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New drugs and vaccines for tuberculosis

New drugs and vaccines for tuberculosis. Dr. M. Gönenç Ortaköylü Yedikule Göğüs Hastalıkları ve Göğüs Cerrahisi Eğitim ve araştırma Hastanesi. There is no any conflict and interest. WHO İS HE?. Who is he?. Selman Abraham Waksman (1888 – 1973)

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New drugs and vaccines for tuberculosis

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  1. New drugs and vaccines for tuberculosis Dr. M. Gönenç Ortaköylü Yedikule Göğüs Hastalıkları ve Göğüs Cerrahisi Eğitim ve araştırma Hastanesi

  2. There is no any conflict and interest

  3. WHO İS HE?

  4. Who is he? • Selman Abraham Waksman • (1888 – 1973) • In 1952 he was awarded the Nobel Prize "for his discovery of "streptomycin," the first antibiotic active against tuberculosis."

  5. TREATMENT OF TUBERCULOSİS • SM, PAS, INH, PZA, CYC,EMB, RİF were discovered between 1940 and 1963 • The standard "short" course treatment for TB was developed in 1980s. • High TB insidans and MDR-TB emerged in 1990s. • The contrubution of HIV Pandemic • There were an estimated 12.0million prevalent cases, 1.4 million people died of TB, 650 000 cases of MDR-TB in the world (9% XDR) in 2010.

  6. Problems in Current Tuberculosis (TB) Treatment and Goals for TB Drug Development Problems in TB treatment Goals for TB drug development

  7. Problems in Current Tuberculosis (TB) Treatment and Goals for TB Drug Development Problems in TB treatment Goals for TB drug development

  8. OVERVİEW OF CURRENT TB DRUG DEVELOPMENT STRATEGİES • Phase I: A trial designed assess the safety, tolerability, and pharmacokinetics of a candidate drug in small (20-200) group of healthy volunteers • Phase II: A trial designed assess safety and efficacy of a drug on small groups of tuberculosis patients (20-300) • Phase IIA: is specifically designed to assess dosing requirements • Phase IIB: is specifically designed to study efficacy at the prescribe dose • Phase III: A randomized controlled, multicenter trial on large patients groups (300-3000 or more) that is aimed at being the definitive assesment of candidate drug efficacy in comparison with the gold standart treatment

  9. Drugs currently in development to improve TB treatment Rip Van Winkle

  10. rifamycins(higher dose and more frequently administered rifapentine)

  11. FLUOROQUİNOLONES(gatifloxacin / moxifloxacin)

  12. NİTROİMİDAZOLEOPC67683 ( Nitro-dihydro-imidazooxazole (Delamanid)) ( PA-824Nitroimidazol-oxazine)

  13. DiarylquinolineTMC207(bedaquiline)

  14. Oxazolidinone(sutezolide (PNU 100480); linezolide)

  15. SQ-109Ethylenediamine

  16. FUNDING REQUIREMENTS US$ 3.7 billion (2011–2015)

  17. Prospects for the future • by 2015 • a new four-month TB treatment regimen • two new drugs will be approved • at least one new drug for the treatment of drugresistantTB will be introduced into the market; • a nine-month regimen for the treatment of drugresistantTB – including at least one new drug • a safer, higher-efficacy regimen will be available fortreatment of latent TB infection; • child-friendly first-line TB drug formulations will be • under development.

  18. New vaccines for tuberculosis

  19. BCG Vaccine • Calmette&Guerin (1906-1921) • Attenuated M.Bovis • First used in 1921 • Widespread use after 1945 • Most widely used vaccine • It is used about 160 country • It’s mandotary in more than 60 country

  20. Variable efficacy of BCG • Genetic variation in BCG strains • Genetic variation in population • Differences in virulence between TB strains (eg.Beijing) • Interference by non-tuberculous mycobacteria (eg.M.Avium) • Interference by concurrent parasitic infection (Th2-induction) • Protection against endogenous infection but not exogene re-infection

  21. BCG VACCİNE • BCG provides some protection against severe forms of pediatric TB. • It is unreliable against adult forms of pulmonary TB. • It is not effective in latent TB infection • BCG is not recommended for use in infants infected with HIV, due to the risk of disseminated BCG disease

  22. GOALS FOR BETTER TB VACCİNES • More effective and longer immunity than BCG • Prevent from disease that infected persons • Effective in persons with vaccinated BCG • Should be immunogenic • Eliminate TB as a public health threat, in line with global targets (<1 case/million), in conjunction with new drugs and diagnostics • Safe and effective in preventing TB in children, adolescents and adults, including people with HIV (for whom BCG is unsafe) • Protect against all forms of TB – including MDR and XDR

  23. Historic opportunities arose in 2000 for development of new TB vaccines, • the availability of techniques for the genetic manipulation of mycobacteria, • completion of the genome sequence of M. tuberculosis.

  24. DESİGN OF NEW VACCİNES • Improve BCG • Adding antigens from RD regions (eg.ESAT 6) • Overexpression of antigens ( Ag85) • Engineering phagosome escape ( Hly, Pfo) • Attenuate M.tuberculosis • Deleting essential genes (eg. Phop., Auxotrophic mutants) • Viral vector based • MVA, Adenovirus, rBCG • Subunit antigens combined with adjuvants • Secreted antigens (Ag85, ESAT6, TB10.4) • Strong immunogenes (Rv1196, Rv0125) • Latency antigens (hsp16, DosR etc) • Adjuvants (IC31, AS02/1B, DDA/TDB)

  25. CATEGORİES OF TB VACCİNES UNDER DEVELOPMENT Priming, Pre-Exposure: Vaccine candidates that would serve as the "prime" in a prime-boost regimen and be intended to prevent TB in people who have not been infected with M.tb.Boosting, Pre-Exposure: Vaccine candidates that would serve as the "boost" in a prime-boost regimen and that are intended to prevent TB in people who have not been infected with M.tb.Post Exposure — Immunotherapy: Vaccines candidates that could be administered after a person has been exposed to M.tb to prevent reactivation or progression to the disease stage and shorten or improve response to chemotherapy

  26. PRİME BOOST STRATEGY Induction of Immunity: Prime –Boost Infants • An initial vaccine, either the existing BCG vaccine or a new recombinant BCG (rBCG) • This "prime" inoculation would be followed by a "booster" shot. • Infants and young children who have never been exposed to TB might get a shot of a different vaccine. • a separate booster for young adults, the booster shot might be used to treat the disease itself as an adjunct to treatment with TB drugs. • "prime-boost" strategy will not only enhance protection, but also extend protection over a longer period of time. IM or as an aerosol Capsids in bacteria or as an aerosol 24 Weeks 14 Weeks

  27. -As of 2009 • -12 TB vaccinecandidates had enteredclinicaltrials. • -9 arestillbeingtested: • -5 are in Phase I (safety) clinicaltrials, • -2 areinPhase II trials, • -2 are in PhaseIIb ‘proof-of-concept’ trials

  28. The target and impact of vaccination • A)The impact of four strategies that use vaccines alone • B) The impact of combining drug treatment and vaccination

  29. FUNDING REQUIREMENTS US$ 1.9 billion (2011-2015)

  30. PROSPECTS FOR THE FUTURE • indicate that three new vaccines will have completed Phase IIb “proof of concept” trials by 2015. • and if successful, will enter large Phase III safety and efficacy trials. • It can be anticipated that one or more new TB vaccines could be available by 2020.

  31. http://www.tbvi.eu/projects/esi-tbvi.html http://www.newtbdrugs.org/project.php?id=160 http://www.aeras.org/about-tb/need.php

  32. THANK YOU

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