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Immune Strategies for HIV Prevention

Immune Strategies for HIV Prevention. Dr L Stranix-Chibanda UZ-UCSF Annual Research Day 17 April 2015. Outline. Active immunisation Recent history of HIV vaccine development – RV144 trial The P5 initiative and Uhambo Passive immunisation Monoclonal antibodies against HIV

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Immune Strategies for HIV Prevention

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  1. Immune Strategies for HIV Prevention Dr L Stranix-Chibanda UZ-UCSF Annual Research Day 17 April 2015

  2. Outline • Active immunisation • Recent history of HIV vaccine development – RV144 trial • The P5 initiative and Uhambo • Passive immunisation • Monoclonal antibodies against HIV • Immunoprophylaxis by gene transfer

  3. Administer an antigen and wait for the immune system to respond Requires immune system capable of responding Takes some time for response to develop If successful, results in long term protection Generally results in both antibody and T cell responses Active Immunisation

  4. RV144 – study design • Thailand,>16,000 healthy, heterosexual, HIV negative adults • Intervention 2004-2006, 3-year follow-up concluded 2009 • Tested 2 HIV vaccines • Prime: ALVAC HIV (vCP1521) pox • Boost: AIDSVAX B/E (gp120)protein

  5. RV144 – proof of concept/2009

  6. P5 &Uhambo – a journey of hope • Identify a product submitted for regulatory approval and eventual public health introduction. Graphic: AVAC Report 2014/5

  7. P5 &Uhambo – a journey of hope • Correlates of protection – AB & T-cell Graphic: AVAC Report 2014/5

  8. Administer pre-formed antibodies Does not require intact immune system Immediate levels of antibodies detectable Only lasts as long as the antibodies last Passive Immunisation

  9. Passive immunisation is used to prevent a variety of infections • Polyclonal • Rabies Immune Globulin (RIG) • Hepatitis B Immune Globulin (HBIG) • Varicella Zoster Immune Globulin (VZIG) • Tetanus Immune Globulin • Monoclonal • Respiratory Syncitial Virus (Paluvizimab) • Anthrax

  10. Monoclonal AB against HIV • Developed a few in 1990’s • Explosion in AB development >2008 • next-generation sequencing • advances in in vitro B cell clonal amplification • high-throughput neutralisation assays • Identification of monoclonal antibodies from HIV-infected patients with broad and potent neutralisation potential

  11. Sites of Vulnerability for HIV Neutralisation V1V2 PG9/16, CH01-04, PGT 141-145 V3/glycan 2G12, PGT125-128, PGT131-135, 10-1074 membrane proximal domain 2F5, 4E10, CAP206-CH12, 10E8 CD4 binding site B12, VRC01-03, PG04, HJ16 CH30-34, NIH45-46, 12A12, VRC07, 3BNC17 Haynes et al. (2012) Nat.Biot.5: 423-433 Kwong and Mascola et al. (2012) Immunity. 37: 412-425

  12. Possible Roles for Monoclonals • Strong pre-clinical evidence that potent monoclonal antibodies (like VRC01) could be important for prevention and treatment of HIV. • Prevention of vertical transmission • Augment therapy in treated children and adults • Early treatment of infected infants • Strategy for cure Barin, Jourdain, Brunet et al. JID 2006

  13. Antibody therapy • Advantages • Single or intermittent injection, does not require daily meds, adherence • Could prevent disease or modify disease in those already infected • If it works, it provides critical data to inform the entire vaccine field • Disadvantages • Requires monthly injection • Currently expensive

  14. bnAB clinical trials VRC/NIH • Phase 1 trial US, S Africa, Zim • Single dose of SC VRC01 to high-risk newborns at birth (0-72hr) • In addition to the standard-of-care HIV prevention regimens • Verify safety • Determine PK profile of 20mg/kg dose • Proceed to 40mg/kg dose, if safe • VRC601/602 in adults, ?pregnancy

  15. Antibody summary • Potent and broadly neutralizing monoclonal antibodies provide a new opportunity for HIV prevention (also treatment / cure) • If effective, antibody production can be scaled up and altered to increase duration of effect (> 1 month)

  16. Immunoprophylaxis by gene transfer (IGT) • A form of gene therapy to modify the DNA of patients to enable them to produce antibodies that deactivate HIV • Pre-clinical studies in monkeys/mice • identify the genes that produce powerful antibodies against disease • create artificial versions of these genes • insert them into viruses  inject muscle • transfer the genetically engineered DNA to the muscle cells  alter programming

  17. In conclusion, • Various immune approaches are being explored against HIV infection • Advancements in laboratory techniques mean that the knowledge base is expanding rapidly • None are yet ready for clinical use • Immune strategies are required to guarantee a sustained end to the AIDS pandemic

  18. Acknowledgements • UZ College of Health Sciences • UZ-UCSF Collaborative Research Programme • HIV Vaccine Trials Network • IMPAACT Network • Dr C Cunningham and VRC

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