1. AVAC Global Advocacy for HIV Prevention HIV Vaccines: The basics May 2016

2. Presentation Overview What is a vaccine? How would an HIV vaccine work? Where are we in the search? What is needed now?

3. What is a vaccine? A substance that teaches the immune system how to protect itself against a virus or bacteria No effective HIV vaccine available today HIV vaccines cannot cause HIV No vaccine is 100% effective Most vaccines licensed in the US 70%-95% effective

4. Why the interest in HIV vaccines? Proven prevention options have slowed HIV’s spread – but thousands of people continue to get infected daily There is a need for a range of HIV prevention methods; there is no silver bullet Vaccines are one of the world’s most effective public health tools Cost-effective – single or several doses likely provide protection for years

5. How vaccines are crucial to ending HIV

6. Types of HIV vaccines Preventive vaccines – Designed for people who are not infected with HIV – If effective, would reduce risk of infection – May also reduce viral load set point after infection Therapeutic vaccines – Designed for people who are living with HIV – If effective, would use the body’s immune system to help control or clear HIV in the body

7. How do preventive vaccines work? By teaching the body to recognize and fight a pathogen Vaccine carries something that ‘looks and feels’ like the pathogen, but is not really the pathogen Body reacts by creating antibodies or killer cells and a memory response Upon exposure to the ‘real’ pathogen, antibodies and killer cells are waiting to respond and attack Note: This is a general definition, not specific to HIV vaccines

8. How might preventive HIV vaccine work? A preventive vaccine would teach the body to recognize and fight HIV, should it be exposed Vaccine would carry a component that ‘looks and feels’ like HIV, but is not HIV and cannot cause HIV infection Component might be a synthetic fragment of HIV known to generate an immune response Body would react by creating antibodies and/or killer cells and a memory response Upon possible exposure to HIV, antibodies and killer cells would be waiting to prevent and/or control infection

9. Immune responses (1) Humoral immunity Primary action of humoral arm is creating antibodies Antibodies are Y-shaped proteins developed in response to a pathogen to prevent infection Preventive HIV vaccines are meant to elicit two arms of the immune system – humoral and cellular

10. Immune responses (2) Cellular immunity Cytotoxic T lymphocytes and T- helper cells Cells recognize HIV- infected cells and kill them Preventive HIV vaccines are meant to elicit two arms of the immune system – humoral and cellular

11. Preventing vs. controlling infection Courtesy of HIV Vaccine Trials Network HIV PREVENT ESTABLISHED INFECTION? ***** Vaccine Administered A A. Lower Initial Peak of Viremia A B B. Lower Set Point B C. C. Delay Progression C HAART

12. How have many vaccines been made? Live attenuated vaccines (examples: measles, mumps, and rubella) Whole killed virus vaccines (example: influenza and rabies)

13. How are HIV vaccines made? Recombinant vaccines DNA vaccines Vector vaccines Subunit vaccines Do not contain HIV – only synthetic copies of fragments of HIV that will create an immune response but do not cause HIV infection

14. Developing an HIV vaccine is difficult Numerous modes of transmission HIV kills the very immune cells used in defending the body against HIV HIV makes many copies of itself and mutates, making itself unrecognizable to the immune system Mutation leads to different subtypes of the virus throughout the world

15. Vaccine research in history Virus or bacteriaYear cause discovered Year vaccine licensed Years elapsed Typhoid18841989105 Haemophilus Influenzae1889198192 Malaria1893None– Pertussis1906199589 Polio1908195547 Measles1953199542 Hepatitis B1965198116 Rotavirus1973199825 HPV1974200733 HIV1983None– Duration between discovery of microbiologic cause of selected infectious diseases and development of a vaccine Source: AIDS Vaccine Handbook, AVAC, 2005

16. HIV vaccine efficacy trial results www.avac.org/presentations YEARPRODUCT/ CLADE/ TRIAL NAME LOCATION#RESULT 2003AIDSVAX B/B VAX003 Canada, Netherlands, Puerto Rico, US 5,417No effect 2003AIDSVAX B/E VAX004 Thailand2,546No effect 2007MRK-Ad5 B Step Australia, Brazil, Canada, Dominican Republic, Haiti, Jamaica, Peru, Puerto Rico, US 3,000Immunizations halted early for futility; subsequent data analysis found potential for increased risk of HIV infection among Ad5- seropositive, uncircumcised men. 2007MRK-Ad5 B Phambili South Africa801Immunizations halted based on Step result. 2009ALVAC-HIV (vCP1521) and AIDSVAX B/E Thai Prime-Boost/RV 144 Thailand16,402Modest effect (31.2%) 2013DNA and Ad5 A/B/C HVTN 505 US2,500Immunizations halted early for futility; vaccine regimen did not prevent HIV infection nor reduce viral load among vaccine recipients who became infected with HIV; follow-up continues.

17. Pox-Protein strategies In 2009 clinical study in Thailand (‘RV144’) showed evidence that a vaccine can reduce HIV risk – Pox-protein, prime-boost regimen using canary pox (ALVAC) and manufactured HIV protein-GP120 – Moderately effective – 31% protection; not licensable – Follow up research identified possible explanations for vaccine- related protection and avenues for improvement New clinical trials launched by P5 in southern Africa in January 2015 – Modified regimen being tested in South Africa; potential efficacy trial that might lead to licensure could start in late 2016 – Other regimens being tested for proof-of-concept, improved responses More information about Rv144 and the follow-up at: http://hivresearch.org/research.php?ServiceID=13http://hivresearch.org/research.php?ServiceID=13

19. Antibody research 100s of broadly neutralizing antibodies (bNAbs) identified since 2009 – Work against majority of HIV strains – Target limited number of sites on HIV surface Direct transfer of antibodies—passive immunization—being tested as prevention, treatment, part of cure – Multiple bNAbs tested in early clinical trials: www.bnaber.orgwww.bnaber.org – Many show safety, tolerability, significant viral reduction among HIV- positive participants – First large-scale study of bNAb VRC01 initiated April 2016 for proof of concept, called AMP study: www.ampstudy.orgwww.ampstudy.org – Hope to increase potency of bNAbs, duration of responses – Possible alternate delivery mechanisms to infusion, e.g. series of subcutaneous shots – Possible future combination bNAb approaches

20. Antibody research

21. Future priorities P5 – large-scale trials following RV144 results in South Africa, possibly Thailand Janssen-sponsored product and clinical testing of ‘mosaic’ (cross-clade) based strategy Implications of AMP Study results for future of bNAb research and vaccine design Advancement of candidates/strategies in smaller-scale trial Pre-clinical discovery and advancement of individual bNAbs and combinations in clinical trials Continued identification of novel vectors, adjuvants and other strategies for improved candidates

22. Advocates’ checklist Monitor timelines of clinical trials, especially delays and the reasons for them Ensure diversity of approaches beyond pox-protein strategy, exploring novel directions for vaccine design Push for more stakeholder involvement, e.g., on trial design, standard of prevention/care, decision- making on moving candidates through the clinical pipeline

23. Key resources AVAC: www.avac.org/vaccineswww.avac.org/vaccines Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) o At Duke: www.chavi-id-duke.orgwww.chavi-id-duke.org o At Scripps: www.cavi-id.orgwww.cavi-id.org Collaboration for AIDS Vaccine Discovery: www.cavd.orgwww.cavd.org Global HIV Vaccine Enterprise: www.vaccineenterprise.orgwww.vaccineenterprise.org HIV Px R&D Database (PxRD): www.data.avac.orgwww.data.avac.org HIV Vaccines & Microbicides Resource Tracking Working Group: www.hivresourcetracking.orgwww.hivresourcetracking.org HIV Vaccine Trials Network (HVTN): www.hvtn.orgwww.hvtn.org International AIDS Vaccine Initiative (IAVI): www.iavi.orgwww.iavi.org Military HIV Research Program (MHRP): www.hivresearch.orgwww.hivresearch.org NIAID: www.niaid.nih.gov/topics/hivaids/research/vaccines/Pages/default.aspxwww.niaid.nih.gov/topics/hivaids/research/vaccines/Pages/default.aspx NIH Vaccine Research Center (VRC): www.vrc.nih.govwww.vrc.nih.gov Pox-Protein Public-Private Partnership (P5): www.hivresearch.org/media/pnc/9/media.749.pdfwww.hivresearch.org/media/pnc/9/media.749.pdf

24. Connect With Us Questions, comments and requests for materials should be sent to avac@avac.org avac@avac.org For the latest news and updates, sign up for our Advocates’ Network mailing list at www.avac.org/signup or follow us on Facebook at www.facebook.com/hivpxresearch and on Twitter at www.twitter.com/hivpxresearch www.avac.org/signup www.facebook.com/hivpxresearch www.twitter.com/hivpxresearch

25. The HIV CURE research training curriculum is a collaborative project aimed at making HIV cure research science accessible to the community and the HIV research field. The Basics of HIV Cure Research HIV Cure Research Training Curriculum HIV and Cure Basics Module Presented by Jessica Salzwedel: July 2016

26. Objectives Describe: ● Different ways to conceptualize an HIV cure ● Why it is difficult to cure HIV ● Rationale for exploring a cure ● Current cure strategies being researched

27. What is an HIV Cure? What Does HIV Cure Mean?

28. ● No need for on-going medication (ARV treatment) ● No symptoms ● No viral progression/immune damage ● No risk of transmission

29. The Language of “Cure” ● Sterilizing/Eradication- ●HIV is completely removed from every cell in the body ●Person is HIV-free (virus free) ● Functional/Remission- ●HIV is NOT completely gone from the body ●All requirements from previous slide met ●HIV has potential to resurface.

30. What is an HIV Cure? Why is it so Hard to Cure HIV?

31. Why is HIV so Hard to Cure? ● HIV enters a cell and integrates into the cell’s DNA ● Most cells recognize infection- causing cell death ● A few infected cells become “long-lived” memory cells or “resting memory” cells ● The collection of long-lived memory cells is called the Latent Reservoir

32. Why is HIV so Hard to Cure?

33. Why is it so Hard to Cure HIV: Establishing the Latent Reservoir Resting Memory CD4+ T cell Activated CD4+ T cell HIV Cell Death Latent Reservoir Naïve CD4+ T cell Cell Survival Adapted from D. Persaud

34. Why is it so Hard to Cure HIV: Establishing the Latent Reservoir Latent Reservoir Reactivated CD4+ T cell Adapted from D. Persaud

35. Where is the HIV Reservoir? ● Brain ● Lymph nodes ● Peripheral blood ● Gut ● Bone marrow ● Genital tract Adapted from A. Fauci

36. How Can the Reservoir be Measured? ● Reservoir size varies from person to person. Different factors, like genetics, when ART was initiated, and viral load during exposure- will influence reservoir size ● Obtaining samples from some tissues (e.g. spleen, brain) can be difficult because of location ● Currently, there is no standard test that accurately measures the reservoir

37. VOA Intact HIV DNA Scale=100/10 6 Ho et al, Cell, 2013 How Can the Reservoir be Measured?

38. Why is an HIV Cure Important? ● Disparity of access to care/HIV treatment globally ● Medication burden ● Medication side effects ● Expense

39. HIV Cure: Proof of Concept ● HIV+ Acute Myeloid Leukemia Patient ● Identification of HLA-identical, CCR5Δ32 homozygous bone marrow donor ● Chemo- and Radiotherapy Conditioning ● Allogeneic stem cell transplant ● 7 years later: remains cured

40. What are the Research Stages? Basic research Preclinical research Concept studies Lab studies Animal studies Phase I Smaller safety studies Phase IIb Even larger look at safety and efficacy Phase III Even larger look at safety and efficacy Demonstration Project Phase IV Marketing studies Product introduction Basic science Translational research Clinical (human) trials LicensePost- effectiveness Post licensure activities vary with each product/intervention Open-label extension (OLE)/Post-trial access Often a product /intervention does not progress in a linear fashion Real-world effectiveness Population scale-up Phase II Larger, longer look at safety and immunogenicity Safety and efficacy

41. What is an HIV Cure? Current Strategies

42. What is an HIV Cure? Kick and Kill or Shock and Kill

43. Kick and Kill The Economist, July 17, 2011

44. What is Kick and Kill ● A two step approach that: ●Stimulates virus production from latent cells ●Kills virus particles outside the cell and infected cells

45. What is kick and kill? LRA Cell death

46. Latency Reversing Agents ● A category of drugs that stimulate HIV-positive long-lived memory cells to begin producing virus ● HDAC Inhibitors- Histone Deacetylase Inhibitors have been one of the class of drugs being pursued in the field Notable LRAs TLR7- Agonist Bromodomain Inhibitors Ingenol

47. What is an HDAC Inhibitor?

48. Current Challenges of Kick and Kill ● Measurement of reservoir size/Getting it all ● New reservoirs ● Medication side effects

49. What is an HIV Cure? Immune Modulation

50. What are Immune Modulators? ● Category of research that harnesses the innate and adaptive immune system to better recognize and/or fight HIV ● All immune modulators would likely need to be used in combination with each other or other approaches Innate immunity- Innate immunity- No specific response; first line of defense like skin Adaptive immunity- Adaptive immunity- Targeted responses to specific pathogens- creating a whole army dedicated to attacking one enemy

51. How the Immune System Works HVTN “Soldiers” of the Immune System

52. Therapeutic Vaccines ● Rationale: Strengthen or create new and more effective immune responses to HIV in people living with HIV ● Generate long-lived adaptive immune responses to HIV that can continue to control the virus without medication

53. Broadly Neutralizing Antibodies ● Broadly Neutralizing Antibodies (bNAbs) are able to make many different mutations of HIV harmless by binding to 1 of 3 places on HIV ● bNAbs are currently being explored for use in HIV prevention, treatment and cure

54. Current Challenges of Immune Modulation ● Complex regulatory issues because each vaccine component will need to be evaluated separately and in combination ● Animal models do not always translate to humans ● Proving that strict immune control of HIV is clinically equivalent or better than ART

55. What is an HIV Cure? Gene Alteration/Modification

56. What is Gene Alteration/Modification? ● A process to edit the DNA inside immune cells in some way to make the cell less susceptible to HIV ● A process to edit the DNA inside immune cells to increase the killing potential of the cells ● A process to edit the DNA inside the virus to reduce it’s ability to impact people

57. What is Gene Alteration/Modification

58. Creating HIV Immunity ● HIV needs a receptor, CCR5, to be present on a cell surface in order to enter the cell and cause damage ● One focus of gene therapy in trials is to remove or block this receptor ● Zinc Fingers, molecular scissors used to edit genes, are one of the main tools being explored in clinical research Other Tools Used CRISPR/Cas9 Mega Tals TAL Effector Nucleases

59. Patient Mobilization Leukapheresis OR Bone Marrow Harvest Reinfusion Isolation of Stem Cells or T cells Virus-Mediated Transfer of Therapeutic Gene Creating HIV Immunity

60. Challenges to Gene Alteration/Modification ● Assuring only on-target modifications made ● Unknown how much modification is needed to produce benefit (therapeutic threshold) ● Development of potential immunity to the tools used to make gene alterations occur ● Current cost and scalability

61. What is an HIV Cure? Ethical Challenges

62. What Are the Social & Ethical Challenges ● Balancing resources ● Risk versus reward ● Participant selection ● Trial design ● Cost ● Scalability

63. What Does an HIV Cure Need to Be? ● Safe ● Effective ● Durable ● Affordable ● Accessible

64. Questions www.avac.org/CUREiculum For additional information visit:

65. Acknowledgements