Download L10 HIV Vaccine

BME 301
Lecture Ten
Summary of Lecture 9
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How do vaccines work?
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How are vaccines made?
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Non-infectious vaccines
Live, attenuated bacterial or viral vaccines
Carrier Vaccines
DNA Vaccines
How are vaccines tested?
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Stimulate immunity without causing disease
Lab/Animal testing
Phase I-III human testing
Post-licensure surveillance
Impact of vaccines
Follow Up: WA5
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What did you find?
Vaccine Safety Video
Today: Making a Vaccine for HIV/AIDS
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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
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HIV Infection
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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
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AIDS
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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
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1984:
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1997:
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President Clinton declares, “an HIV vaccine will be
developed in a decade’s time.”
2003:
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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
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Many forms of HIV
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HIV-1
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HIV-2 – Western Africa
Each sub-type may require different vaccine
Many routes of transmission
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Many subtypes
Sexual contact
Contact with contaminated blood
Must provide immunity for mucous
membranes & bloodstream
Challenge of HIV Vaccine
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HIV can be transmitted by:
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Cells infected with virus
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Cell-free virus
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Cell mediated immunity
Antibody mediated immunity
HIV infection results in:
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Recognized and eliminated by antibodies
Vaccine must generate:
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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
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Must produce both:
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Antibody mediated immunity (B cells)
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Immune system must see virus or viral debris
Cell mediated immunity (killer T cells)
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HIV viral proteins must be presented to immune
system on MHC receptors
Strategies for HIV Vaccination
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Live Attenuated Viral Vaccine
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Non-infectious vaccine
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Killed virus
Subunit
Stimulates only B cells
Carrier Vaccine
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Stimulates both B cells and killer T cells
Stimulates both B cells and killer T cells
DNA Vaccine
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Stimulates both B cells and killer T cells
Live Attenuated Viral Vaccine for HIV
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Most likely to stimulate necessary immune
response
Too dangerous!
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Virus mutates constantly
If it undergoes mutation that restores its
strength, would be devastating
Monkey experiments:
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All vaccinated animals developed AIDS and
died (although more slowly than those
infected with unaltered virus)
Inactivated Viral Vaccine for HIV
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Whole virus
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May not inactivate all virus
Animal studies:
Does not stimulate cell mediated immunity
 Stimulates Ab which block a small # of HIV viruses
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Inactivated Viral Vaccine for HIV
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Viral subunit – envelope proteins
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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
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Phase III Clinical trials:
2,500 volunteer IV drug users in Thailand
 5,000 Americans at risk for HIV-1
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Carrier Vaccine for HIV
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Need carrier that:
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New strategy: Prime/boost
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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:
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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
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Strategy:
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Successful in animal trials
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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
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http://www.iavi.org/trialsdb/basicsearchfor
m.asp
How do we test for
immunogenicity?
TB skin test
HIV test
TB Testing
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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
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Bump < 5 mm across is normal
Bump > 5 mm typically indicates exposure to TB
TB tests cannot determine:
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How long you have been infected
If it is active TB
Enzyme Linked Immuno-Sorbent Assay
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Blood is taken from
person that may
contain HIV
antibodies
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In lab, blood is added
to laboratory HIV
virus
ELISA Test
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HIV antibodies from
blood attach to HIV
antigens
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A chemical that attaches
only to antibody/antigen
complexes is added
ELISA Test
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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
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ELISA tests:
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A positive ELISA tests requires another
test, a Western Blot
Western Blots:
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Very sensitive but
Not very specific
Not as sensitive but
Are more specific
These two tests:
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Detect 99.8% of individuals making HIV Ab
HIV Results
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HIV positive test:
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HIV negative test:
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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
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Difficulties associated with HIV vaccine:
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Many forms of the virus
Virus mutates rapidly
Need to stimulate cell & Ab mediated immunity
HIV vaccines in trials:
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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
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Two reading assignments:
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http://www.michaelspecter.com/
ny/1999/1999_10_11_comm_
vaccine.html
http://www.michaelspecter.com/
pdf/aidsfact.pdf
WA6