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Anti- Chlamydia Vaccine: From Bench to Bedside

Ashlesh Murthy, M.B.B.S., Ph.D Research Assistant Professor University of Texas at San Antonio. Anti- Chlamydia Vaccine: From Bench to Bedside. Chlamydia. Obligate intracellular pathogen C. trachomatis , C. pneumoniae , C. psittaci , C. pecorum , C. muridarum

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Anti- Chlamydia Vaccine: From Bench to Bedside

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  1. Ashlesh Murthy, M.B.B.S., Ph.D Research Assistant Professor University of Texas at San Antonio Anti-Chlamydia Vaccine:From Bench to Bedside

  2. Chlamydia • Obligate intracellular pathogen • C. trachomatis, C. pneumoniae, C. psittaci, C. pecorum, C. muridarum • C. trachomatismultiple serovars: A-K, L1-3

  3. Trachoma and Inclusion Conjunctivitis Serovars- A, B, Ba, C • Urogenital Infections • Serovars - D, Da, E, F, G, Ga, H, I, J, K LymphoGranulomaVenereum Serovars- L1, L2, L3 Chlamydia trachomatis Infections

  4. Global Prevalence of Chlamydial STD

  5. ChlamydialSTD Adapted from http://www.cdc.gov/std/stats/tables/table1.htm

  6. Chlamydial STD-Ascending Infection Eskilsden and Gupta et al., In Revision

  7. Antimicrobials No Symptoms Chlamydial STD-Ascending Infection PID Dye alone Dye+Chlamydia Salpingitis Endometritis Cervicitis Vaginitis

  8. Normal Pelvic Inflammatory Disease Ectopic pregnancy Infertility Chlamydial STD-Reproductive Damage

  9. Chlamydial STD- Statistics • 90 million cases • 50-70% of patients initially asymptomatic: not treated • 40% of untreated females – pelvic inflammatory disease • 20% of PID cases- infertility Adapted from www.cdc.gov-2006 STD statistics

  10. Anti-Chlamydial Vaccine

  11. Immunity Goals for Chlamydial Vaccine No Symptoms (75%) Transmission Symptoms (25%) Re-Infection Sequelae Infection • Prevent infection (Sterilizing immunity)- ideal • Reduce transmission / Duration of shedding- practical • Prevent pathological sequelae • Protection against multiple serovars

  12. Chlamydial Vaccine Trials of 1960s • Formalin-killed whole chlamydial organisms • Reduction in incidence for ~ 1 year • Comparable/exaggerated ocular pathology in vaccinees • Focus on sub-unit vaccines

  13. Chlamydial Developmental Cycle

  14. Vaccines Against Chlamydial STD • Major outer membrane protein (MOMP) • Chlamydia-purified MOMP • Recombinant MOMP • MOMP DNA • MOMP synthetic peptides • MOMP plus outer membrane protein 2 (omp2) • Chlamydia-purified MOMP refolded to native configuration • Cons: MOMP - serovar-specific • Currently no licensed vaccine against C. trachomatis • Need for identification of new vaccine candidates

  15. Chlamydial Developmental Cycle

  16. Nucleus Inclusion CPAF Overlay Chlamydial Protease-Like Activity Factor (CPAF) • Secreted into host cytosol

  17. CPAF-Human Antibody Responses CPAF Sharma et al., Infect Immun. 2006

  18. CPAF-Highly Conserved Dong et al., Infect Immun. 2005

  19. CPAF- A Potential Vaccine Candidate

  20. Mouse Model of Chlamydial Infection C. muridarum 106 Vaginal chlamydial shedding Oviduct dilatation 0 30 80 Days after challenge

  21. Protocol For Vaccination Studies Intranasal Day –1: IL-12 (0.5 mg) Day 0:rCPAF(15mg)+ IL-12 (0.5 mg) Day +1: IL-12 (0.5 mg) Recombinant CPAF from C. trachomatis L2 cloned into E. coli Day 14: rCPAF (15 mg)+IL-12 (0.5 mg) Day 28: rCPAF (15 mg)+ IL-12 (0.5 mg) 30 day Rest Vaginal challenge Estimation of bacterial shedding Examination of disease pathology Day 60: 5X104 IFU C. muridarum

  22. Early Responses to Immunization

  23. CPAF Vaccine : Robust IFN-gResponse Murthy et al., Infect Immun. 2007

  24. CPAF Vaccine: Systemic Antibodies Murthy et al., Infect Immun. 2007

  25. CPAF Vaccine: Mucosal Antibodies Murthy et al., Infect Immun. 2007

  26. CPAF Vaccine: Chlamydial Clearance Murthy et al., Infect Immun. 2007

  27. CPAF+IL-12: Prevents Hydrosalpinx Murthy et al., Infect Immun. 2007

  28. CPAF Vaccine: Preserves Fertility Murthy et al., In Review, 2010

  29. Role of Human HLA-DR Murthy et al., Infect Immun. 2006

  30. Minimal Role for Antibody Murthy et al., FEMS Immunol. Med. Microbiol. 2009

  31. Role of CD4+ T-cells CD4+ T cell adoptive transfer Murphey et al., Cell. Immunol. 2006

  32. Role of IFN-g Murthy et al., J. Immunol. 2008

  33. Summary • CPAF vaccine administered with Th1 adjuvant: • Enhances clearance of infection • Protects against severe pathology • Induces robust cellular IFN-g response • Induces systemic and mucosal antibody • Protection is dependent upon CPAF-specific • cellular IFN-g responses but not antibody

  34. Ongoing Collaborative Effort US Patent Application No. 12/243,769: Inventors- Arulanandam, Murthy, Zhong

  35. Bench to Bedside Identification of pathogenic mechanisms Vaccine antigen discovery Validation of protection and pathogenesis correlates in clinical samples Routes, Delivery systems Adjuvants, Formulations Non-Human Primates Clinical Trials Anti-Chlamydia vaccine

  36. Acknowledgements • Bernard Arulanandam, Ph.D., M.B.A. • Weidang Li, M.D., Ph.D. • Bharat Chaganty, MS • Sangamithra Kamalakaran, B.Tech • Kishan Evani, MS • Rishein Gupta, Ph.D. • Yu Cong, M.D. • Madhulika Jupelli, Ph.D. • Cathi Murphey, M.S. Guangming Zhong, M.D., Ph.D., UTHSCSA M. Neal Guentzel, Ph.D., STCEID, UTSA Aruna Mittal, Ph.D, IOP, India 1R03AI088342

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