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Dengue Fever – plant derived vaccines and other coping strategies in a changing climate Jihong Liu Clarke Bioforsk- Norwegian Institute for Agricultural and Environmental Research, Høgskoleveien 7, 1432 Ås, Norway [email protected] Dengue fever (DF) and dengue haemorrhagic fever (DHF), and their global status How would climate change affect vector borne diseases such as dengue? Coping strategies: prevention, early warning, production of effective and affordable vaccines in plants, vector control, law enforcement, public education etc. Summary and future work Aedes aegypti http://www.who.int 2009 Infected female mosquito transmits dengue Primarily a daytime feeder Lives around human habitation Lays eggs in stagnating water Dengue virus (+)ssRNA Family: Flaviviridae Genus: Flavivirus Species: Dengue virus Serotypes: 4 (DEN 1-4) Source: Dr. Kanna, ICGEB, India Dengue: Current Global Status 2.5 billion people at risk 50 million DF cases/yr 500,000 DHF, largely children DHF fatality rates 2.5-20% No drugs or vaccine Included in WHO/TDR WHO (2009) Dengue continues to spread around the globe Only 9 countries had DHF epidemics before 1970 Exceeded 100 countries in 2009 (www.who.int) MacKenzie et al., Nature Med., 2004 Dengue continues to spread around the globe Recently, an outbreak of dengue fever on the island of Pulau Besar outside Malaysia was reported (www.dagbladet.no/2010/05/24). Dengue fever (DF) and dengue haemorrhagic fever (DHF) and the global status How would climate change affect vector borne diseases such as dengue? Coping strategies: prevention, early warning, production of effective and affordable vaccines in plants, vector control, law enforcement, public education etc. Summary and future work May promote “vertical” spread of dengue to previously unexposed regions and countries (reaching higher)? Example: Aedes aegypti, the dengue causing mosquito, was previously found normally at a height of not more than 500 metres above sea level. Of late, these have been sighted at an altitude of 2200 meters in Darjeeling and 4000 meters in Nepal (Dr. Jai P Narain 2008) Photo: FreakingNews.com Global warming may also contribute to spreading of dengue “horizontally”? As a result of increased temperature which is optimum for mosquito breeding, vector borne diseases will have new destinations where populations were earlier unexposed to such diseases. We are already seeing such cases in Europe. “Chikungunya (CHIKU, a viral disease spreading by mosquitoes) resurfaced in India after 31 years in 2006 and has been reported for the first time from Italy (South Asia Voice, 2008, Vol 1, p 67). Coping strategies: Prevention Vaccination (vaccine is not available) Vector control Law enforcement Public education etc. Status of dengue vaccine? No licensed vaccine at present Effective vaccine must be tetravalent (ADE) against all the 4 serotypes (DEN1-4) Effective, safe and affordable vaccine is absolutely needed for controlling dengue Vaccination is considered to be the most efficient and cost-effective means for health intervention to combat infectious diseases. Can plants be used as factories for low cost production of vaccines? Production cost using green leaves (chloroplast engineering) is about 1% of that via traditional cell cultures Plants- Green Factories Plants cells are eukaryotic, like human cells. They can assemble, modify and secrete complex proteins. Minimized risk of contamination from human pathogens as plants are not hosts for the pathogens Easy scaling up and low production cost (as no initial investment is required) No need for field cultivation. Adequate production scale can be reached in a confined greenhouse. Plants- Green Factories (Continued) Plants are ideal bioreactors for the production of orally administered vaccines, eliminating the need for expensive fermentation, purification, cold storage and sterile delivery (Daniell et al. 2009) Three plant-based production systems Nulear transformation Chloroplast engineering Transient system Mitochondria Nucleus Source: Klemsdal 2008 with modification Vaccine antigens expressed in plants Number of antigens by 2009 Expression system Expression level 35 Nuclear transformation 0 -3.0 % 29 Chloroplast transformation 0.25-40% 25 Transient system 400 mg kg-1 FW Daniell et al. 2009. Trends in Plant Science Progress of plant derived vaccines DowAgro Newcastle disease vaccine, approved Feb 2006 Therapeutical vaccine for non-Hodgkin‘s lymphoma in Phase I clinical trial IFN-α2b to combat hepatitis C has reached Phase II clinical trial (www.biolex.com). Human glucocerebrosidase against Gaucher’s disease has entered Phase III clinical trial Source: Daniell et al. 2009 Multigene Engineering Gene Containment High level expression Advantages and limitations of chloroplast transformation system No Vector Sequences No Gene Silencing No Position Effect No glycoproteins expressed in cp Only successful in a few crops, no monocots Daniell 2006 GLOBVAC: Indo-Norwegian joint project Expression and evaluation of envelope domain IIIbased experimental tetravalent dengue vaccine using a tobacco chloroplast expression system Institutions responsible for the project: Bioforsk- Norwegian Institute for Agricultural and Environmental Research, Norway. ICGEB -The International Centre for Genetic Engineering and Biotechnology, India Partner: BOKU-University of Natural Resources & Applied Life Sciences, Austria Tobacco, an ideal plant factory Non food, non feed Objectives Development and characterization of a new experimental tetravalent vaccine candidate against dengue by expressing the host cell receptor binding dengue envelope domain III (EDIII) of all four dengue virus serotypes Engineering of tobacco chloroplasts to facilitate a costeffective production system for the experimental dengue vaccine which is safe, efficacious and affordable. Domain III of DEN Envelope Protein Cell, 2002 Host cell receptor binding site Accessible on virion surface Serotype-specific neutralizing epitope mAb- efficient virus blockers Highly stable Recombinant domain III protein can block DEN infection to cells Independently folding domain amenable to tetravalent design Vector construction DEN-1 DEN-3 DEN-4 Tetravalent candidate was successfully expressed in the yeast P. pastoris and showed promising immunological response in mice (Etemad et al. 2008). A Chloroplast Transformation Vectors Single gene: Cp DNA Cp DNA P T P Marker RBS RBS Multiple genes: T X RBS Cp DNA Cp DNA P Marker X Y Z T B With antibiotic Gene delivery Selection Regenerated plantlets Regeneration C Eukaryotic Nuclear genome Nucleus Prokaryotic Plastid/chloroplast Mitochondria A heteroplasmic diploid plant cell (First round of selection) A homoplasmic diploid plant cell (Second round of selection) Daniell 2006 Photo: Even Sannes Riiser Summary Understanding the impact of climate change on vector borne diseases such as dengue is essential for their effective management in the future Multi- disciplinary coping strategy including vector control, production of effective, safe and affordable vaccine etc. is required for controlling DF and DHF Plant-based vaccine production systems, in particular the chloroplast engineering-based system, could facilitate the production of a wide array of vaccines in a safe and easy-toscale-up manner with low production cost The limitations and challenges of the chloroplast poduction system must be overcome to advance the technology Future work The expression and functionality of the tobacco chloroplastderived tetravalent dengue vaccine will be investigated The economic and social benefits of the chloroplast derived dengue vaccine will be evaluated Expression of the DEN 1-4 antigens in an edible crop (e.g. broccoli) to produce oral dengue vaccine, further reducing the production costs and making the vaccine more accessible and affordable Acknowledgements Bioforsk Even Sannes Riiser Sonja S Klemsdal Nagothu Udaya Sekhar Rebekka Øvstegård Sissel Haugslien Research Council of Norway and DBT in India ICGEB Navin Khanna Sathyamangalam Swaminathan Vanga Siva Reddy Sadhu Leelavathi GLOBVAC BOKU Andreas Lössl