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BME 301

BME 301. Lecture Eleven. 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

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BME 301

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  1. BME 301 Lecture Eleven

  2. 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 • Early Human Trials  DNA vaccines

  3. Follow Up: WA6

  4. IAVI = International AIDS Vaccine Initiative

  5. Today • Humans have not always treated each other humanely in the name of science • Ethics of Clinical Research • Famous Case Studies • Codes governing ethical conduct of research: • Nuremberg Code • Belmont Report • Case Studies Revisited • Functions of the IRB • Applications to HIV/AIDS Vaccine Testing

  6. Case I:Tuskegee Syphilis Study • Goal: • Examine natural history of untreated syphilis • Subjects: • 400 black men with syphilis • 200 normal controls

  7. Case I:Tuskegee Syphilis Study • Experiment: • 1932: • Standard Rx: injection of compounds containing heavy metals • Treatment reduced mortality but heavy metals thought to cause syphilis complications • Treatment withheld from infected men • 1942: • Death rate 2X as high in treatment group • 1940s: • Penicillin available • Men not informed of this • Study continued until 1972 when first publicized

  8. Case I:Tuskegee Syphilis Study • Consent Process: • No informed consent • Men misinformed that some study procedures (spinal taps) were free ‘extra treatment’

  9. Case II: Willowbrook Studies • Goal: • Understand natural history of infectious hepatitis • Subjects: • Children at Willowbrook State School • An institution for mentally defective persons • Experiment: • Subjects deliberately infected with hepatitis • Fed extracts of stool from infected persons • Injected with purified virus • Vast majority of children admitted acquired hepatitis

  10. Case II: Willowbrook Studies • Consent Process • Parents gave consent • Due to crowding, Willowbrook was at times closed to new patients • Hepatitis project had its own space • In some cases, only way to gain admission was to participate in the study

  11. Case III:Jewish Chronic Disease Hospital Study • Goal: Study rejection of cancer cells • Healthy patients reject cancer cell implants quickly • Cancer patients reject cancer cell implants much more slowly • Is this due to decreased immunity because of presence of cancer or is it manifestation of debility? • Subjects: • Patients hospitalized with various chronic debilitating diseases • Experiment: • Patients injected with live liver cancer cells

  12. Case III:Jewish Chronic Disease Hospital Study • Consent Process: • Negotiated orally, but not documented • Patients not told that cancer cells would be injected because this might scare them unnecessarily • Investigators justified this because they were reasonably certain the cancer cells would be rejected

  13. Case IV: San Antonio Contraceptive Study • Goal: • Which side effects of OCP are due to drug? • Which are by-products of every-day life? • Subjects: • 76 Impoverished Mexican-American women with previous multiple pregnancies • Patients had come to a public clinic seeking contraceptive assistance.

  14. Case IV: San Antonio Contraceptive Study • Experiment: • Randomized, double-blind, placebo controlled trial • Cross-over design • All women were instructed to use vaginal cream as contraceptive during the study • 11 women became pregnant during study, 10 while using placebo • Consent Process: • None of the women were told study involved placebo

  15. Nuremberg Code: 1949 • Voluntary consent of the human subject is absolutely essential • Experiment should yield fruitful results for good of society, obtainable in no other way • Experiments should avoid all unnecessary mental and physical suffering • No experiment should be performed if it is believed that death or disabling injury may occur

  16. Belmont Report: 1979 • From Dept. of Health, Education & Welfare • Statement of: • Basic ethical principles and guidelines to resolve ethical problems associated with conduct of research with human subjects • Three basic ethical principles: • Respect for persons • Beneficence • Justice

  17. Belmont Report: What is research? • Clinical Practice: • Interventions designed solely to enhance well-being of an individual patient that have a reasonable expectation of success • Research: • An activity to test a hypothesis • Permit conclusions to be drawn • Contribute to generalizable knowledge • Usually described in formal protocol that sets forth an objective and procedures to reach that objective

  18. Respect for Persons • All individuals should be treated as autonomous agents • Persons with diminished autonomy are entitled to special protection • Prisoners • Children • Demands that subjects enter into research: • Voluntarily • With enough information to make a decision

  19. Beneficence • Make efforts to secure patients’ well-being • Do No Harm • Maximize possible benefits • Minimize possible harms • One should not injure one person regardless of benefits that may come to others

  20. Justice • Who should receive benefits of research and who should bear its burdens? • Some ways to distribute burdens & benefits: • To each person an equal share • To each person according to individual need • To each person according to individual effort • 19th Century: • Poor ward patients were research subjects • Wealthy private patients received benefits of research • Selection of research subjects must be scrutinized: • Are some classes are being selected because of easy availability, compromised position or manipulability.

  21. Application of Belmont Report • Informed Consent • Assessment of Risks and Benefits • Selection of Subjects

  22. Informed Consent • Information: • Research procedure, purpose of study, risks and anticipated benefits, alternative procedures, statement offering subject opportunity to withdraw at any time • Comprehension: • Must present information in a way subject can understand • Must not be disorganized, too rapid, above subject’s educational level • Voluntariness: • Consent must be given voluntarily • Persons in positions of authority cannot urge course of action

  23. Assessment of Risks & Benefits • Research must be justified based on favorable risk/benefit assessment • Risk: • Possibility that harm may occur • Brutal or inhumane treatment of subjects is never morally justified • Risks should be reduced to those necessary to achieve research objective • Benefit: • Positive value related to health or welfare

  24. Selection of Subjects • Individual Justice: • Researchers must select subjects fairly • Must not select only potentially beneficial research to some subjects in their favor • Must not select only “undesirable” persons for risky research. • Social Justice: • Distinctions be drawn between classes that ought and ought not to participate in research based on ability of that class to bear burdens • Adults before children

  25. Case I:Tuskegee Syphilis Study • Respect for persons • Beneficence • Justice

  26. Case II: Willowbrook Studies • Respect for persons • Beneficence • Justice

  27. Case III:Jewish Chronic Disease Hospital Study • Respect for persons • Beneficence • Justice

  28. Case IV: San Antonio Contraceptive Study • Respect for persons • Beneficence • Justice

  29. Role of IRB • Work with investigators to be sure that the rights of subjects are protected • Educate research community and public about ethical conduct of research • Resource centers for information about Federal guidelines • Not a police force

  30. Role of IRB

  31. Role of IRB

  32. Discussion • Specter Article • Health data • Science • Town Meeting

  33. Health Data: Uganda • Stable political situation • African country most willing to openly confront HIV • Adult HIV infection rate: • Ten years ago: 20% • Today: 6% • Each of the past 10 yrs: Fewer infections than yr before • Life Expectancy: • Before HIV: 64 years • Today: 42 years • Annual Income: • $300 per person • Annual Health Expenditures: • $6 per person • Vaccination rate • 1995: 47% • 2002: 37%

  34. Dangers of Vaccine Trials • Most researchers feel first HIV vaccines will not be more than 40-50% effective • Will vaccinated individuals engage in higher risk behaviors? • Vaccine could cause as much harm as it prevents • Future vaccines cannot be tested against placebo, would be unethical

  35. Two Vaccines • Subunit vaccine based on HIV coat protein • Made by VaxGen • Donald Francis, president of VaxGen • Would be pleased if vaccine worked 1/3 of the time • Won’t distribute if works < 30% of the time • Nairobi Prostitute Vaccine • Developed at Oxford

  36. Inactivated Viral Vaccine for HIV • Viral subunit – envelope proteins • Animal trials • Conferred protection only against virus with exactly same envelope proteins • Early phase human trials • 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 • http://www.iavi.org/trials/searchresults.asp?list=vaccine&vm=vaxgen&ts=ongoing

  37. New Strategy for Vaccine Design • Nairobi Prostitutes • Initially no killer T cells against HIV • 2 yrs: 25% have killer T cells against HIV • 3-4 yrs: 50% have killer T cells against HIV • Killer T cells recognize fragments of 2 HIV related proteins presented on MHC receptors • When prostitutes stop having sex with HIV + people, immune systems lose power to fight HIV

  38. Nairobi Prostitute: Vaccine Strategy • Combination vaccine: • Naked DNA which codes for these proteins • Carrier based vaccine: • Modified vaccine Ankara carrying same DNA • Early evidence: • Combination generates bigger immune response than either component alone • Booster shots may be needed • http://www.iavi.org/trials/vaccinedetail.asp?i=11

  39. Town Hall Meeting http://www.lonelyplanet.com/mapimages/africa/uganda/map-thumb-uganda.gif

  40. Goal of Town Meeting YOU ARE THE RESIDENTS OF MASAKA AND YOU HAVE TO DISCUSS & DECIDE: • Should your community: • Participate in VaxGen Trial • No treatment for those who develop AIDS • Wait for Oxford Vaccine • No treatment for those who develop AIDS • Not participate in any trial unless treatment is provided for those who develop AIDS

  41. Cast of Characters • Don Francis, President of VaxGen • Andrew McMichael & Sarah Rowland-Jones • Developers of Nairobi prostitute vaccine • Marcia Angel, former editor of NEJM • Peter Lurie, Public Citizen’s Health Group • Pontiano Kaleebu, virologist in Uganda • Seth Berkley, IAVI • Larry Conroy, coordinates NIH vaccine trials • Ugandan Medical Student • Ezekial Emanual, Chief of Bioethics, NIH • Edward Mbidde, Uganda Cancer Inst.

  42. Ezekial Emanual, Chief of Bioethics NIH • Simple idea: justice requires treating everyone, everywhere in exactly the same way • Justice requires no such thing. It simply requires us to treat people fairly. • If rules of clinical trials require participants to receive the best care on earth, there would be no clinical trials.

  43. Marcia Angel • Medical ethics has no borders • What is morally right in America is morally right in Africa, too • International rules of medical expt. require: • Volunteers in vaccine trial receive best treatment available, NOT level of care in poor country • People are not guinea pigs. Research must hold human welfare above interest of society and science. If you don’t, you’re on a slippery slope where first humans are exploited for worthwhile purposes, then for not so worthwhile purposes.

  44. Peter Lurie • Fears scientists will use poor quality of care available in Africa to do what they want • You are not permitted to use subjects to collect data just because it is useful to you • That is exploitation and abuse • That is what Tuskegee was • Scientists will withhold treatments they know will work in the name of science • Will be greatest injustice in hx of medicine • Tests of AZT proved there was a two-tiered standard for health care in the world • One set of rules for rich people, and another for those who are poor

  45. Andrew McMichael • Abhors hype • Rarely discusses his vaccine work without saying it all might come to nothing • First vaccine to target specific viral subtype most prevalent in East Africa • Might require frequent booster shots

  46. Sarah Rowland-Jones • Infectious disease specialist • First vaccine to target specific viral subtype most prevalent in East Africa • Might require frequent booster shots

  47. Pontiano Kaleebu • We have asked Ugandans to be guinea pigs before. We have not come back to say, “Here is your reward.” • Worried that question of whether trials can be done fairly and ethically, will overshadow science • We will give people the best care we can afford. That is fair. • If I could distribute anti-retroviral drugs, I would be thrilled. But, I don’t see how and I don’t see when. And the debate is a bit patronizing. • This is not an issue of individual rights. It is a public health emergency. • I never though AIDS would be in my children's futures. I have come to realize that now. And it frightens me.

  48. Edward Mbidde, Uganda Cancer Inst. • Last 15 years have best Uganda has seen • We have leadership, support, we are united • If we need to go to work and we cannot afford a Mercedes Benz, should we refuse to ride a motorcycle? Or should we get there by the best route we have? • Principles matter to us as much to us as they do to Americans. But we have been dying for a long time, and you cannot respond to death with principles.

  49. Seth Berkley • You have to ask yourself what on earth the people on this planet are doing • In the end only a vaccine will matter • There is no incentive for companies to make vaccines • Society can’t get it together. These trials cost hundreds of millions of dollars. How do we pay for it?

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