Impact and challenges of the Hib initiative understanding and communicating burden of disease

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1 Impact and challenges of the Hib initiative understanding and communicating burden of disease Kim Mulholland London School of Hygiene and Tropical Medicine

2 22 years of Hib vaccine introduction st Hib conjugate vaccine trial Finland 1992 Hib vaccine used in US, too expensive for most countries 1997 Routine vaccination started in Gambia; Hib in Asia Conference, Bali 2002 GAVI providing Hib vaccine free for African countries, not Asia 2005 Hib Initiative project launched

3 In 1992 Hib vaccines in use in US since 1991 Too expensive for Australia Gambia 4 th Phase 2 trial underway PRP T preferred to PRP OMP due to better immunogenicity and compatibility with DTP Maternal immunization study underway

4 Gambia maternal +/or infant Hib (PRP-T) immunization study JAMA 1996; 275: Total anti-prp ( µg/ml by RIA) Mother and infant PRP-T Mother only PRP-T Infant only PRP-T p<0.01) 0.1 PredeliveryDelivery Maternal Cord 2 mo 3 mo 4 mo 5 mo Infant

5 Specific vs Total siga antibody ratio results compared across colostrum and mature milk samples from PRP T immunizaed and unimmunized mothers 4.00 A=143 p values < Specific:Total siga ratio s D=160 E=141 P=63 A=55 D=88 E=78 P= Imm Non-Imm colostrum(a) 2 months(d) 3 months(e) 5 months(p)

6 Gambia Hib trial ,000 infants randomized to receive DTP+Hib DTP alone Primary outcomes All invasive Hib disease Hib pneumonia 2,400 episodes of clinical pneumonia investigated over 3 years Time between onset of symptoms and start of usually 3-5 days Lancet 1997,349:1191 7

7 Gambia Hib trial Results In children who had received at least 2 doses of vaccine: All invasive Hib disease Controls 29/Vaccinees 2: VE = 93% Proven Hib pneumonia Controls 10/Vaccinees 0: VE = 100% But Is this a real reflection of Hib pneumonia burden? Perhaps the vaccine only affects the sensitivity of blood culture? Lancet 1997,349:1191 7

8 Gambia Radiology 1260 Chest X rays available Read by 5 paediatricians looking for obvious consolidation 449 films read as positive (36%) Controls 251 Vaccinees 198 Conclusions: Hib vaccine does prevent pneumonia (~20%) This is the best way to determine the burden of pneumonia, by ætiology

9 Hib in Asia Conference, Bali 1996 Sponsored by Fondation Mérieux, Childrens Vaccine Initiative (CVI) and WHO Industry sponsored studies presented from a range of Asian countries Conclusion Insufficient data to support widespread introduction of Hib vaccine in Asia Gambia results presented Hib probe approach suggested for Asia

10 In In Gambia: Hib vaccine trial completed in 1996 Cases now returning, government frustrated Hib vaccine (PRP T) introduced nationally using a donation from Aventis Pasteur (Sanofi Pasteur) Australia and most western countries now using vaccine UK 2,3,4 months plus catch up Routine use in 3 latin American countries PATH and AMP set up Hib probe study on the Indonesian island of Lombok

11 Gambia: Incidence of Hib meningitis in children under 5 in Western Region (cases/10 5 /yr) Hib Trial National Immunization Program Jan 1990 Jan 1991 Jan 1992 Jan 1993 Jan 1994 Jan 1995 Jan 1996 Jan 1997 Jan 1998 Jan 1999 Jan 2000 Jan 2001 Jan 2002 Adegbola et al., Lancet 2005; 366:

12 In 1999 Hib vaccine introduction in Gambia had lead to virtual disappearance of Hib disease and carriage Children s Vaccine Initiative (CVI) and WHO criticized for failure to introduce new vaccines At a meeting in Rome, CVI was dissolved by its board to make way for GAVI Gates Foundation establishes Children s Vaccine Program at PATH to promote the introduction of Hib, Pnc and Rota vaccines in developing countries

13 In 2000 GAVI established, initially with big grant from the Bill and Melinda Gates Foundation ($700m) Focus on new and underutilized vaccines Hib vaccine promoted for areas where Hib disease burden is established, esp. Africa GAVI applications rushed out, mainly by external consultants Kenya, Ghana, Rwanda, Malawi apply

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15 In 2002 Malaysia became the first Asian country to introduce Hib vaccine Burden estimated 38/10 5 /year Other credible estimates of Hib burden in Asia Thailand 3.8/10 5 /year Hong Kong 2.7/10 5 /year Pediatr Infect Dis J 1998;17(9 Suppl):S Vaccine 2004;22(8): Acta Paediatr 1995;84(2):173 6.

16 In 2004 Limited interest in Hib vaccine introduction in Africa Introduction in Kenya and Ghana seen as driven by foreigners Concerns about who would pay for the vaccine after 2005 Price of Hib vaccine had risen contrary to GAVI predictions Industry blitz in Asia backfiring

17 In 2005 Hib Initiative project awarded to consortium Johns Hopkins University London School of Hygiene and Tropical Medicine US Centers for Disease Control and Prevention $37m, including $7m for Hib Probe study to be undertaken in India

18 Hib Initiative mission To expedite sustainable evidence-informed decisions at the global, regional, and country levels regarding the use of Hib vaccination to prevent childhood meningitis and pneumonia Country driven Focus on decision making Considers health system implications

19 Strategic Approach Communication Research and Surveillance Evidenceinformed decisions Coordination

20 Problematic issues Working with WHO Holding large regional meetings Serious accusations pushing Hib vaccine collusion with industry

21 Research Clarification of Hib meningitis burden Vaccine impact, especially on pneumonia Continuum between research and surveillance Need for booster Country support Economic analyses Assistance with financial planning Communication activities mainly providing important information to key government staff

22 WHO Position Paper on Haemophilus Influenzae type B (Hib) Conjugate Vaccines In view of their demonstrated safety and efficacy, Hib conjugate vaccines should be included in all routine infant immunization programmes. Lack of local surveillance data should not delay the introduction of the vaccines, especially in countries where regional evidence indicates a high burden of disease. WER 24 Nov, 2006

23 Key new information for Asia Lombok Hib Probe study (published 2005) Cluster randomized trial 55,000 infants Primary outcome radiological pneumonia Bangladesh case control study (published 2007) Random assignment of Hib vaccine to health centres Case control study of radiological pneumonia Both studies used WHO CXR pneumonia definition

24 Radiological Pneumonia dense fluffy consolidation (alveolar infiltrate), of a portion of a lobe or entire lung that has been identified by this group as the appearance likely to be associated with bacterial pneumonia Cherian T et al. Bull WHO 2005;83:353 9.

25 Lancet 2005;365:43 52

26 Pneumonia results Incidences per 100,000 child-years in children less than 2 years Outcome Control group Hib vaccine group Preventable disease incidence Clinical pneumonia 39,516 37,954 1,561 (270 2,853) Any severe pneumonia Pneumonia hospital admission 5,460 5, ( ) 4,518 4, ( ) X-ray confirmed ( ) Fatal pneumonia ( )

27 Compare to Gambian study Gambia 2,400 cases of clinical pneumonia from 43,000 children over 3 years 1260 CXRs 449 CXR +ve (36%) Lombok 28,500 cases of clinical pneumonia identified from 55,000 children over 2 years 3171 CXRs 691 CXR +ve (22%) 9 times as many pneumonia cases in Indonesia than Gambia 1.2 times as many CXR+ cases in Indonesia than Gambia Is there really more pneumonia in Indonesia than Gambia?

28 Meningitis results Incidences per 100,000 child-years in children less than 2 years Outcome Laboratory confirmed Hib Purulent bacterial meningitis All meningitis or acute seizures* Control group Hib vaccine group Preventable disease incidence (1.4 31) (13 81) (42 273) Meningitis deaths (-17 97) * Many of these children were not admitted

29 An Effectiveness Trial of Hib Vaccine in Bangladesh Objective: Determine proportion of pneumonia and meningitis in <2 children preventable by Hib vaccination Methods: Case control study in birth cohort 68,000 in Dhaka Health centres randomized to use DTP or DTP Hib Controls 4 matched community and 2 hospital controls/case Results : Prevented 34 44% of X ray proven pneumonia 71 83% protection against probable bacterial meningitis PIDJ June 27, 2007

30 Potential for bias Community controls Include non health care users Against vaccine Include convenient controls For vaccine Hospital controls Include chronic, hospitalized patients For vaccine Include malnourished children Against vaccine

31 Hib vaccine introduction, October 2009

32 Outstanding issues India India Hib probe study abandoned 2007 Logistical issues Ethical concerns due to availability of Hib in private market Concerns that the study would slow down Hib vaccine introduction Hib in Asia Overall burden Contribution of bacteria to the pneumonia burden Need for a booster dose

33 Hib in Asia The Chinese Hib paradox? IGKV2D 29 3 major alleles Define kappa IgG light chain characteristics Shown to be important for the anti Hib response Important differences between Caucasians, Chinese and Navajo peoples J Clin Invest 1991;88(6): Immunogenetics 2001;53(1): J Clin Invest 1993;91(3): JAMA 1992;267(11):

34 Data courtesy Prof. YH Yang, Beijing Children s Hospital

35 The global Hib/pneumococcal disease burden project: main inputs Hib meningitis burden scattered Hib burden studies of variable quality Hib meningitis mortality burden X CFR Hib pneumonia burden clinical pneumonia burden (many studies) X fraction prevented in Hib vaccine trials (Gambia and Lombok) Hib pneumonia mortality Child mortality X fraction due to pneumonia X fraction of radiological pneumonia due to Hib (Gambia, Lombok, Chile, Bangladesh) Lancet 2009;374:

36 Relevant data to come Hib impact case control studies Mozambique Ethiopia Bangladesh Pakistan Modelled Hib impact on pneumonia burden Vietnam

37 Conclusions Regional differences in disease burden exist and explain delayed Hib introduction in Asia May be due in part or wholly to antibiotic usage practices Importance of disease burden vaccine price All children have some risk of Hib disease Eventually all children will get Hib vaccine as a component of DTP