1 / 54

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

millerbrian
Télécharger la présentation

BME 301

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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?

More Related