Control of cholera by vaccination?

Transcription

1 Control of cholera by vaccination? Jan Holmgren University of Gothenburg Vaccine Research Institute (GUVAX) NHV Seminar Vaccines for Global health, Gothenburg, March 26-28, 2008

2 University of Gothenburg Vaccine Research Institute GUVAX Mucosal infections Mucosal immunology Mucosal vaccinology Identify protective antigens, delivery systems and adjuvants Mucosal vaccines DC vaccination Mucosal immunotherapy INFECTIONS CANCERS AUTOIMMUNE DIS. & ALLERGIES

3 An important global health priority : VACCINES FOR DIARRHOEAL AND OTHER ENTERIC INFECTIONS Annual mortality: ca 2.5 M Cholera (>120,000 deaths) ETEC (400,000 deaths) Typhoid (600,000 deaths) Shigella (800,000 deaths) Rotavirus (600,000 deaths)

4 Cholera is the most severe of all enteric infections Infection leads to life-threatening diarrhea and fluid loss > Up to % case fatality rate in untreated patients Caused by Vibrio cholerae > V. cholerae O1 Classical and El Tor biotypes Inaba and Ogawa serotypes > Since 1992 also O139 (El tor mutant) Leads to outbreaks and large pandemics > 7 large O1 pandemics since th pandemic with O1 El Tor since 1961 > Risk of 8th pandemic by O139??

5 Cholera leads to life-threatening dehydration Effective rehydration treatment by intravenous replacement of salt and fluid losses brings down mortality to less than 1% (ORT is usually not enough!) Antibiotic treatment (usually with tetracycline) is also given to shorten duration of disease A child with cholera before and after one day of rehydration

6 Cholera and cholera vaccine: From concept to product development Basic research New knowledge Basic research in the 1970ies clarified the mechanisms of disease and immunity in cholera : Cholera became the best understood of all infectious diseases Development research Development work, including substantial methodological research, and extensive clinical research phase I, II and III studies - led to vaccine with proven safety, immunogenicity and efficacy Product Licensed vaccine 1993 (now registered in ca 50 countries) Better health

7 VACCINE DEVELOPMENT I. Clarify the mechanisms of disease Cholera pathogenesis Cholera toxin Diarrhea GM1 receptor NaCl Cyclic AMP H 2O, Cl -

8 Cholera toxin and its receptor A:B5 Active site A1 A2 B-subunit GM1-receptor binding site

9 VACCINE DEVELOPMENT II. Clarify protective immune mechanisms Locally produced IgA preventing bacterial colonization and toxin binding Cholera toxin Diarrhea GM1 receptor NaCl H 2O, Cl-

10 Strategy for vaccine development : Oral B subunit inactivated whole cell vaccine Vaccination should stimulate an intestinal-mucosal IgA antibacterial and antitoxic antibody response comparable to that in convalescents from clinical cholera disease

11 The Dukoral oral cholera vaccine Contains: rctb + inactivated cholera vibrios Gives % protection against cholera % cross-protection against LT ETEC diarrhea Is the only WHOrecommended cholera vaccine and is licensed in >50 countries world-wide

12 Documented properties of oral B subunit-whole cholera vaccine : - Safe - Immunogenic - PROTECTIVE in large field trials 85 % short-term and 60 % long-term protection against cholera Significant cross-protection also against LT-ETEC diarrhea

13 High effectiveness of Dukoral in an African population with high HIV incidence Beira, Mozambique 2004 Cholera patients in the hospital Waiting for oral cholera vaccination

14 Effectiveness of Mass Oral Cholera Vaccination in Beira, Mozambique M Lucas et al.. Design Two doses of oral rctb-wc cholera vaccine (Dukoral ) were given through the public-health system Results: The vaccine was highly effective in an African population with a high prevalence of HIV infection (80% protection against clinically significant cholera and 90% protection against severe disease)

15 Added benefit of the oral cholera whole cell B subunit vaccine: Cross-protection against diarrhea caused by heat-labile enterotoxigenic E. coli (ETEC) Due to strong immunologic cross-reactivity between cholera toxin and E. coli heat-labile toxin (LT) 67 % protection against dehydrating LT and LT/ST disease in Bangladesh study ( 86% protection against life-threatening disease) % protection against LT ETEC disease in 3 studies in travellers

16 Technology transfer and collaboration has led to local production and public health use of cholera vaccine in Vietnam Local cholera vaccine production is also under way in India, Indonesia and Bangladesh

17 Different types of oral cholera vaccines Inactivated Whole cell vibrios (WCV-O1) + cholera B subunit (CTB)» Licensed and marketed in >50 countries (Dukoral, Crucell/SBL) Whole cell vibrios alone (O1 + O139)» Licensed and marketed in Vietnam (VaBiotech)» Tech transfer to India and phase III trial ongoing (Shantha Biotech/IVI) Expected licensure 2009 Live attenuated CVD HgR» Based on classical Inaba (569B): the gene encoding CTA (ctx) deleted + gene encoding mercury resistance inserted» Licensed (Orochol, Crucell/Berna) but no longer produced Peru-15» Based on El Tor Inaba strain: non-motile mutant with deletion of attrs1, ctx, reca» In clinical trials (Phase II) Dukoral is at present the only WHO prequalified cholera vaccine

18 Control of cholera The role of vaccination Vaccine or clean water? Hopefully both! Vaccine is not a stand-alone intervention Bangladesh arsenic crisis + Epidemiological surveillance Improved sanitation Adequate treatment Prediction: Vaccine will synergize with other interventions! Arsenic causes potentially fatal tumours and respiratory problems Tests on 50,000 wells in Bangladesh have shown that around 40% are too contaminated with arsenic to provide drinking water.

19 Control of cholera by vaccination? Target populations? Possible? Cost-effective?

20 Potential use of cholera vaccines - Mass vaccination as an adjunct control measure (together with epidemiologic surveillance, sanitation, and adequate treatment) in endemic areas, especially where seasonal peaks of cholera are predictable, e.g. in Bangladesh, Mozambique etc in epidemic situations e.g. ca 3/4 of all refugee camps in Africa and Asia have outbreaks of cholera during natural disasters especially in settings where such disasters are known to often lead to cholera epidemics, e.g. floodings, earthquakes etc

21 Cost-effectiveness of cholera vaccination Traditional CE studies indicate that cholera vaccination is cost-effective in cholera endemic areas with cholera incidence rates at or above 1/1000 per year and at vaccine cost of <$0.5-1 per dose

22 Technology transfer and collaboration has led to local production and public health use of cholera vaccine in Vietnam Local cholera vaccine production is also under way in India, Indonesia and Bangladesh A way towards greater vaccine availability and affordability

23 Control of cholera by vaccination? Recent evidence of strong herd protection by oral cholera vaccine is important!

24 Oral cholera vaccines provide strong indirect protection ( herd protection ) in addition to specific vaccine efficacy Lancet 366:44-49, 2005 Herd immunity is conferred by killed oral cholera vaccines in Bangladesh: a reanalysis M Ali, M Emch, L von Seidlein, M Yunus, D A Sack, M Rao, J Holmgren, J D Clemens Vaccine coverage of the targeted population ranged from 4% to 65%. Incidence rates of cholera among placebo recipients were inversely related to levels of vaccine coverage (7 01 cases per 1000 in the lowest quintile of coverage vs 1 47 cases per 1000 in the highest quintile; p< for trend corresponds to 79% herd protection between highest and lowest quintile of coverage).

25 Direct and indirect vaccination effects by coverage Longini et al. 2008

26 Predicted impact % Predicted total impact of oral cholera vaccination - based on combined direct (efficacy) and indirect ( herd immunity ) protection >90% expected impact at 50% coverage Coverage % Longini et al. 2008

27 Herd protection - Conclusions Vaccine herd protection may be crucial to the ability of a vaccine to control a disease under realistic public health conditions, and also to a vaccine s cost-effectiveness. The strong herd protection by oral cholera vaccines indicates that their public health impact could be substantially higher than evident from their vaccine-specific efficacy We now aim to test whether a twice repeated mass vaccination can control cholera in a high-endemicity population in Bangladesh (joint ICDDR,B-IVI-GUVAX initiative)

28 Cost-effectiveness of cholera vaccination Traditional CE studies indicate that cholera vaccination is cost-effective in cholera endemic areas with cholera incidence rates at or above 1/1000 per year and at vaccine cost of <$0.5-1 per dose New CE studies are needed that also take into account the strong herd protection effects of mass vaccination against cholera!! It may be predicted that such studies would indicate high cost-effectiveness even for a substantially more expensive vaccine Willingness-to-pay studies as well as recent WHO expert rating indicate a higher-than-previously-expected priority of cholera vaccination Cholera vaccination an investment case for GAVI?

29 Potential use of cholera vaccines - Mass vaccination as an adjunct control measure (together with epidemiologic surveillance, sanitation, and adequate treatment) in endemic areas, especially where seasonal peaks of cholera are predictable, e.g. in Bangladesh, Mozambique etc in epidemic situations e.g. ca 3/4 of all refugee camps in Africa and Asia have outbreaks of cholera during natural disasters especially in settings where such disasters are known to often lead to cholera epidemics, e.g. floodings, earthquakes etc

30 With thanks To all co-workers at the University of Gothenburg & To many other Swedish and international collegues and organisations Ann-Mari Svennerholm John Clemens B Ivanoff, R Glass, DD Trach, J Clemens