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BME 301 Lecture Ten Summary of Lecture 9 How do vaccines work? How are vaccines made? Non-infectious vaccines Live, attenuated bacterial or viral vaccines Carrier Vaccines DNA Vaccines How are vaccines tested? Stimulate immunity without causing disease Lab/Animal testing Phase I-III human testing Post-licensure surveillance Impact of vaccines Follow Up: WA5 What did you find? Vaccine Safety Video Today: Making a Vaccine for HIV/AIDS Review of HIV/AIDS pathophysiology History of HIV/AIDS vaccines How do we design a new vaccine? Why is it so hard to make an HIV vaccine? How do we test to see if vaccine worked? What vaccines are in clinical trials? Ethics of research involving humans Clinical Course of HIV/AIDS HIV Infection Virus deposited on mucosal surface Acute infection (mono-like symptoms) Viral dissemination HIV-specific immune response Replication of virus Destruction of CD4+ lymphocytes Rate of progression is correlated with viral load Latent Period Clinical Course of HIV/AIDS AIDS Immunologic dysregulation Opportunistic infections and cancers Risk of infections is correlated with number of CD4+ lymphocytes Average patient with AIDS dies in 1-3 years Pathophysiology of HIV/AIDS http://health.howstuffworks.com/aids3.htm Pathophysiology of HIV/AIDS http://www.roche.com/pages/facets/4/hiv_life_cycle2.jpg History of HIV/AIDS Vaccines 1984: 1997: President Clinton declares, “an HIV vaccine will be developed in a decade’s time.” 2003: Robert Gallo discovers virus that causes HIV Margaret Heckler, Secretary of HEW, predicts we will have vaccine within 2 years President Bush asks congress to appropriate $15B to combat the spread of HIV in Africa and the Caribbean Today: Where is the vaccine? Challenge of HIV Vaccine Many forms of HIV HIV-1 HIV-2 – Western Africa Each sub-type may require different vaccine Many routes of transmission Many subtypes Sexual contact Contact with contaminated blood Must provide immunity for mucous membranes & bloodstream Challenge of HIV Vaccine HIV can be transmitted by: Cells infected with virus Cell-free virus Cell mediated immunity Antibody mediated immunity HIV infection results in: Recognized and eliminated by antibodies Vaccine must generate: Recognized and eliminated by killer T cells Production of large amounts of virus Even in presence of killer T cells and antibody Can any vaccine generate immune response that can contain or eliminate HIV? Design 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 receptors Strategies for HIV Vaccination Live Attenuated Viral Vaccine Non-infectious vaccine Killed virus Subunit Stimulates only B cells Carrier Vaccine Stimulates both B cells and killer T cells Stimulates both B cells and killer T cells DNA Vaccine Stimulates both B cells and killer T cells Live Attenuated Viral Vaccine for HIV 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) Inactivated Viral Vaccine for HIV Whole virus May not inactivate all virus Animal studies: Does not stimulate cell mediated immunity Stimulates Ab which block a small # of HIV viruses Inactivated Viral Vaccine for HIV Viral subunit – envelope proteins Not successful in animals – conferred protection only against virus with exactly same envelope proteins Early phase human trials Answer question: Are memory B cells enough to protect against HIV infection? Modest Ab response, effective against limited spectrum of HIV strains No CTL response Phase III Clinical trials: 2,500 volunteer IV drug users in Thailand 5,000 Americans at risk for HIV-1 Carrier Vaccine for HIV Need carrier that: New strategy: Prime/boost Does not cause serious disease, especially in immunosuppressed individuals People have not previously been exposed to If booster is needed, different carrier must be used Prime vaccine using carrier to stimulate killer T cells Boost vaccine using subunit vaccine to stimulate B cells Clinical trials: 400 subjects Canarypox carrier 70% of people made HIV antibodies 30% made killer T cells that could kill HIV-1 infected cells in lab DNA Vaccine for HIV Strategy: Successful in animal trials Inject large amounts of DNA which codes for viral protein Elicits immune response against that protein Generate CTL response Can we find a single protein that will elicit immune response against many HIV strains? Human Clinical Trials http://www.iavi.org/trialsdb/basicsearchfor m.asp How do we test for immunogenicity? TB skin test HIV test TB Testing Harmless antigens of TB bacteria are injected into top layer of skin Previous exposure to TB will cause a reaction to the antigens within 2 days Bump < 5 mm across is normal Bump > 5 mm typically indicates exposure to TB TB tests cannot determine: How long you have been infected If it is active TB Enzyme Linked Immuno-Sorbent Assay Blood is taken from person that may contain HIV antibodies In lab, blood is added to laboratory HIV virus ELISA Test HIV antibodies from blood attach to HIV antigens A chemical that attaches only to antibody/antigen complexes is added ELISA Test If the chemical turns yellow, the person is making antibodies against HIV http://images.google.co m/images?q=tbn:MIKn7 Ail5CoJ:http://www.lifesc ience.de/images_sheets/ elisa.jpg ELISA Results ELISA tests: A positive ELISA tests requires another test, a Western Blot Western Blots: Very sensitive but Not very specific Not as sensitive but Are more specific These two tests: Detect 99.8% of individuals making HIV Ab HIV Results HIV positive test: HIV negative test: Person is infected with the HIV virus, but may not have AIDS yet Person is not infected with HIV Person is infected with HIV, but not making detectable level of antibodies It may take 1-3 months (and up to 6 mo.) before the body makes enough antibodies to be detected by an ELISA http://www.nyscience.org/whataboutaids/protect/test/content.html What happens if you get an HIV vaccine, and you take an HIV test? Summary of Lecture 10 Difficulties associated with HIV vaccine: Many forms of the virus Virus mutates rapidly Need to stimulate cell & Ab mediated immunity HIV vaccines in trials: Animal trials Live, attenuated viral vaccines Human trials Subunit vaccines, only Ab response Human Trials Carrier vaccines, good Ab response, some CTL response Animal Trials DNA vaccines Assignments Due Next Time Two reading assignments: http://www.michaelspecter.com/ ny/1999/1999_10_11_comm_ vaccine.html http://www.michaelspecter.com/ pdf/aidsfact.pdf WA6