BIOE 301 Lecture Ten Summary of Lecture 9

BIOE 301 Lecture Ten

Summary of Lecture 9 n How do vaccines work? n n How are vaccines made? n n n Non-infectious vaccines Live, attenuated bacterial or viral vaccines Carrier Vaccines DNA Vaccines How are vaccines tested? n n Stimulate immunity without causing disease Lab/Animal testing Phase I-III human testing Post-licensure surveillance Impact of vaccines

Pop Quiz

Follow Up: HW 7 n n What did you find? Vaccine Safety Video

Today: Making a Vaccine for HIV/AIDS n n n n 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 n HIV Infection n n n n Virus deposited on mucosal surface Acute infection (mono-like symptoms) Viral dissemination HIV-specific immune response Replication of virus Destruction of CD 4+ lymphocytes Rate of progression is correlated with viral load Latent Period

Clinical Course of HIV/AIDS n n n n Immunologic dysregulation Opportunistic infections and cancers Risk of infections is correlated with number of CD 4+ lymphocytes Average patient with AIDS dies in 1 -3 years

Pathophysiology of HIV/AIDS http: //health. howstuffworks. com/aids 3. htm

Pathophysiology of HIV/AIDS http: //www. roche. com/pages/facets/4/hiv_life_cycle 2. jpg

History of HIV/AIDS Vaccines n 1984: n n n 1997: n n President Clinton declares, “an HIV vaccine will be developed in a decade’s time. ” 2003: n n 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 $15 B to combat the spread of HIV in Africa and the Caribbean Today: Where is the vaccine?

Challenge of HIV Vaccine n Many forms of HIV n HIV-1 n n HIV-2 – Western Africa Each sub-type may require different vaccine Many routes of transmission n Many subtypes Sexual contact Contact with contaminated blood Must provide immunity for mucous membranes & bloodstream

Challenge of HIV Vaccine n HIV can be transmitted by: n Cells infected with virus n n Cell-free virus n n n Cell mediated immunity Antibody mediated immunity HIV infection results in: n n n Recognized and eliminated by antibodies Vaccine must generate: n n 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 n Must produce both: n Antibody mediated immunity (B cells) n n Immune system must see virus or viral debris Cell mediated immunity (killer T cells) n HIV viral proteins must be presented to immune system on MHC receptors

Strategies for HIV Vaccination n Live Attenuated Viral Vaccine n n Non-infectious vaccine n n Killed virus Subunit Stimulates only B cells Carrier Vaccine n n Stimulates both B cells and killer T cells DNA Vaccine n Stimulates both B cells and killer T cells

Live Attenuated Viral Vaccine for HIV n n Most likely to stimulate necessary immune response Too dangerous! n n n Virus mutates constantly If it undergoes mutation that restores its strength, would be devastating Monkey experiments: n All vaccinated animals developed AIDS and died (although more slowly than those infected with unaltered virus)

Inactivated Viral Vaccine for HIV n Whole virus n n May not inactivate all virus Animal studies: Does not stimulate cell mediated immunity n Stimulates Ab which block a small # of HIV viruses n

Inactivated Viral Vaccine for HIV n Viral subunit – envelope proteins n n 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? n Modest Ab response, effective against limited spectrum of HIV strains n No CTL response n n Phase III Clinical trials: 2, 500 volunteer IV drug users in Thailand n 5, 000 Americans at risk for HIV-1 n

Carrier Vaccine for HIV n Need carrier that: n n New strategy: Prime/boost n n n 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: n n 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 n Strategy: n n n Successful in animal trials n n 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 n n http: //www. iavi. org/trialsdb/basicsearchfo rm. asp

Dangers of Vaccine Trials n Most researchers feel first HIV vaccines will not be more than 40 -50% effective n n n 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

Discussion n Specter Article Health data n Science n Town Meeting n

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

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

Vax. Gen Subunit Vaccine for HIV n Viral subunit – envelope proteins n Animal trials n n Conferred protection only against virus with exactly same envelope proteins Early phase human trials Modest Ab response, effective against limited spectrum of HIV strains n No CTL response n n Phase III Clinical trials: n 2, 500 volunteer IV drug users in Thailand

New Strategy for Vaccine Design n n http: //www. pbs. org/wgbh/rxforsurvival/se ries/diseases/hiv_aids. html Nairobi Prostitutes n n n 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

Nairobi Prostitute: Vaccine Strategy n Combination vaccine: n n Naked DNA which codes for these proteins Carrier based vaccine: n n Early evidence: n n Modified vaccine Ankara carrying same DNA Combination generates bigger immune response than either component alone Booster shots may be needed

Town Hall Meeting http: //www. lonelyplanet. com/mapimages/africa/u ganda/map-thumbuganda. gif

Cast of Characters n n Don Francis, President of Vax. Gen Andrew Mc. Michael & Sarah Rowland-Jones n n n n n 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.

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

Summary of Lecture 10 n Difficulties associated with HIV vaccine: n n Many forms of the virus Virus mutates rapidly Need to stimulate cell & Ab mediated immunity HIV vaccines in trials: n n 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 n HW 8

Ezekial Emanual, Chief of Bioethics NIH n n n 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.

Marcia Angel n n n Medical ethics has no borders What is morally right in America is morally right in Africa, too International rules of medical expt. require: n n 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.

Peter Lurie n n 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 n n n Scientists will withhold treatments they know will work in the name of science n n That is exploitation and abuse That is what Tuskegee was Will be greatest injustice in hx of medicine Tests of AZT proved there was a two-tiered standard for health care in the world n One set of rules for rich people, and another for those who are poor

Andrew Mc. Michael n n 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

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

Pontiano Kaleebu n n 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 n n 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.

Edward Mbidde, Uganda Cancer Inst. n Last 15 years have best Uganda has seen n 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.

Seth Berkley n n 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?

Don Francis n n Would be pleased if vaccine worked 1/3 of the time If his vaccine is introduced and proven effective, no other vaccines can be tested against placebo

Ugandan Medical Student n Would it be fair for village people to enter trial if those who became infected did not get anti-retroviral drugs? n n Indicated missing medical supplies – aspirin, basic antibiotics We do not get the care you get. We never will. But I would line up tomorrow to test anything that might help us in any way. And I am sure the rest of the village would too.

Larry Corey n n n Let’s be realistic for 5 minutes To create a vaccine that works 40% of the time, costs $1, 000, and requires that you go to the lab to get a blood test every 6 weeks is crap We need a 90% biologically active product with no side-effects that costs at most $150 -$200. We are asking the Third World to take risks that we have never taken ourselves Every other time that we have gone in with a vaccine, we have been able to say, “It works on our people. ” Now – I have to say I have no idea if I have schlock or I have gold. But you need it and we need it, so we will have to test it on you.