HIV Vaccines

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Presentation by Dennis Burton, Scripps Research Institute.

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HIV Vaccines

  1. 1. “An HIV Vaccine: The Neutralizing Antibody Problem:” Dennis Burton Dept of Immunology & Microbial Science and IAVINeutralizing Antibody Center, The Scripps Research Institute Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) Ragon Institute of MGH, Harvard and MIT Symposium on Innovations in Vaccines R&D London, Sep 5th 2012
  2. 2. A global view of HIV-1 infection 33 million people living with HIV, 2009UNAIDS: 2010 Report on the global AIDS epidemic. 2010
  3. 3. AIDS compromises human development …Reversing the spread of AIDS is one of the eight U.N. Millennium Development GoalsThe AIDS pandemic undermines:• Poverty reduction• Improvements in child and maternal health• Improvements in nutrition• Gains in basic education• Control of other infectious diseases
  4. 4. Host cellTheproteinsin HIV CCR5entry. CD4 Env spike (gp120)3 (gp41)3 Virion
  5. 5. NAbs blockviral entry.SuccessfulvaccinesinduceNAbs. Neutralizing Antibody (NAb)For HIV,need toinducebroadlyNAbs(bNAbs).
  6. 6. Can antibodies be made to conserved parts of the HIV spike: are there vulnerabilities in the armor? Yes A proportion of HIV-infected donors, overtime, make broadly neutralizing antibodies.
  7. 7. Reverse engineering an HIV vaccine broadly neutralizing (protective) antibodies EnvHIV-infected individual Molecular characterization of Ab-Env Immunogen design and testing * * combination of several immunogens *modified Env = vaccine (adapted from Burton, Nat. Rev. Immunol., 2:706, 2002)
  8. 8. The NAb Problem: IAVI NAC Approach Structure-based bnMAbs immunogen design Determining structure Analysis of Ab responses of Env-Ab complexes MAb Structural Immunogen Immunogen ClinicalIdentification Biology Design Screening Dev. Feedback loops Major Block Tools of IAVI Slow structuralProtocol G Immunogen genomics Screen
  9. 9. Rapid progress since 2009 in terms of potency and breadth of bnMAbs coverage (%)
  10. 10. A low dose of MAb PGT121 protects against high dose SHIV162P3 vaginal challenge in macaques av. serum conc. dose PGT121 at challenge no. of macaques (mg/kg) (μg/ml) protected % protection 5 95 5/5 100 1 15 5/5 100 0.2 1.7 3/5 60 control Ab n.d. 0/4 0 5mg/kg
  11. 11. >12 V2 / glycans Vaccine targets defined MAbs (PG9) by bnMAbs, Sep 2012 Glycans 1 (2G12) V3 / V4 / glycans>25 (cluster of targets: PGT120s, PGT130s) V3/CD4i 2 (3BC176) gp120 MPER >5 (10E8) CD4bs gp41>25 (VRC01) viral membrane
  12. 12. The NAb Problem: IAVI NAC Approach Structure-based bnMAbs immunogen design Determining structure Analysis of Ab responses of Env-Ab complexes MAb Structural Immunogen Immunogen ClinicalIdentification Biology Design Screening Dev. Feedback loops Major Block Tools of IAVI Slow structuralProtocol G Immunogen genomics Screen
  13. 13. Ab-gp120 structures, 2011-12 (Ian Wilson et al) mini-V3 N332 N30PGV04-gp120 outerdomain complex: CD4bs PGT128-gp120 outer domain complex V3/glycans PGT128-trimer complex by EM
  14. 14. The NAb Problem: IAVI NAC Approach Structure-based bnMAbs immunogen design Determining structure Analysis of Ab responses of Env-Ab complexes MAb Structural Immunogen Immunogen ClinicalIdentification Biology Design Screening Dev. Feedback loops Major Block Tools of IAVI Slow structuralProtocol G Immunogen genomics Screen
  15. 15. Successful HIV vaccination will requireconsiderable ingenuity in immunogen design and immunization protocols that go far beyond current norms.
  16. 16. How to translate structural data into immunogens?•Stabilize the antibody-bound target epitope conformation.•Expose that conformation to the immune system.Dampen responses to off-target epitopes.•Multimerize with epitope pointed outward.Additional immunogen features may be needed for HIV,including the ability to activate germ line B cells and to boostguide antibody maturation along certain pathways. prime Bill Schief and colleagues
  17. 17. High affinity antibodies are generated byantigen-driven mutation and selection from a naïve repertoire Ab affinity Somatic hypermutation Memory B cell naïve Antigen B-cell mature Ab Plasma Y Germline Ab cell
  18. 18. The evolution of antibodies in natural HIV infection: clues for vaccine design and strategies? From germ line antibodies to broadly neutralizing antibodies in natural HIV infection-what is the route? IAVI Protocol G: 1,800 donors, few time points Protocol C: 500 donors, longitudinal study
  19. 19. The central role of CD4 T helper (Tfh) cells in Ab responses Memory B cell naïve Antigen B-cell mature Ab Tfh cell Germline Ab Germinal center Plasma Y cell
  20. 20. NAC/CHAVI-ID Priorities (Sept 2012)I. Complete definition of HIV Env vulnerabilities (“enough” bnMAbs, “enough” structures).II. Understanding the development of bnAb responses in natural HIV infectionIII. Epitope directed Immunogen DesignIV. Trimer-based Immunogen DesignV. Immunogen evaluation
  21. 21. CollaboratorsScripps IAVI VRC CHAVI-IDIan Wilson Wayne Koff Gary Nabel Rafi AhmedPascal Poignard Rick King John Mascola Dan Barouch Dennis BurtonBill Schief Clinical sites Peter Kwong Shane CrottyRich Wyatt Members of the Adam Godzik Neutralizing Ragon Julie McElrathAndrew Ward Bruce Walker Michel Nussenzweig AntibodyChi-Huey Wong Consortium Galit Alter Bali Pulendran Joe Sodroski Chris Scanlan Protocol G & C Bill Schief scientists & Cornell Guido SilvestriMonogram donors John Moore Bruce WalkerTheraclone Ian Wilson Miami Rich Wyatt David Watkins

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