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Lecture 5

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McGill University
Microbiology and Immun (Sci)
MIMM 413
Edith Zorychta

Lecture 5 – elimination of VL Elimination of VL – case down to 1 in 10,000 - Vaccine considerations  Currently no available vaccine  Can understanding of immunology help develop vaccine?  Are there good animal models for vaccine development? - Treatment and vector (sandfly) control  Currently excellent treatments available  Can point of care diagnosis and treatment and vector control be used to eliminate VL? Imiquimod: Synthetic molecules, which activate TLR7/8 receptors – mediate a Th1 response against Leishmania? - Th1 response – macrophage activation in killing the parasite  Activation of TLR 7/8 leads to Th1 response (IL-12) - Th2 response – survival of the parasite  No TLR activation - Vaccine adjuvants for TLR? – there is one with Human papillomavirus R848 /Imiquimod vaccine adjuvant experiment – aka TLR vaccine adjuvant - BALB/c were immunized with: 1. Control PBS 2. Autoclaved Leishmania major (ALM) Ag (no adjuvant) – just kill the parasite with autoclaving 3. ALM subcutaneously plus topical Imiquimod (footpad) - BALB/c mice were challenged with L. major subcutaneously in the opposite footpad 2 weeks after immunization - Measure protection with the swelling of the footpad Challenge infections in vaccinated BALB/c mice: adjuvant effect of Imiquimod/R848 - No protection with PBS (thicker footpad) - No protection with ALM - IMQ 1 and then ALM = much fewer parasite (thinner footpad) - Conclusion: TLR vaccine adjuvant gives better immunological protection - Why do you get stronger immunological protection? – due to IFNy production  IFNy production from vaccinated mice challenged with L. major Ags  THEREFORE topical IMQ + ALM provides a better IFNy response, which is needed for protection - You need a proper Ags AND adjuvants for proper vaccination Conclusions for vaccine - Topical Imiquimod can be used a vaccine adjuvant with subcutaneous immunization. - Topical Imiquimod enhance the IFN-γ response when antigens are delivered subcutaneously. - Adjuvants to bias the response to Th1 (IFN-γ) may be useful to for the next generation of Leishmania vaccines and for potentially other pathogens Comparison of a ‘Patch’ for subcutaneous vaccination VS. a ‘needle’ which is currently used for vaccination in the muscle - Delivery of the vaccine (Ags) - Better to deliver the Ags in the skin  Patch - small abrasion makes it easier to deliver the Ags into the skin - Our skin has DCs  The patch is better designed to deliver vaccines to the skin epidermis where APCs such as DCs are located and can be activated by TLR agonists Dogs as the animal reservoir for VL, caused by L. infantum - Vaccination of dogs in the endemic areas would reduce transmission to humans and be a relevant model for a human vaccine - Sandflies bites dogs  then bites human  transmission to human  Cycle of DOG  SANDFLY  HUMAN - Brazil, Northern Africa = endemic areas  Movement of sandflies from Northern Africa to Southern Europe in recent years - Dogs are reachable to be vaccinated - Vaccination of dogs would block the cycle for transmission of VL to humans Treatment and vector control - Today we can’t really think of vaccination level Vector borne diseases in Indian sub-continent - Malaria - Lymphatic filariasis - Leishmaniasis - Dengue virus - JE virus - Chikungunya virus - ALL the above viruses are capable of causing encephalitis and death Infectious diseases burden worldwide, in terms of DALYs - Leishmania is the MOST PROBLEM in Southeast Asia (including India) - Target the VL in India! Geographic regions - Estimated incidence of 500,000 cases per year, 60% in the worldwide basis, occur in the Indian subcontinent (India, Bangladesh and Nepal) - Mainly amongst the poorest population living in remote poor areas Opportunities in the Indian subcontinent - Epidemiological features in the Indian sub-continent  Human beings the only reservoir (L. donovani)  Only one vector species, which is amenable to vector control (ex. DDT)  Geographical distribution is limited and highly clustered - Recent developments:  New drugs: AmBiosome (best treatment), Miltefosine and Paramomycin - $70~80 per patient but the 3 world countries patients don’t have to pay! Yay!  Rapid diagnostic test: simple and rapid rk39 Dipstick test for VL (blood test looking for the Ab against the parasite Ag) Leishmaniasis implementation research initiatives in the Indian subcontinent - Case detection in endemic villages – you have to go into the village to find the cases  Thousands of villages - Vector control in endemic village houses - Therapeutic options delivered at the community level (close to the village) Training of village ASHAs to identify potential VL cases - ASHAs – women living in the village and they work with the pregnant women (maternal health)  They greatly reduced the mortality of child and women giving birth - Villages – usual
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