MELIOIDOSIS VACCINE. At LEPTOSPIROSIS: NOW AND THEN Meeting, July 2014 Miracle Grant Hotel, Bangkok, Thailand death globally

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1 MELIOIDOSIS VACCINE Asst. Prof. Direk Limmathurotsakul Mahidol-Oxford Tropical Medicine Research Unit (MORU) Faculty of Tropical Medicine, Mahidol University At LEPTOSPIROSIS: NOW AND THEN Meeting, July 2014 Miracle Grant Hotel, Bangkok, Thailand death globally

2 Content Epidemiology of melioidosis Population at risk of human melioidosis Population at risk of animal melioidosis Current campaign for melioidosis prevention Route of melioidosis infection Intended use of melioidosis vaccine Development of melioidosis vaccine What is the current status? What is next?

3 Introduction: melioidosis (1/2) Caused by the Gram-ve bacillus, Burkholderia pseudomallei 2 nd most common cause of community-acquired bacteremia in NE Thailand, and most common cause of septicaemic pneumonia in Northern Australia Difficult to diagnose, difficult to treat Mortality rate is 40% in NE Thailand and 12% in Northern Australia Paramesawaran et al, MJA (2012) Kanoksil et al, PLoS ONE (2013)

4 Introduction: melioidosis (2/2) The organism is present in soil and water in endemic areas Tier 1 disease agents The disease is not contagious Routes of infection include inoculation, ingestion and inhalation Category B select agent Tier 1 disease agent Limmathurotsakul and Peacock, BMB (2012) Butler, Nature (2012)

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6 Population mortality rate of melioidosis > 1,000 died of melioidosis in NE Thailand each year Limmathurotsakul et al, AJTMH (2010)

7 Epidemiology of melioidosis Currie et al, TRSTMH (2008)

8 Incidence of melioidosis Country Population Incidence rate (per 100,000) Number of cases per year Mortality rate NE Thailand 21 million 8.7 1,865 40% Top End of N Australia North Queensland 140, % 510, % Singapore 5 million % Malaysia 28 million unknown unknown unknown Indonesia 238 million unknown unknown unknown India 1.2 billion unknown unknown unknown Limmathurotsakul and Peacock, BMB (2012)

9 Population at risk of melioidosis 21.3 in 2006 & keep rising Most of the patients are older than 35 years old Half of the patients are diabetes Limmathurotsakul et al, AJTMH (2010)

10 Risk factors for acquiring melioidosis Soil/water exposure Male Adult Diabetes Thalassemia Chronic Kidney disease Chronic lung disease Steroid abuse Alcoholism Smoking Population Age Cases (%) Incidence rate < 35 years old 21 % years old 79 % 26.2 Diabetes No diabetes 52 % 6.8 Known diabetes 31 % Undiagnosed diabetes 17 % 84.4 Limmathurotsakul et al, AJTMH (2010); Cheng and Currie, CMR (2005)

11 Target population for vaccine Population Age Cases (%) Incidence rate < 35 years old 21 % years old 79 % 26.2 Diabetes No diabetes 52 % 6.8 Known diabetes 31 % Undiagnosed diabetes 17 % 84.4 Less cost-effective but large portion of patients (8.2 million people in NE Thailand older than 35 yr) More cost-effective but small portion of patients (0.6 million people are diabetes)

12 Epidemiology of animal melioidosis Wide variety of animals have been reported to be susceptible to melioidosis, including horses, camels, goats, sheep, cattle, pigs, dolphins, panda, kangaroos, koalas, cats and dogs Animals in Thailand Population (million) Number of cases in 5-yr Poultry Cattle Pigs Goats Non-farm animals Unknown 7 Limmathurotsakul et al (EID, 2012)

13 Epidemiology of melioidosis Environment Human cases Animal cases

14 Prevention Recommendation is not applicable in developing countries such as Thailand Incidence of melioidosis also rises in N Australia

15 Possible routes of melioidosis infection Inoculation Inhalation Ingestion - B. ps is in soil - High rate in rice farmers & aboriginals - High rate in rainy season (working) - Animal model - High rate in helicopter crew (VN) - High proportion of pneumonia & severe case in rainy season - B. ps is in water - Outbreak from contamination in water plant - Acute parotitis in children

16 Activities Related to skin inoculation Conditional Odds ratio No activities exposure to soil/water 1.0 Working in a rice field 2.1 ( ) Other activities exposure to soil/water 1.4 ( ) Open wound 2.0 ( ) Related to ingestion Eating food contaminated with soil/dust 1.5 ( ) Drinking untreated water 1.7 ( ) Related to inhalation Outdoor exposure to dust cloud 1.3 ( ) Outdoor exposure to rain 2.1 ( ) History of water inhalation 2.4 ( ) Limmathurotsakul et al (PLoS NTD,. 2012)

17 How can we make it happen?

18 CEA of vaccine for public health purpose Peacock et al (2012, PLoS NTD)

19 Summary Indication of vaccine sought High efficacy from all routes of melioidosis acquisition High efficacy in immuno-compromised hosts High safety Target population Scenario 1: high risk group - population older than 35 yr old Scenario 2: very high risk group - diabetic patients Melioidosis Vaccine does not have to provide sterile immunity to be cost-effectiveness in Thailand for public health purpose!!!

20 Candidate vaccines Live attenuated vaccine, Whole cell kill, Sub unit vaccine, etc Antigen Composition Protective? Ref LPS lipopolysaccharide Partial Nelson, et al., CPS Polysaccharide Partial Nelson, et al., Flagellin Naked DNA Partial Chen et al., 2006 a,b; Brett et al., 1994 Flagellin-O-antigen conjugate Protein polysaccharide Partial Brett & Woods 1996 BipB, BipC, BipD Protein No Druar et al., 2008 Omp85 Protein Partial Su et al., 2010 ET-TU Protein Reduced colonisation Nieves et al, 2010 BPSL2522 (Omp3) Protein Partial Hara et al., 2009 BPSL2765 (Omp7) Protein Partial Hara et al., 2009 LolC Protein Partial Harland et al, 2007

21 Candidate vaccines Live attenuated vaccine, Whole cell kill, Sub unit vaccine, etc Immunogen Relative Efficacy Likely safety in diabetics Research required before development Live attenuated 2D2 Killed cell Sub-unit

22 Animal models Type of mice? BALB/c, etc Diabetic mice model? Need? Which one? Route of bacteria challenge? Inhalation / Ingestion Strain of bacteria challenge? K96243, other strains? Dose of bacteria challenge? 40 MLD, 50 MLD, 100 MLD? Negative control Positive control? Need? Mice follow-up period? 14d, 28d, 50d?

23 Should we learn from the big three? (Malaria, AIDS, TB) Who?

24 Melioidosis Vaccine Development Committee (MVDC) Hold a meeting at PHE UK (March 2014) Supported by NIH/NIAID USA 15 experts worldwide met 5 external experts invited Discussion about development of melioidosis vaccine What should we do next? Consensus from GLOBAL scientific community

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26 What s next? Should we wait until we buy melioidosis vaccine from US or UK?

27 Acknowledgement Prof Sharon Peacock, Cambridge Prof Nicholas Day MORU, Thailand Rungrueng Kitphati MOPH, Thailand

28 Thailand-Lao Melioidosis Network Melioidosis is an urgent issue that requires a raise in public awareness Pitfalls of the surveillance system of MoPH was discussed and compared with published evidences

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31 Functions Facebook pages Group Links Steering committee Contributors

32 Government Policy makers Stakeholders Public Awareness Prevention

33 Problem Why doesn t WHO concern about melioidosis? Take years to identify the key person in WHO for melioidosis Melioidosis is at the bottom of his responsibilities (within the others ) How many died of melioidosis each year?

34 Global distribution of B. pseudomallei with level of evidence in each country Black, orange and yellow colors are for countries where the evidence is definite, probable and possible, respectively

35 Using environmental factors to predict global distribution of B. pseudomallei Latitude Factors in the model: land surface temperature (in figure), rainfall, soil type, soil ph, altitude, and vegetation index at 5 x 5 kilometers resolution Methods was published in Bhatt et al, Nature (2013) Apr 25; 496(7446): 504-7

36 Predicted probability of B. pseudomallei in the environment Red and orange colors represent areas where B. ps are likely to be present Preliminary analysis estimated that population at risk is 1.5 billion worldwide

37 Predicted mortality of melioidosis worldwide Disease Predicted incidence Predicted mortality Predicted case fatality rate Source of data Tuberculosis 8,600,000 1,300,000 15% WHO website Malaria 219,000, , % WHO website 2009 Pandemic Influenza A H1N1 N/A 284,000 N/A LID 2012, 12(9) Melioidosis 430, ,000 58% Preliminary data of this study Severe Dengue 500, , % WHO website Leptospirosis 1,000,000 60,000 6% ILS 2013