1. Katharine Kripke, Ph.D. Assistant Director, Vaccine Research Program Division of AIDS, NIAID, NIH, HHS

2. Our ultimate aim

3. Overview Transmission and infection How vaccines work Scientific challenges

4. Transmission Unprotected sexual contact vaginal sex anal sex oral sex (very low risk) Direct blood contact injection drug needles/equipment blood transfusions accidents in health care settings Mother to baby before birth during birth through breast milk

8. Genetic bottleneck during transmission of HIV

9. Acute HIV Infection 2–4 weeks post-exposure 80 to 90% of individuals develop influenza- or mononucleosis-like illness Duration of symptoms: average 28 days at least a week

11. HIIV Antibody Response in Acute Infection Onset of symptoms: 5-30 days after exposure to HIV Ab response (ELISA): 17-90 days after onset of symptoms 2 weeks to 3 months when HIV antibody test not diagnostic ?need HIV RNA PCR to diagnose acute infection in this period

12. Overview Transmission and infection How vaccines work Scientific challenges

13. Immune system basics The immune system can specifically recognize unique molecules in bacteria and viruses (called antigens) The immune system has memory T cells Recognize chopped up antigens presented by infected cells and other immune cells Tell other immune cells what to do, OR Kill cells that are infected with bacteria or viruses B cells Secrete antibodies, which stick to intact antigens outside of cells

14. This is how we traditionally understand vaccines to work; however, we are not sure that the same mechanisms will eventually be effective for HIV vaccines.This is how we traditionally understand vaccines to work; however, we are not sure that the same mechanisms will eventually be effective for HIV vaccines.

15. What does the immune system see?

16. Vaccines After vaccination, if exposed to the actual virus or bacterium, the immune system is ready to attack and can often fight off the infection even before disease occurs, or lessen symptoms

17. Vaccine research involves several different stages, from basic research and discovery all the way through clinical trials.Vaccine research involves several different stages, from basic research and discovery all the way through clinical trials.

18. Information cycleIterative process forward

19. How many molecules does it take to develop an approved drug? 10,000 molecules screened for activity in lab 250 evaluated in full preclinical tests 5 enter phase I clinical testing 1 approved drug 30% fail for lack of efficacy 40% fail for safety issues 10% fail for other reasons 20% approved Pharmaceutical Manufacturers of America, 2006 In fact, let’s look at some information on how hard it is to get an approved drug. Remember the whole process—from idea to bench research to animal studies to human studies. Not only does it take a long time to get through the whole process, but it also takes a lot of failures.In fact, let’s look at some information on how hard it is to get an approved drug. Remember the whole process—from idea to bench research to animal studies to human studies. Not only does it take a long time to get through the whole process, but it also takes a lot of failures.

20. Overview Transmission and infection How vaccines work Scientific challenges

21. HIV is different HIV hides inside some long-lived cells where it can’t be reached by drugs or the immune system HIV attacks the immune system itself HIV is a shape-shifter HIV hides its keys Vaccine-induced immune responses have to be unusually quick and smart to combat HIV

22. An example of vaccine strategies – in this case, possible strategies for HIV vaccines (Walt may have alternative, more comprehensive slide) An example of vaccine strategies – in this case, possible strategies for HIV vaccines (Walt may have alternative, more comprehensive slide)

23. Why do we think an HIV vaccine may be possible? Neutralizing antibodies can prevent infection by SIV in monkeys Some people’s immune systems can naturally control the virus for years, sometimes decades Vaccines can protect monkeys from SIV infection or significantly delay disease A vaccine has provided modest protection from HIV infection in humans We now have a compelling reason to believe that an HIV vaccine is possible!We now have a compelling reason to believe that an HIV vaccine is possible!

24. Key milestones: HIV vaccine research Here is a simplified timeline of HIV vaccine research milestones – you saw this at last year’s meeting; this time, we have some good news to highlight. Here is a simplified timeline of HIV vaccine research milestones – you saw this at last year’s meeting; this time, we have some good news to highlight.

25. All participants receive the best risk reduction education available It is important to understand that preventive HIV Vaccine trials are randomized. This means participants are randomly assigned to different groups, so that some people receive the experimental vaccine and others receive a placebo. The trials are also double blinded, which means that none of the participants will know if they are getting the vaccine or the placebo, and none of the researchers know either. This information does not become available until the end of the trial, when all of the participants have completed the study. Since we do not know if the vaccine works to prevent infection, and since some people will get placebo, we make certain that ALL participants receive counseling and information about ways to reduce their risk for becoming infected with HIV so that they can stay healthy. It is important to understand that preventive HIV Vaccine trials are randomized. This means participants are randomly assigned to different groups, so that some people receive the experimental vaccine and others receive a placebo. The trials are also double blinded, which means that none of the participants will know if they are getting the vaccine or the placebo, and none of the researchers know either. This information does not become available until the end of the trial, when all of the participants have completed the study. Since we do not know if the vaccine works to prevent infection, and since some people will get placebo, we make certain that ALL participants receive counseling and information about ways to reduce their risk for becoming infected with HIV so that they can stay healthy.

26. Thai trial (RV144) Canarypox prime + envelope protein boost [ALVAC-HIV (vCP1521) + gp120 B/E (AIDSVAX® B/E)] Phase III trial; 16,000+ volunteers 125 infections: Incidence: 74 placebo – 0.28% placebo 51 vaccine – 0.19% vaccine VE = 31.2%; p = .0385; CI = 1.1 - 52.1 No effect on setpoint viral load No safety issues apparent

27. What do the Thai results mean? NOT—a product that’s ready to be rolled out now NOT—ho humWhat do the Thai results mean? NOT—a product that’s ready to be rolled out now NOT—ho hum

28. Thai trial follow-up Immune correlates of protection Follow-up trials in Thailand Late boosting of a subset of RV144 participants Detailed studies of immune responses to RV144 regimen Next IIB study in Thailand among MSM? Reproducing RV144 results in monkey models Additional human studies in the works Evaluate impact of protein boosts Determine if RV144 results can be extended to other populations

29. HVTN 505 Exploratory Phase II study Vaccine regimen designed by NIAID VRC Will the vaccine significantly reduce VL in individuals who become infected with HIV? Participants: 1350 U.S. men or trans-women who have sex with men Circumcised No measurable Ad5 antibodies Other clinical studies, such as HVTN 505, will provide more pieces of the puzzle. The regimen under study in HVTN 505 contains envelope (Env), which is the viral protein present on the outer surface of HIV and may be associated with greater immune responses compared to regimens without it. Update: 505 is enrolling, HVTN and NHVREI provide extensive educational support Town hall meetings Background print materials Web site (hopetakesaction.org) Informed consent video (still in progress) Highly trained recruitment staff Supplemental funds to NHVREI partners so that they can support HVTUs in 505-related educational activities Other clinical studies, such as HVTN 505, will provide more pieces of the puzzle. The regimen under study in HVTN 505 contains envelope (Env), which is the viral protein present on the outer surface of HIV and may be associated with greater immune responses compared to regimens without it. Update: 505 is enrolling, HVTN and NHVREI provide extensive educational support Town hall meetings Background print materials Web site (hopetakesaction.org) Informed consent video (still in progress) Highly trained recruitment staff Supplemental funds to NHVREI partners so that they can support HVTUs in 505-related educational activities

31. Current scientific questions What types of immune responses prevent HIV infection or control the virus after infection, and how can we stimulate them? How do different vaccine approaches influence the type and magnitude of immune responses? How can HIV vaccines outsmart HIV genetic variation (shape-shifting)? What are the early events in HIV infection? How can we improve the science of HIV vaccine research and development (e.g., animal models, clinical trials, etc.)? In the wake of the Thai trial, we are left with a number of critical questions to address in HIV vaccine research.In the wake of the Thai trial, we are left with a number of critical questions to address in HIV vaccine research.

32. Usually clinical trials are most of what you hear about in the news about HIV vaccine research, so I want to remind you that large clinical trials are just the tip of the iceberg. In addition to these large clinical trials, there is lots of exciting basic and prelinical research going on, and many vaccine concepts are being developed. Much of this will be discussed at the conference.Usually clinical trials are most of what you hear about in the news about HIV vaccine research, so I want to remind you that large clinical trials are just the tip of the iceberg. In addition to these large clinical trials, there is lots of exciting basic and prelinical research going on, and many vaccine concepts are being developed. Much of this will be discussed at the conference.

33. Developing a vaccine—a long road It will still be a long road, which will include more laboratory studies, animal studies, and clinical studies that address key questions but don’t necessarily advance a particular promising product.It will still be a long road, which will include more laboratory studies, animal studies, and clinical studies that address key questions but don’t necessarily advance a particular promising product.

34. HIV prevention research:guiding principles Multiple strategies needed to assemble a well-rounded “prevention toolkit.” No one prevention strategy will be 100% effective, appropriate to or accepted by everyone. Multiple prevention strategies must be evaluated in different populations, domestically and globally, to determine the best combinations for a given population.

35. Future considerations for prevention technologies Is it licensed? What is the level of efficacy? Is it only proven for certain modes of transmission? In what populations has it been tested? How much does it cost? Is it acceptable? Do people use it as indicated? Can it be used in combination with other prevention approaches? Is use associated with decreased use of other prevention approaches?

37. How might new prevention options work together? Combining microbicides or PreP with vaccines may deliver even better protection – the window for placebo controlled trials my be closing Provides protection during the immunization period Reduces infectious challenge. Boosts local immunity (virus/antigen) Broadening localized immunity through protected exposure to prevalent virus. Converting high risk challenge to low risk challenge (RV144) Vaccine induced immunity may cover intermittent compliance, break through virus and prevent resistance evolution

38. What you say matters Journalists are a primary source of scientific information for the general public. Whether you choose to present something as a scandal or controversy, or to educate your audience and be fair and balanced, will make a difference for how fast the research proceeds.Journalists are a primary source of scientific information for the general public. Whether you choose to present something as a scandal or controversy, or to educate your audience and be fair and balanced, will make a difference for how fast the research proceeds.

39. Thank You BeTheGeneration.NIH.gov

40. BACKUP SLIDES

41. Vaccine-induced seropositivity HIV vaccines are designed to provoke immune responses – this includes antibody production. Standard tests for HIV detect antibodies, not virus. Study participants who receive HIV vaccines will often test positive (seropositive) on these standard tests but it doesn’t mean they are HIV-infected. Frequency varies by immunogen—can be >80% Durability: Potentially >10 years We refer to this as Vaccine-Induced SeroPositivity, or VISP. VISP can happen with any vaccine that causes the body to produce antibodies to fight against an infection, and where people are screened with tests that measure the presence of antibodies. These concerns exist for any researchers conducting HIV vaccine trials. VISP can happen with any vaccine that causes the body to produce antibodies to fight against an infection, and where people are screened with tests that measure the presence of antibodies. These concerns exist for any researchers conducting HIV vaccine trials.

42. Isn’t VISP just a “false positive?” NO. If an HIV test is designed to look for antibodies to HIV, then the test has done exactly what it was supposed to, and got an accurate result. What may be false is the interpretation of the results We want to get away from saying “false positive” so that we do not undermine public confidence in HIV testing.

43. Issues related to VISP Several factors may affect study participants who have VISP: Personal issues – feelings of anxiety, stress, frustration Social issues – stigma or discrimination if you are mistakenly thought to be HIV-infected Medical issues – what do you need to talk about with your doctor? Do providers believe their patients when they decline testing because of being in a study? Public Health policy – what is the HIV testing policy in your community/country? Can people opt out? Research – what if someone wants to join another trial (of any kind) in the future? What are the implications for that research?