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New developments in the search for an HIV/AIDS vaccine

Uganda Virus Research Institute. New developments in the search for an HIV/AIDS vaccine. Medical Research Council (MRC UK) Uganda Virus Research Institute (UVRI) Pontiano Kaleebu UVRI. Summary. The need for a vaccine The types of vaccines On-going trials

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New developments in the search for an HIV/AIDS vaccine

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  1. Uganda Virus Research Institute New developments in the search for an HIV/AIDS vaccine Medical Research Council (MRC UK) Uganda Virus Research Institute (UVRI) Pontiano Kaleebu UVRI

  2. Summary • The need for a vaccine • The types of vaccines • On-going trials • Three exciting advances in vaccine research • How RV 144 trial is advancing vaccine research • Advancing broadly neutralizing antibodies to vaccine design • Highly protective vaccines in NHP

  3. New prevention technologies will reduce HIV incidence… but only a vaccine will end the epidemic 45k Rural Zimbabwe 35k Status Quo 30,685 Scaled Interventions 25k Annual New HIV Infections 38% 18,892 Microbicides/PrEP 53% 14,440 15k Vaccine* 5k 90% 3,211 2010 2015 2020 2025 2030 2035 3 Source: Imperial College and BMGF, 2010. *Assumed efficacy of 60% and uptake of 50%

  4. Long term goals for a prophylactic AIDS vaccine Primary Prevent the establishment of persistent HIV infection Secondary Control HIV infection/ progression to AIDS Tertiary Reduce HIV transmission (public health vaccine) Neutralizing Antibodies Cell Mediated Immunity

  5. Antigens for induction Neutralizing antibody First candidate vaccines Recombinant proteins

  6. DNA: Naked, replicon, adjuvants (CMI) Viral vectors: Canarypox, Adeno5, MVA, AAV (CMI) Second approach Type of Vaccine

  7. Brief History of HIV Vaccines gp160/gp120 subunits Poxvirus vector + protein rAd5-gag/pol/nef DNA/rAd5-Env/gag/pol/nef Antibody Relative focus on vaccine effector mechanisms CD8 T cells

  8. On-going trials-IAVI report Oct 2012 Globally: 36 phase I/IIa and one IIb efficacy trial • 19 of these USA • Most prime-boost - DNA + Viral vector (Pox and Adeno) Pox mostly MVA; various adeno, 5,26, 35 etc) • Improved DNA delivery e.g electroporation

  9. On-going trials in Africa IAVI report by October 2012

  10. RV144 Trial- Renewed hope

  11. Case Control Study • Measured immune responses from: • 41 Infected Vaccinees • 205 Uninfected Vaccinees • 40 Placebo Recipients Question: What are the immunologic measurements in vaccinees that predict HIV-1 infection over 3 year follow-up? • Sample Time point: Peak Immunogenicity (2 weeks after final vaccination) • Cryopreserved specimens

  12. Two Correlates of Infection Risk Found (Haynes, NEJM 366: 1275, 2012) • IgG antibodies that bind to a V1V2 recombinant fusion protein correlated inversely with infection rate. (Higher V1V2, lower infection rate) • Env binding plasma (monomeric) IgA correlated directly with infection rate. (Higher IgA to Env, higher infection rate).

  13. CH58 CH59 PG9 Jason McLellan, Peter Kwong

  14. Plans to move RV144 forward Pox-Protein Public-Private Partnership (P5) Seeks to advance and ultimately licence HIV pox-protein vaccine candidates Plans: 1) Improving the vaccine regimen 2) Conduct other trials RV 305 trial in Thailand- evaluating re-boosting of volunteers who participated in RV144 Other trials in Thailand and S. Africa

  15. Retrovaccinology:From antibody to antigen Infected individual Broadly neutralizing (protective) antibodies Molecular characterization of interaction of antibodywith pathogen antigen Ag Vaccine volunteer Immunogen design and testing * Modified antigen * Combination of several immunogens = vaccine 18 Source: Adapted from Burton, Nat. Rev. Immunol., 2:706, 2002

  16. An innovative approach: Passive Immunity THE FIND THE GOAL INTERIM STEPS Multiple broadly neutralizing antibodies against HIV Elicit those antibodies through vaccination Prove concept through … Passive immunizationby injecting antibodies Gene transfer through a vector that produces the antibodies 19

  17. Progress • AAV 1 vector expressing gene for PG9 antibody has been developed (IAVI and NIAID) will be tested in phase 1 soon • Passive immunotherapy infants- GHVI consultative workshop using VRC01 held 22-23 Jan 2013-Entebbe

  18. Correlates of protection against acquisition of infection and virological control with Adeno/pox vaccines • T cell responses to gag (core proteins) • Antibodies to V2

  19. Trial design challenges • Future efficacy trials- large and expensive • Kublin J. et al It will require 5100 volunteers in S. Africa at 20 sites to observe a 50% efficacy with 4% incidence in a setting of male circumcision, increased ART uptake, possible PreP • Most cohorts have much lower incidence

  20. We need to continue to support HIV vaccine research and development Major International funders of HIV Vaccine Research and development in Uganda

  21. Conclusion • There is some progress in understanding correlates of risk and mechanisms in RV144 relevant for vaccine design • There is progress in moving bNab to vaccine design • Optimised HIV vaccines can block acquisition in heterologous neutralization resistant SHIV in NHP • Future efficacy trials will be more complicated and expensive to design

  22. Thank you

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