HIV Vaccine Research

1. HIV Vaccine Research Dina Kovarik, M.S., Ph.D. Program Manager, NWABR May 16, 2009 www.uhaweb.hartford.edu/bugl/images/HIV_bud2.jpg

2. The HIV/AIDS Pandemic Report on the Global AIDS Epidemic. Executive Summary. 2007. www.unaids.org http://www.notablebiographies.com/images/uewb_01_img0046.jpg http://lowposts.com/wp-content/uploads/2009/03/fat_magic.jpg http://images.absoluteastronomy.com/images/topicimages/l/li/liberace.gif www.lincolncountyhealth.com. www.mlm.nih.gov http://www.iconocast.com/B000000000000087/B6/News8_6.jpg http://www.abc.net.au/reslib/200707/r163084_600500.jpg http://www.chicagobooth.edu/magazine/29/2/images/AIDS.jpg http://www.deza.admin.ch/pictures/E_Bereich/Factsheets_SOSA/south_africa/ZAFwomanandchild_1.jpg http://www.workofwomen.org/images/orphanedchildren.JPG

3. gp41 gp120 vif gag rev pol tat nef env vpr vpu TM Human Immunodeficiency Virus (HIV) http://www.rhodes.edu/biology/glindquester/viruses/pagespass/hiv/attachment.jpg Burton et al. 2005. PNAS 102:14943.

4. Immune Responses to Infection Virion Antigen Presenting Cell (APC, Phagocyte)

5. Immune Responses to Infection Virion CD8+ T Cell Kill Infected Cells Killer T Cells Antigen Presenting Cell (APC, Phagocyte)

6. Immune Responses to Infection Virion CD8+ T Cell Kill Infected Cells Antibodies Coat Pathogen Killer T Cells Antigen Presenting Cell (APC, Phagocyte) B Cell

7. Immune Responses to Infection Virion CD8+ T Cell Killer T Cells CD4+ T Cell T Helper Cells Antigen Presenting Cell (APC, Phagocyte) B Cell

8. Peak Virus Load CD4+ T Cells Antibodies T Cell Count or Antibody Titer Neutralizing Abs RNA Copies per Milliliter CD8+ T Cells Weeks Months Years Time Post-Infection Immune Correlates and HIV Infection

9. Y Binding Versus Neutralizing Antibodies Neutralizing Antibodies (NAb) Binding Antibodies (BAbs) Y X Adapted from Wendy Blay Puryear, Ph.D.

10. Nonhuman primate models for AIDS Macaca fascicularis Macaca nemestrina Macaca mulatta • HIV-1: only replicates in chimpanzees--disease in 10 years • Simian Immunodeficiency Virus (SIV): causes AIDS in months to years • Simian Human Immunodeficiency Virus (SHIV): chimera with HIV env gene in the backbone of SIV; disease progression similar to SIV http://upload.wikimedia.org/wikipedia/commons/9/9f/Macaca_fascicularis.jpg http://www.aaas.org/news/releases/2007/images/0416macaque_lone.jpg http://www.theprimata.com/macaca_nemestrina.jpg

11. Antibodies and HIV: Passive Transfer Studies • Passive transfer of SIV-specific neutralizing antibodies (NAbs) one and 14 days after SIV infection reduced viral load and prolonged healthy life. (Shibata et al.1999. Nat Med 5:204) • Passive transfer of high-dose NAbs 6 hours before, but not 24 hours after, virus challenge can prevent infection. (Nishimura et al. 2003. PNAS 100:15131.) • Administration of NAbs after infection can accelerate the de novo antibody response. (Haigwood et al. 2004. J Virol78:5883)

12. The Role of CD8+ T Cells in HIV Infection • A rise in CD8+ T cells early in HIV infection is associated with a reduction in viral load. (Koup et al. 1994. J Virol 68:4650) • A decrease in CD8+ T cells numbers late in HIV infection correlates with an increase in viral load. (Walker et al. 1987. Nature 328:345; Ogg et al.1998.Science 279:2103.) • Depletion of CD8+ T cells in SIV-infected macaques resulted in immediate increases in viral load, while CD8+ T cell restoration resulted in virus control. (Schmitz et al.1999.Science 283:857; Jin et al. 1999. J Exp Med 189:991.)

13. If antibodies and T cells protect from HIV infection or disease, why don’t we have an effective HIV vaccine? • Timing is everything • The devil is in the details

14. The Power of Immune Memory MemoryResponse MemoryResponse PrimaryResponse PrimaryResponse Strength of Response Strength of Response 1st Infection Vaccination 2nd Infection 1st Infection

15. The Race to Catch HIV Brenchley et al. 2004. J Exp Med 200:749. Mattapallil et al. 2005. Science 434:1093.

16. But HIV Keeps Running Away… Virus Time Point 0 1 2 3 4 5 6 - - - - - - - 0 1 2 3 4 5 6 - - - - - - - + = patient serum able to neutralize patient virus + - - - - - - + + - - - - - Serum Time Point + + + - - - - + + + + - - - + + + + + - - Richman et al. 2003. PNAS 100:4144.

17. If antibodies and T cells protect from HIV infection or disease, why don’t we have an effective HIV vaccine? • Timing is everything • The devil is in the details

18. Diversity Within the Individual Homogeneous new infection Replicates ~ 24hrs Produces 1010 new virions a day Average 1 mutation per replicated genome Rapidly develop a “quasispecies” Wendy Blay Puryear, Ph.D.

19. HIV-1 Diversity Worldwide HIV-1 group M: - 9 subtypes (>30% difference) - several circulating recombinant forms Subtype A B C D F, G, H, J. K CRF01_AE CRF02_AG CRF03_AB other Hemelaar et al. 2004. WHO/UNAIDS.

20. Comparative Genetic Diversity of HIV and Influenza Weiss. 2003. Nat Med. 9:887, adapted from Korber et al. 2001. Brit Med Bull 58:19.

21. Components of a Potentially Successful HIV Vaccine • Target multiple HIV antigens • Overcome viral resistance and diversity • Cell Mediated Immunity • CD4+ T Helper Cells • CD8+ “Killer” T Cells • Humoral Immunity / Antibodies • Binding antibodies  Antibody-dependent cellular cytotoxicity • Neutralizing antibodies (NAbs)  Block infection of target cells

22. Vaccines in Clinical Use

23. Recombinant Proteins Moderately Potent NAbs gp120 Peptides gp140 trimers Safety (HIV) and Efficacy (Merck) Live Infection Vector Viruses (Adenovirus, Poxvirus) Attenuated HIV Inactivated Virions Other Approaches Plasmid DNA Virus-Like Particles (VLPs) http://www.aids.harvard.edu/images/laboratories/figure_virionstructure.jpg A Brief History of HIV Vaccines

24. Variables in HIV Vaccine Development Vaccine Modality Gene Model Virus Whole, killed env Mouse SHIVSF162 Attenuated gag Rabbit SHIV89.6/P DNA pol Guinea Pig SIVmac239/251 Recombinant Proteins nef Ferret SIV E660 Peptides tat Monkey SIV mne Virus-like particles revMacaca nemestrina Mimetopes vifMacaca fascicularis Vectors: vprMacaca mulatta Vaccinia vpu Modified Vaccinia Ankara Fowlpox Canarypox Adenovirus Herpes simplex virus Rabies virus Vesicular Stomatitis Virus Semiliki Forest Virus Adeno-associated virus OPV Salmonella Moloney Leukemia virus Hepatitis B virus Listeria monocytogenes Adjuvant Adminitration Alum Dose Cytokines Route Pulsed DC Timing Co-stimulatory QS-21 CpGoligos PROPRIETARY Adapted from Nancy Haigwood, Ph.D.

25. Stages of Vaccine Clinical Trials

26. Clinical HIV Trial Sponsors • National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) • Vaccine Research Center (VRC), • HIV Vaccine Trials Network (HVTN) • International AIDS Vaccine Initiative (IAVI) • Center for HIV/AIDS Vaccine Immunology (CHAVI) • South African AIDS Vaccine Initiative (SAAVI) Pharmexa-Epimmune Aventis-Sanofi Pasteur/ANRS Bavarian Nordic Therion Aaron Diamond AIDS Research Center Chrion Wyeth VaxGen GeoVax Merck

27. B AIDSVAX: Targeting gp120 B E B World’s First Phase III Trial of an AIDS Vaccine N=5,400 in USA, Canada, Netherlands (5,100 MSM) and N=2,500 in Thailand Sponsors: VaxGen, a spin-off of Genetech run by Dr. Don Francis, formerly of the CDC Study Design: VaxGen’s AIDSVAX, two forms of rgp120 from clade B (B/B) or one from clade B and one from clade E (B/E) Immunize @ 0, 1, 6, 12, 18, 24 & 30 months Follow up for 3 years (1998-2001) Endpoints: Prevention of HIV Infection Reduction in Viral Load Maintenance of CD4+ T cells Protective Effectiveness less than 30% (or indeterminant) However, the vaccine was safe, and the trial itself was a success Nitayaphan et al. 2004. J Infect Dis 190:702.

28. B Thai Prime-Boost Study E N = 16,000 volunteers ages 20-30 Sponsors: Thai Government, Aventis Pasteur, VaxGen, US Military Study Design: Prominent clade in Thailand is CRF01_AE VaxGen’s AIDSVAX rgp120 from clades B and E Prime @ 0, 1, 3 & 6 months with ALVAC canarypox vaccine (vCP1521, Aventis Pasteur); contains HIV genes gag, pol, and nef, clade B Co-administer AIDSVAX B/E at 3 and 6 months Started in 2003, 6 year study Endpoints: Prevention of HIV Infection Reduction in Viral Load Maintenance of CD4+ T cells http://www.primeboost3.org/eng/

29. Thai Prime-Boost Study Trial Cost: $119 million Cost of rgp120: $3 million 2007 Interim Analysis: No safety concerns Final results expected by the end of 2009. “We have a concern about the wisdom of the U.S. government’s sponsoring a recently initiated phase III trial in Thailand…Multiple phase I and II clinical trial have revealed that the ALVAC vector is poorly immunogenic. The gp120 component as now been proven in phase III trials in the United States and Thailand to be completely incapable of prevention or ameliorating HIV-1 infection. Society expects the scientific community to develop a vaccine to counter the AIDS pandemic, but there are adverse consequences to conducting large-scale trials of inadequate HIV-1 vaccines…. …One price for repetitive failure could be crucial erosion of confidence by the public and politicians in our capability of developing an effective AIDS vaccine collectively… …The decision about whether or not to proceed with mounting a phase III HIV-1 vaccine trial needs to take into account the likelihood of success and the consequences of failure, the value of what can realistically be learned, and the human and financial costs involved.” Burton et al. 2004. Science 303:316.

30. http://www.iavireport.org/

31. V520: The STEP & Phambili Trials N = 3,000 volunteers (STEP, begin in 2004); 801 (Phambili). Sponsors: HIV Vaccine Trials Network (HVTN) & Merck Study Design: Ad5 is a replication-defective adenovirus (common cold virus) Three doses of Clade B Ad5-gag, Ad5-pol & Ad5-nef Doses at 0, 1 and 6 months Target cellular immune responses Started in 2004 Sites: North & South America, Australia (STEP); South Africa (Phambili) Endpoints: Prevention of HIV Infection Reduction of Viral Load: Delayed onset of AIDS, reduced transmission STEP Trial Efficacy Analyses: HVTN Full Group Meeting. Nov 7, 2007.

32. STEP Interim Analysis 2007 Interim Analysis: Modified intent-to-treat (MITT) population includes all participants who received at least one study injection Per protocol (PP) population includes all participants who received at least the first 2 study injections STEP Trial Efficacy Analyses: HVTN Full Group Meeting. Nov 7, 2007.

33. HIV Infection Associated with Pre-existing Ad5 Antibodies Incidence (%) of HIV Infection MITT Population (males) USA: Approximately half population Ad5+ East Africa: 95% population Ad5+ *Note: 18 is the limit of detection for the Ad5 assay. http://www.iavireport.org/Issues/Issue11-5/Step.asp

34. Immediate Implications for Future Studies: PAVE STEP Partnership for AIDS Vaccine Evaluation (PAVE) Steinbrook. 20057 NEJM 357:2653.

35. According to Anthony Fauci, the director of the NIAID, "To bebrutally honest with ourselves, we have to leave open the possibility. . . that we might not ever get a vaccine for HIV.People are afraid to say that because they think it would thenindicate that maybe we are giving up. We are not giving up.We are going to push this agenda as aggressively and energeticallyas we always have. But there is a possibility — a clearfinite possibility — that that's the case."

36. The longest journey begins with a single step, and then another, and then another…. Development of Clinical Vaccines Source: Stefan Kappe, Ph.D. Seattle Biomedical Research Institute. 2007.

37. Questions?