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HIV VACCINES

HIV VACCINES What does an HIV vaccine need to do immunologically and clinically? What have we learned so far in vaccine clinical trials and where are we going? Neutralization Binding Antibodies What Does an HIV Vaccine Need to Do? Bind up free virions in infected secretions CTL CTL Kill

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HIV VACCINES

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  1. HIV VACCINES • What does an HIV vaccine need to do immunologically and clinically? • What have we learned so far in vaccine clinical trials and where are we going?

  2. Neutralization BindingAntibodies What Does an HIV Vaccine Need to Do? • Bind up free virions in infected secretions

  3. CTL CTL Kill HIV Infected Cell Apoptotic Death What Does an HIV Vaccine Need to Do? • Produce T cell memory to eliminate HIV infected cells

  4. Localized Infection in Mucosal Tissue 1-3 days Regional Spread and Latency 3-5 days Systemic Dissemination 6-9 days What is the Time Frame for These Immune Responses?

  5. HIV VACCINE TRIALS NETWORK Why Has It Been Difficult to Construct an HIV Vaccine?

  6. Scientific Reasons Why an HIV Vaccine Has Been Difficult to Develop • No definitive marker of protection exists, even among long term non-progressors • HIV employs several immune evasion strategies • HIV proteins mask their neutralizing sites • HIV-1 proteins down regulate T cell immune response to the virus • Antigenic diversity results in escape from both neutralizing antibodies, as well as CD8+ and CD4+ T cell responses

  7. Economic Issues Affecting HIV Vaccine Development • Economic incentives for large scale development of vaccines is miniscule compared to those for therapeutic drugs • Vaccines require high efficacy and negligible toxicity • Vaccines need to be inexpensive • Vaccines are not administered chronically • Development of an HIV vaccine is a high risk venture, requiring a diversion of resources from programs with a perceived higher degree of success

  8. Fortunately These Economic Perceptions are Starting to be Altered • Global Fund and Gates Foundation have given confidence that if there are useful vaccine(s) there will be a mechanism to buy them • Government funding in U.S. and European Communities for HIV-1 vaccine development has increased • NGO support has also increased (IAVI)

  9. Political Recognition of the Importance of an HIV Vaccine • Recognition that poor health leads to poor economies • Recognition at the presidential/ cabinet level that an HIV vaccine is essential to the control of the HIV pandemic

  10. Ideal Pipeline for HIV Vaccine Development Vaccine Concepts Vaccine Constructs Vaccine Clinical Trials • Money • People • Laboratory and animal resources • Money • People • Resources • Regulatory approval

  11. HIV Vaccines: Current Pipeline Situation Vaccine Constructs in Concept Stage 66 # GMP lots made 25 # Entered Phase I 25 # Entered Phase II 5 # Entered Phase III 2

  12. HIV Vaccines The road so far traveled

  13. HIV Vaccines 1987-2000: The First Wave • Between 1987 and 2000 over 20 different HIV vaccine products tested • Trials involved over 5,000 subjects • Trials conducted in U.S., Thailand, China, Kenya, and Europe • Vaccines extremely safe • Only local side effects • No immunosuppressive effects • No long or short term toxicities • One subunit vaccine advanced to phase 3 trials

  14. HIV Vaccines 1995-2000:The Second Wave • In mid 1990’s recognition of the importance of CD8+ T cell responses in abrogating HIV-1 viremia • Initiation of clinical trials of recombinant vectors to deliver HIV-1 genes into class I pathway • Poxvirus vector major prototype • Development of DNA vaccines

  15. Second Wave Vaccines • Clinical trials of viral vector vaccines demonstrate CD8+ T cell responses after vaccination • Replication defective canary pox virus vectors (ALVAC) • Vaccinia/MVA vectors

  16. HIV Vaccine Clinical Trials in 2002 • Near completion of phase 3 trials of gp120 VaxGen trials in U.S. and Thailand • Taught us that doing clinical trials of HIV vaccine in different regions of the world can be done and done well • Thailand proposal to move into a phase 3 clinical trial - a Clade E ALVAC vector in combination with gp120

  17. HIV Vaccines 2002:The Third Wave • Use of combination vaccines to increase T cell responses after vaccination • Adjuvanted DNA vaccine to prime • Viral vector vaccine (adenovirus replicon or MVA vector) to boost • Enhanced efficacy of such vaccines in primate models in controlling HIV-1 viremia after experimental inoculation

  18. 107 DPeak 106 105 RNA copies/ml 104 DSet-pt 103 102 101 0 1 2 3 4 5 HIV VACCINE TRIALS NETWORK Years Vaccines that do not prevent infection but modify viral replication after acquisition of HIV infection

  19. Localized Infection in Mucosal Tissue 1-3 days Regional Spread and Latency 3-5 days Systemic Dissemination 6-9 days Mechanism of Action of T Cell Vaccine Directed at gag Gene Products

  20. HIV VACCINE TRIALS NETWORK T Cell Directed Vaccines Bring with them Several New Scientific and Policy Issues

  21. Vaccines That Modify Viral Replication • It is conceptually “easy” to see that a vaccine that reduces viral setpoint would help the individual • Increase time to AIDS • Reduce need for or number of antivirals • Improve efficacy of antiretrovirals, reduce frequency of resistance

  22. HIV VACCINE TRIALS NETWORK Vaccines Designed to Modify Replication Offer New Challenges in Clinical Trial Design • What level and duration of set point viremia would be adequate for use of such a vaccine regimen? • Durability of viremic control is the major determinant in clinical as well as epidemiological effects of such vaccines • Late breakthroughs associated with low grade replication and escape mutations from CTL control have been documented in non-human primate experiments

  23. HIV VACCINE TRIALS NETWORK Would such a vaccine reduce transmission?

  24. Relationship to Viral Load and Heterosexual Transmission(Rakai Discordant Couple Trial, n=415) Quinn et al, NEJM 342(13):921-9, 2000 Mar 30 Annual Frequency of Transmission RNA Viral Load in HIV+ Source Partner

  25. Population Based Effects of Vaccines that Control Viremia • Vaccines that control viremia can potentially impact the epidemic spread of HIV in a community.

  26. Mathematical Model of Impact of a Vaccine That Reduced Viral Load Over Time(Ira Longini, Emory University) Prevalence of HIV in Population Years

  27. HIV VACCINE TRIALS NETWORK Determining the Effectiveness of Vaccines that Control Viremia • Effective mathematical models require data • We must generate such data concomitant with phase 3 trials of these vaccines • Design clinical trials to directly measure the effects on transmission • Partner studies • Community level randomized controlled trials

  28. HIV VACCINE TRIALS NETWORK T Cell Based Vaccines also Raise the Issue of Whether Clade-Specific Vaccines are Needed

  29. Clades and T Cell Vaccines • Strain/clade typing is largely based on envelope sequence and antibody diversity • Cross clade T cell responses are well documented in both natural infection and after ALVAC vaccination or DNA/adenovirus vaccination

  30. Cross-Clade CTL Responses After Receipt of Clade B ALVAC Vaccination(vCP205 - HVTN Protocol 022) % Specific Lysis Primary Isolate Targets (HIV-1 Clades) Ferrari et al. PNAS 1997:94

  31. Clade A Clade B Clade C 10 / 13 13 / 13 10 / 13 77% 100% 77% Frequency of T cell Responses by ELISPOT to Clade A, B and C Prototype Peptides After Receipt of Ad5-gag Clade B Vaccine Shiver and Emini - 5/7/2002

  32. Message Number 1 • Momentum and progress in HIV-1 vaccine development is picking up • more vaccine candidates are entering clinical trials • more novelty in the scientific approach • more T cell immunogenicity

  33. HIV VACCINE TRIALS NETWORK T cell based vaccines are approaching the immunogenicity that we feel is needed for effectiveness

  34. 700 Vesicle Formation No Vesicle Formation 600 500 400 Interferon-g-Producing Cells (per 106 PBMC) 300 200 100 0 -100 Undiluted 1:10 1:100 Dilution Dilution Elispot Responses After Vaccinia Vaccine(Frey, et al; NEJM 4/25/02)

  35. Anti-gag T Cell ELISPOT Responses After DNA Priming and Adenovirus Boosting at 108 vp Dose Immunizations at Weeks 0, 4 and 26 Weeks Post Boosting 4 8 16 Subject # 1 2 3 4 5 6 7 359 418 - 230 618 461 69 398 333 729 141 1739 230 241 - - 898 243 1038 180 - Response = # HIV-1 gag-specific SFC / 10^6 PBMCs in a -IFN ELISPOT assay Emini, Shiver, et al

  36. Message Number 2 • While we still lack approaches that give the breadth and magnitude of neutralizing antibodies we feel are needed for an effective vaccine that prevents acquisition of HIV , it is likely we can achieve a reduction in transmission of HIV-1 with T cell based vaccines.

  37. Message Number 3 • Cross clade T cell responses to HIV are being achieved at high frequency with many vaccines currently in clinical trials • The scientific rationale to study clade mismatched T cell vaccines exists

  38. Why Should one Conduct non Clade Matched HIV Vaccine Trials? • Many vaccines, especially recombinant viral vectors, are technically difficult to manufacture, even for large scale clinical trials. • The resources and technical support to manufacture country-specific vaccines are very limited • speed of regulatory approval and manufacturing scale up of novel vector based vaccines is not commensurate with the needed pace of vaccine development

  39. Corollary of Message 3 • Cross clade responses to a potent vaccine may provide greater efficacy than clade specific responses to a less potent vaccine

  40. Message Number 4 • Evaluation of HIV-1 vaccines requires international cooperation between agencies involved in HIV vaccine development and testing • Combination vaccines are likely to be needed • This increases the complexity of preclinical and clinical development • This requires coordination and cooperation among developers and clinical trial sites

  41. HIV VACCINE TRIALS NETWORK An International Program to Test HIV Vaccines New York, NY Baltimore, MD Boston, MA Washington, DC Port-au-Prince, Haiti Chicago, IL Rochester, NY Providence, RI Fairfax, VA St. Louis, MO Nashville, TN Seattle, WA *Yunnan, China Nanning, China San Francisco, CA Birmingham, AL *Kingston, Jamaica Chiang Mai, Thailand *Tegucigalpa, Honduras *Santo Domingo, Dominican Republic *Pune, India San Juan, Puerto Rico Blantyre, Malawi Port of Spain, Trinidad & Tobago Gaborone, Botswana Lima, Peru Soweto, South Africa Sao Paulo, Brazil Rio de Janeiro, Brazil Durban, South Africa *Capetown, South Africa *Potential Expansion Sites

  42. Message Number 5 • Global development means investment of international scientists and organizations earlier in vaccine development than any previous vaccine effort • Development of a National HIV vaccine plan is critical for facilitating participation in this global vaccine effort

  43. HIV VACCINE TRIALS NETWORK Message Number 6 • HIV-1 vaccines need to be developed in the context of a larger prevention effort • This is a marathon - not a sprint • Initial vaccines partially effective • Community education is critical not only in trials, but to continue safe sex and safe injection behaviors • ART therapy is complementary and not competitive with HIV vaccine development

  44. HIV VACCINE TRIALS NETWORK ART and Vaccine Trial Participation • International investigators in the HVTN believe that ART should be available for its trial participants when they need it. • Communities who participate in vaccine research should be provided ART, but if this is not possible, then individuals who participate in vaccine trials and develop HIV while on the trials should be eligible for ART when they and their physician feel it is needed. • HVTN is committed to utilize its expanding global network to bring these messages to HIV vaccine development.

  45. Delays in the scientific, regulatory and political process of developing and evaluating HIV vaccines are the most egregious error that we now encounter in the HIV vaccine field.

  46. HIV VACCINE TRIALS NETWORK The HIV vaccine field should be a model for science and medicine ; a world that values rich and poor, north and south, women and men, young and old alike. A world that speeds vaccine development to all in need.

  47. The virus recognizes the similarity among people on the planet - scientists, policy makers, and communities must act similarly.

  48. Judy Wasserheit Peggy Johnston Ed Tramont Jorge Flores Julie McElrath Kent Weinhold Steve Self Steve Wakefield Emilio Emini, Jeff Chodokowitz, Jerry Sadoff, John Shiver and Scott Thaler of Merck Research Labs Jim Tartaglia, Sanjay Gurunathan of Aventis Pasteur Debbie Birx and John McNeal of WRAIR Jose Esparza, UNAIDS Contributors

  49. Special Thanks Tony Fauci

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