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An AIDS vaccine: challenges and progress Christine White-Ziegler Kahn Institute Fellow,“Biotechnology and World Health” Global estimates for adults and children end 2004 People living with HIV New HIV infections in 2004 Deaths due to AIDS in 2004 http://www.who.int/hiv/facts/en/ 39.4 million [35.9 – 44.3 million] 4.9 million [4.3 – 6.4 million] 3.1 million [2.8 – 3.5 million] HIV infection and progression to AIDS HIV virus structure HIV life cycle HAART treatment extremely efficient (Highly active anti-retroviral therapy) Reverse transcriptase inhibitors (2) • Nucleoside analogs (AZT, 3TC) • Nonnucleoside inhibitors (nevirapine) Protease inhibitors (1) • Saquinavir, ritonavir, indinavir http://www.who.int/hiv/facts/en/ http://www.who.int/hiv/facts/en/ Biological challenges to vaccine development Different subtypes of HIV Difficulties in raising neutralizing antibodies Quick evolution of virus No animal model for testing Different subtypes of HIV HIV-1 – Accounts for most infections – At least 10 subtypes • Subytpe B- Americas, Japan, Australia, the Caribbean and Europe • Subtype E- Central African Republic, Thailand and other countries of southeast Asia • Subtypes A and D predominate in sub-Saharan Africa HIV-2 – Primarily in Angola, Mozambique, and other West African countries – At least 6 subtypes http://www.avert.org/hivtypes.htm Most antibodies to gp120 are not neutralizing Wyatt and Sodroski. Science 280, 1884 (1998). HIV mutants arise rapidly Treatment vs. vaccine for HIV infection Treatment Vaccine Works post-infection Prevents infection Ongoing cost for medication Minimal number of treatments Lifetime treatment Lifetime immunity Side effects Minimal side effects NoncomplianceDecreased efficacy, drug resistant mutants Efficacy, immune evasion, viral subtypes Resources for production and distribution Resources for production and distribution Goals of an ideal AIDS vaccine Activate protective responses-CTL, antibodies Works at mucosal epithelia Provide long term, sterilizing immunity Simple administration A good vaccine prevents HIV attachment and entry into cells Protective correlates: What are they? Immune response is activated, but does not clear infection – Antibody production: • Most antibodies not neutralizing • Need broad base of neutralizing antibodies • Immune evasion allows escape of neutralizing antibodies – Cytotoxic T lymphocytes • Critically important for early control of viremia • Immune evasion later in infection – Role of other aspects of the immune system? Immune system studies Vaccine strategy choice Animal testing Review: Food and Drug Administration, Institutional Review Board Phase I/II clinical trials Phase III clinical trials http://www.iavi.org/science/testing.asp Evaluating a vaccine: Animal models Animal model systems: Human HIV-1 in chimpanzees Simian immune deficiency virus (SIV) in maques SHIV recombinant virus in macques Problems: Cost/care of monkeys Fewer numbers of test subjects for vaccine Ethics/increased regulation for experimenting on non-human primates Testing alternate routes of vaccine delivery: mucosal vs. intravenous Evaluating a vaccine: Clinical trials Phase I trials: – tested in a small number of people (20-80) – healthy, low-risk, uninfected volunteer – determine safety, dosage and immunization schedule Phase II trials: – conducted in larger numbers (up to a few hundred) of people – healthy, uninfected volunteer – further establish safety, refine dosage and immunization schedules Phase III trials(1): – much larger-scale trial involving thousands of people – uninfected, high-risk individuals to determine the protective efficacy of the vaccine – requires the use of a placebo, an inactive substance given to some individuals to compare the effect of the vaccine. http://www.iavi.org/science/trials.asp Clinical trials for HIV vaccine 30 vaccine candidates in 60 phase I/II trials since 1987 Takes optimistically 6-9 years (phase I through phase III) Only two phase III trials completed, both using AIDSVAX Vaccine strategies Attenuated- live, but non-virulent, virus (e.g. influenza) Inactivated- killed, whole virus (e.g. polio) Subunit- protein(s) derived from virus (e.g. AIDSVAX) Viral vectors- canary pox:HIV hybrid (e.g ALVAC) http://chi.ucsf.edu/vaccines/vaccines AIDSVAX vaccine by VAXGEN AIDSVAX by VAXGEN Only vaccine in phase III clinical trials 61 sites worldwide Participants from high risk groups in: – United States/Canada/Netherlands • HIV-1 subtype B, 5400 participants (5100 gay men, 300 women) – Thailand • HIV-1 subtype E, 2500 participants (IDU) Immunization every 6 months for total of 7 shots Monitoring: – Neutralizing Ab production – Progression of disease – Effectiveness against HIV-1 http://www.vaxgen.com/products/AIDSV_clinical_trials.html Results for AIDSVAX: Dismal US/Puerto Rico/Canada/Netherlands: – Completed February 2003 – HIV-infection rate in volunteers who received AIDSVAX not significantly different than the HIV-infection rate in the placebo group – HIV infected individuals not control virus any better than placebo group – Possible vaccine protection in racial subgroups and women Thailand – Completed November 2004 – No significant efficacy in preventing infection Prime-Boost Vaccinations Aventis-Pasteur/Merck – Adenovirus: “DNA vaccine” – Canarypox: Recombinant live vaccine Aventis-Pasteur/Vaxgen – Canarypox: Recombinant live vaccine – Recombinant GP 120 protein Financial investment in AIDS vaccine research Global investment in AIDS vaccine research ~US$ 500 million Investment for AIDS vaccine more than all other vaccines combined 10-15 year time frame, US $100-200 million to bring vaccine to market HIV genome Challenges for vaccine development Biological Ethical Financial Social Political Gp120 binds to two receptors- CD4 and a chemokine receptor (CCR-5 or CXCR-4) Wyatt and Sodroski. Science 280, 1884 (1998). HAART treatment decreases virus levels The six blind men of Indostan and the HIV vaccine elephant (After the Indian fable by the American Poet John Godfrey Saxe, 1816-1887) The problem is CTL induction! Absolutely no. the problem is too many disincentives for industry! No, it is the quality of neutralizing antibodies! It is the genetic variability of HIV! Actually, the problem is the lack of good field sites! It is all of the above! The problem is lack of coordination! And these men of Indostan Disputed loud and long Each in his own opinion Exceeding stiff and strong, Though each was partly in the right And all were in the wrong! A vaccine that confers partial immunity? Decrease disease transmission Increase risk behaviors for transmission Delay progression to AIDS, not prevention AIDS vaccine development costs Primary markets are poorest countries in the world The role of CD8 T cells Opportunistic infections of AIDS Testing for HIV Detection of antibodies in the blood – Rapid immunoassay – ELISA – Western blotting Detection of virus in the blood – PCR CD4 T cell counts in peripheral blood Factors in vaccine development Animal model Testing in humans Different strains of HIV around world Immune evasion by virus Inducing: – – – – Mucosal immunity CD8 T cells Long term immunity Neutralizing antibodies Regional HIV/AIDS statistics and features, end of 2002 Epidemic started Adults & children Adults & children newly infected living with HIV/AIDS with HIV % of HIVMain mode(s) of Adult positive prevalence adults who transmission for those rate * are women living with HIV/AIDS ** 8.8% 58% Hetero 29.4 million 3.5 million North Africa & Middle East late ’70s early ’80s late ’80s 550 000 83 000 0.3% 55% Hetero, IDU South and South-East Asia late ’80s 6.0 million 700 000 0.6% 36% Hetero, IDU East Asia & Pacific late ’80s 1.2 million 270 000 0.1% 24% IDU, Hetero, MSM late ’70s early ’80s late ’70s early ’80s early ’90s 1.5 million 150 000 0.6% 30% MSM, IDU, Hetero 440 000 60 000 2.4% 50% Hetero, MSM 1.2 million 250 000 0.6% 27% IDU late ’70s early ’80s late ’70s early ’80s late ’70s early ’80s 570 000 30 000 0.3% 25% MSM, IDU 980 000 45 000 0.6% 20% MSM, IDU, Hetero 15 000 500 0.1% 7% 42 million 5 million 1.2% 50% Sub-Saharan Africa Latin America Caribbean Eastern Europe & Central Asia Western Europe North America Australia & New Zealand TOTAL MSM * The proportion of adults (15 to 49 years of age) living with HIV/AIDS in 2002, using 2002 population numbers ** Hetero: heterosexual transmission – IDU: transmission through injecting drug use – MSM: sexual transmission among men who have sex with men Global estimates for adults and children end 2002 People living with HIV/AIDS New HIV infections in 2002 42 million 5 million Deaths due to HIV/AIDS in 2002 3.1 million Estimated number of adults and children newly infected with HIV during 2002 North America 45 000 Caribbean 60 000 Latin America 150 000 Western Europe 30 000 North Africa & Middle East Eastern Europe & Central Asia 250 000East Asia & Pacific 270 000 South 83 000 Sub-Saharan Africa & South-East Asia 700 000 3.5 million Total: 5 million Australia & New Zealand 500 Estimated adult and child deaths from HIV/AIDS during 2002 North America 15 000 Caribbean 42 000 Latin America 60 000 Western Europe 8 000 Eastern Europe & Central Asia 25 000 North Africa & Middle East 37 000 Sub-Saharan Africa East Asia & Pacific 45 South & South-East Asia 000 440 000 2.4 million Total: 3.1 million Australia & New Zealand <100 Children (<15 years) estimated to be living with HIV/AIDS as of end 2002 North America 10 000 Caribbean 20 000 Latin America 45 000 Western Europe 5 000 Eastern Europe & Central Asia 16 000 North Africa & Middle East 40 000 sub-Saharan Africa East Asia & Pacific 4 South & South-East Asia 000 240 000 2.8 million Total: 3.2 million Australia & New Zealand < 200 Estimated deaths in children (<15 years) from HIV/AIDS during 2002 North America < 100 Caribbean 7 000 Latin America 5 000 Western Europe < 100 North Africa & Middle East 6 800 Eastern Europe & Central Asia < 100 East Asia & Pacific 2 South & South-East Asia sub-Saharan Africa 550 000 Total: 610 000 000 43 000 Australia & New Zealand < 100 About 14 000 new HIV infections a day in 2002 More than 95% are in developing countries 2000 are in children under 15 years of age About 12 000 are in persons aged 15 to 49 years, of whom: — almost 50% are women — about 50% are 15–24 year olds End-2002 global HIV/AIDS estimates Children (<15 years) Children living with HIV/AIDS New HIV infections in 2002 Deaths due to HIV/AIDS in 2002 3.2 million 800 000 610 000 End-1999 global HIV/AIDS estimates Children (<15 years) Children living with HIV/AIDS New HIV infections in 1999 Deaths due to HIV/AIDS in 1999 1.3 million 620 000 480 000 Cumulative number of deaths due to HIV/AIDS 3.8 million Spread of HIV over time in Asia, 1984 to 1999 2.0% – 5.0% 1.0% – 2.0% 0.5% – 1.0% 0.1% – 0.5% 0.0% – 0.1% trend data unavailable outside region Spread of HIV over time in sub-Saharan Africa, 1984 to 1999 Estimated percentage of adults (15–49) infected with HIV 20.0% – 36.0% 10.0% – 20.0% 5.0% – 10.0% 1.0% – 5.0% 0.0% – 1.0% trend data unavailable outside region Adults and children estimated to be living with HIV/AIDS as of end 1999 North America 900 000 Caribbean 360 000 Latin America 1.3 million Eastern Europe Western Europe & Central Asia 520 000 420 000 North Africa & Middle East 220 000 sub-Saharan Africa East Asia & Pacific 530 South & South-East Asia 000 5.6 million 24.5 million Total: 34.3 million Australia & New Zealand 15 000 End-1999 global HIV/AIDS estimates Children and adults People living with HIV/AIDS New HIV infections in 1999 Deaths due to HIV/AIDS in 1999 34.3 million 5.4 million 2.8 million Cumulative number of deaths due to HIV/AIDS 18.8 million About 15 000 new HIV infections a day in 1999 More than 95% are in developing countries 1 700 are in children under 15 years of age About 13 000 are in persons aged 15 to 49 years, of whom: — almost 50% are women — about 50% are 15–24 year olds Cumulative number of children estimated to have been orphaned by AIDS* at age 14 or younger at the end of 1999 North America 70 000 Caribbean 85 000 Latin America 110 000 Western Europe 9 000 Eastern Europe & Central Asia 500 North Africa & Middle East 15 000 sub-Saharan Africa East Asia & Pacific 5 South & South-East Asia 850 000 12.1 million Total: 13.2 million * Children who have lost their mother or both parents to AIDS before the age of 15 years 600 Australia & New Zealand < 500 Estimated annual number of new HIV infections by region, 1980 to 1999 4,000,000 Highly industrialized countries New infections 3,500,000 3,000,000 2,500,000 North Africa & Middle East Eastern Europe & Central asia Sub-Saharan Africa Latin America & the Caribbean Southern & Eastern Asia 2,000,000 1,500,000 1,000,000 500,000 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 Different modes of transmission Epidemic started Sub-Saharan Africa Adults & children Adults & children newly infected living with HIV/AIDS with HIV Adult prevalence rate * % HIVpositive women Main mode(s) of transmission for those living with HIV/AIDS ** 24.5 million 4 million 8.57% 55% Hetero North Africa & Middle East late ’70s– early ’80s late ’80s 220 000 20 000 0.12% 20% Hetero, IDU South and South-East Asia late ’80s 5.6 million 800 000 0.54% 35% Hetero, IDU East Asia & Pacific late ’80s 530 000 120 000 0.06% 13% IDU, Hetero, MSM 1.3 million 150 000 0.49% 25% MSM, IDU, Hetero 360 000 60 000 2.11% 35% Hetero, MSM 420 000 130 000 0.21% 25% IDU 520 000 30 000 0.23% 25% MSM, IDU 900 000 45 000 0.58% 20% MSM, IDU, Hetero 15 000 500 0.13% 10% MSM 34.3 million 5.4 million 1.07% 47% Latin America late ’70s– early ’80s late ’70s– Caribbean early ’80s Eastern Europe & Central Asia early ’90s Western Europe North America Australia & New Zealand TOTAL late ’70s– early ’80s late ’70s– early ’80s late ’70s– early ’80s * The proportion of adults (15 to 49 years of age) living with HIV/AIDS in 1999 ** Hetero: heterosexual transmission – IDU: transmission through injecting drug use – MSM: sexual transmission among men who have sex with men 10/02 Ongoing Trials Protocol Number Status as of 9/02 Prime Class Boost Producer Product Adjuvant Class Producer Product Adjuvant Name Name HIVNET 026 Immuniza-tions Canary-pox Aventis ALVAC Protein (n=160) completed vector (clade B Pasteur vCP205 subunit (clade hydrox- B Env) ide/thim- Env, Gag, Pro) VaxGen gp120 MN Alum-inum erosol HVTN 039 Immuniza-tions Canary-pox Aventis ALVAC (n=110) completed vector (clade B Pasteur vCP1452 Env, Gag, Pro, (high-dose) RT, Nef) HVTN 041 Immuniza-tions in Protein (clade B Glaxo-Smith- NefTat + (n=87) progress Nef-Tat fusion Kline gp120W61D AS02A protein + clade B Env subunit) HVTN 203 Immuniza-tions Canary-pox Aventis ALVAC Protein (n=330) completed vector Pasteur vCP1452 http://chi.ucsf.edu/vaccines VaxGen AIDSVAX B/B Alumi-num subunit (clade (gp120 MN, hydrox-ide gel B Env) gp120 GNE8) Coreceptor trophism Early in infection – Macrophage trophic strains – Bind CD4 and CCR5 Later in infection – T cell trophic strains – Bind CD4 and CXCR4 – Correlated to progression of disease to AIDS HIV slow and nonprogressors Non-progressors: – 32 bp deletion in CCR5 chemokine receptor gene – Efficient proliferation and perforin expression CD8 cells – -CD8 Noncytotoxic activity Slow progressors – SDF overexpression, binds to CXCR4, prevents HIV attachment – Unknown mechanism for other slow progressors • Group 1= seroconversion, low levels of virus, no progression • Group 2= no seroconversion, CD8 T cells to HIV HIV transcribed in infected, activated cells HIV not transcribed in quiescent cells – Latent infections – Reservoir in lymphoid tissues • Monocytes, T cells, dendritic cells – Brain as a reservoir • Microglia, astrocytes HIV transcribed in activated cells – Macrophages, T cells – Activated by Ag binding, cytokines HIV long terminal repeats (LTR) initiate HIV transcription NFkB, NF-AT= -production/activity upregulated in Ag activated T cells or Mf s HIV transcription Protease cleaves polyproteins HIV protease a target of HIV therapy Other HIV proteins Vpu and Nef – downregulation of CD4 – downregulation of MHC class I expression – Nef: increase in FasL Vpr – Transport of DNA to nucelus Vif – Unknown – Affects viral infectivity Models for loss of CD4 T cells Virus directly kills CD4 cells (a small component!) Apoptosis of CD4 cells – CTL, NK cells kill infected CD4 cells – Gp120 binding to cells – Increase FasL by Nef allows infected cells to kill uninfected cells Immune exhaustion Viral interference with replication/development of new T cells AIDS related diseases Wasting – Weight loss of 10% or more – Chronic diarrhea/fever for 30 days or more – Possible cause: TNF-a Malignancies – Kaposi sarcoma (HHV-8) AIDS Dementia Complex – Hypotheses: cytokines, Mf, HIV glycoproteins Reverse transcriptase (RT) RNA-dependent DNA polymerase – Found only in viruses – Target of HIV inhibitors • Nucleoside analogs (AZT, 3TC) terminate mRNA elongation • Nonnucleoside inhibitors (nevirapine) bind and inhibit function of RT Error prone – High mutation rate of virus – Drug resistance – Immune escape variants= • “Quasi -species” in a single individual • Escape presentation in MHC class I