1. AVAC Global Advocacy for HIV Prevention AIDS Vaccines: The basics May 2015

2. Presentation Overview What is a vaccine? How would an AIDS 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 AIDS vaccine available today AIDS vaccines cannot cause HIV No vaccine is 100% effective Most vaccines licensed in the US 70%-95% effective

4. Why the interest in AIDS 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 AIDS

6. Types of AIDS 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 cell 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 AIDS 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 AIDS 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. AIDS 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 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 for potential licensure; efficacy trial planned to start in 2017 – 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

18. Pox-Protein Public-Private Partnership (P5)

19. Antibody research 100s 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 – Early clinical trials show safety, tolerability, significant viral reduction among HIV-positive participants – Larger-scale studies planned for safety, dosing, efficacy – Hope to increase potency of bNAbs and duration of responses in humans

20. Future priorities Continued clinical research – P5 strategy – large-scale trials following RV 144 results in South Africa and Thailand – Clinical trials of vaccine using “mosaic” (cross-clade) immunogen by Janssen (division of J&J) – Advancement of candidates/strategies currently in smaller- scale trials, depending on results Further bNAb research—pre-clinical discovery and advancement of current bNAbs in clinical trials Continued identification of novel vectors, adjuvants and other strategies for improved candidates

21. What is needed now? 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 More stakeholder involvement, e.g., on trial design, standard of prevention/care, decision-making on moving candidates through the clinical pipeline

22. 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