirus vaccines today is a priority 2,500,000 Estimates of cumulative impact of rotavirus vaccines, ,000, million lives 1,500,000 1,000, , Efficacy Rotavirus vaccines reduce all cause diarrhoea hospitalizations by ~25% Rotavirus vaccines reduce diarrhoeal mortality Rotavirus vaccines show dramatic impact and indirect effects 18