HIV/AIDS vaccine developmentSlide 2Slide 3Slide 4Slide 5How do vaccines work?Lecture mapSlide 8History of HIV/AIDSThe Human Immunodeficiency virus (HIV)Slide 11Clinical course of HIV/AIDSSlide 13Opportunistic infections of AIDSSlide 15Slide 16The social impact of HIVSlide 18Slide 19Slide 20Slide 21Slide 22Slide 23Slide 24Slide 25Slide 26Slide 27Slide 28Slide 29Slide 30Slide 31Slide 32Slide 33Slide 34Slide 35Slide 36Slide 37Ezekial Emanual, Chief of Bioethics NIHMarcia AngelPeter LurieAndrew McMichaelSarah Rowland-JonesPontiano KaleebuEdward Mbidde, Uganda Cancer Inst.Seth BerkleyDon FrancisUgandan Medical StudentLarry CoreySlide 49Slide 50HIV/AIDS vaccine developmentLecture 10Review of lecture 9How do vaccines work?Types ofVaccines:Review of lecture 9Are vaccines effective?-Edward Jenner’s experiment-Name big success example:How are vaccines tested?Review of lecture 9What are some challenges of vaccine development? -Developed countries-Developing countriesThe big three:, ,Review of lecture 9How do vaccines work?Types ofVaccines:- Non infectious: Inactivated, subunit & toxoid - Live-attenuated- Carrier- DNAVaccine effectiveness -From Edward Jenner to Smallpox erradication Vaccine Safety:-Clinical trials/VAERSChallenges of vaccine development-Developed vs. developing world-The big three: TB, Malaria, HIVAntigen presentationT-helper cellKiller T cellB cell: antibodies(neutralize & bridge) Antigen presentation•Non-infectious vaccines•Live attenuated virus•Carrier vaccines•DNA vaccines…By inducing adaptive immunity & memory!How do vaccines work?Lecture mapHIV-1 /AIDS- History of epidemic- The HIV-1 virus- Clinical course of infectionThe HIV vaccine- History of HIV vaccines- Challenges for vaccine development- Types of vaccines-VaxGen’s gp120-Sanofi Pasteur ALVAC: prime/boost strategy- Merk Ad5Discussion:- Specter articleLecture mapHIV-1 /AIDS- History of epidemic- The HIV-1 virus- Clinical course of infectionThe HIV vaccine- History of HIV vaccines- Challenges for vaccine development- Types of vaccines-VaxGen’s gp120-Sanofi Pasteur ALVAC: prime/boost strategy- Merk Ad5Discussion:- Specter articleHistory of HIV/AIDS NY & CA:Men with symptoms of immunodeficiencyPneumocystis carinii in young gay menCDC: IncreasedRx. of pentamidineSyndrome also affected: IV drug users, hemophiliacs, blood transfusion patients & sexual partners of infected peopleHIV isolated(Luc Montaigner/Robert Gallo) Licensed blood test for HIV antibody detection1981 1983 1985100 Cases1000 Cases 1989: 100,000 CasesTODAY= 1.3 million!The Human Immunodeficiency virus (HIV) SpikesViral components: -nucleic acid core (RNA) -protein capsid -envelope -GlycoproteinsThe Human Immunodeficiency virus (HIV)Clinical course of HIV/AIDSAcute: Infection of CD4+ cells (T-helper cells), 50% of memory cells lost! Loss of defense repertoire! High viral load Symptoms 2-8wks: fever, pharyngitis malaise, weight lossChronic: Decreased CD4+ cells cannot support rate of replication Innate and adaptive immune responses control expansion Integrated provirus acts as latent virus reservoir: - no viral synthesis - reservoir protected from antivirals and immune attack Mostly asymptomatic: fatigue & lymphoadenopathyAIDS: Progressive loss of CD4+ (T helper) cells = profound defect on cellular immunity increased viral load & opportunistic infections and cancerClinical course of HIV/AIDS(CD4+)(CD8+)Opportunistic infections of AIDSKSCandidaalbicansCryptococcusHerpes Zoster/SimplexMycobacteriumtuberculosisAdults and children estimated to be living with HIV 2007Total 2.1 millionEstimated adults and child deaths from AIDS during 2007The social impact of HIVhttp://images.google.com/imgres?imgurl=http://news.bbc.co.uk/nol/shared/spl/hi/picture_gallery/06/africa_zimbabwe0s_aids_orphans/img/1.jpg&imgrefurl=http://news.bbc.co.uk/2/shared/spl/hi/picture_gallery/06/africa_zimbabwe0s_aids_orphans/html/1.stm&h=300&w=416&sz=34&hl=en&start=1&um=1&tbnid=-ACSdzqWD7ReVM:&tbnh=90&tbnw=125&prev=/images%3Fq%3Daids%2Borphans%26svnum%3D10%26um%3D1%26hl%3Den%26rls%3DRNWE,RNWE:2006-04,RNWE:en%26sa%3DNhttp://www.pbs.org/wgbh/rxforsurvival/series/diseases/hiv_aids.htmlLecture mapHIV-1 /AIDS- History of epidemic- The HIV-1 virus- Clinical course of infectionThe HIV vaccine- History of HIV vaccines- Challenges for vaccine development- Types of vaccines- VaxGen’s gp120- Sanofi Pasteur ALVAC: prime/boost strategy- Merk Ad5Discussion:- Specter articleHistory of HIV vaccines•1984:–Robert Gallo discovers virus that causes HIV–Margaret Heckler, Secretary of HEW, predicts we will have vaccine within 2 years•1997:–President Clinton declares, “an HIV vaccine will be developed in a decade’s time.”•2003:–President Bush asks congress to appropriate $15B to combat the spread of HIV in Africa and the Caribbean•Today: Where is the vaccine?Challenges of HIV vaccine1. Many forms of HIV•HIV-1: Many subtypes: 9 clades•HIV-2 – Western Africa2. Each sub-type may require different vaccine3. HIV mutates rapidly: error-prone reverse transcriptase4. Surface glycoproteins not readily available for antibodies:•Coated in sugary molecules: N-linked glycans•Change shape after attachment step5. HIV infects, suppresses and destroys key cells of the immune systemDesign Goals for HIV Vaccine•Must produce both:–Antibody mediated immunity (B cells)•Immune system must see virus or viral debris–Cell mediated immunity (killer T cells)•HIV viral proteins must be presented to immune system on MHC receptorsTypes of Vaccine•Non-infectious vaccines–Stimulate B-cells- Killed virus- Subunit- Toxoid•Live attenuated vaccines–Stimulate both B-cells and killer T-cells•Carrier vaccines–Stimulate both B-cells and killer T-cells•DNA vaccines: –Stimulate both B-cells and T-cellsMethods tried for HIV vaccine development(From Robinson H.L., Clin. Pharmacol. Ther. 2007, 82: 686-693)? VaxGen subunit vaccineLive attenuated viral vaccine•Most likely to stimulate necessary immune response•Too dangerous!–Virus mutates constantly–If it undergoes mutation that restores its strength, would be devastating•Monkey experiments:–All vaccinated animals developed AIDS and died (although more slowly than those infected with unaltered virus)Non infectious vaccines- Whole virus: May not inactivate all virus Animal studies: Stimulates Ab which block a small # of HIV viruses Does not
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