an aids vaccine: challenges and progress christine white-ziegler kahn institute...
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An AIDS vaccine: challenges and progress
Christine White-Ziegler
Kahn Institute Fellow,“Biotechnology and World Health”
Global estimates forGlobal estimates for adults and childrenadults and childrenend 2004end 2004
People living with HIV
New HIV infections in 2004
Deaths due to AIDS in 2004
39.4 million [35.9 – 44.3 million]
4.9 million [4.3 – 6.4 million]
3.1 million [2.8 – 3.5 million]
http://www.who.int/hiv/facts/en/
HIV infection and progression to AIDS
HIV virus structure
HIV life cycle
HAART treatment extremely efficient(Highly active anti-retroviral therapy)
Reverse transcriptase inhibitors (2)• Nucleoside analogs (AZT, 3TC)
• Nonnucleoside inhibitors (nevirapine)
Protease inhibitors (1)• Saquinavir, ritonavir, indinavir
http://www.who.int/hiv/facts/en/
http://www.who.int/hiv/facts/en/
Biological challenges to vaccine development
Different subtypes of HIV
Difficulties in raising neutralizing
antibodies
Quick evolution of virus
No animal model for testing
Different subtypes of HIV
HIV-1
– Accounts for most infections– At least 10 subtypes
• Subytpe B- Americas, Japan, Australia, the Caribbean and Europe• Subtype E- Central African Republic, Thailand and other countries of southeast Asia• Subtypes A and D predominate in sub-Saharan Africa
HIV-2
– Primarily in Angola, Mozambique, and other West African countries
– At least 6 subtypes
http://www.avert.org/hivtypes.htm
Most antibodies to gp120 are not neutralizing
Wyatt and Sodroski. Science 280, 1884 (1998).
HIV mutants arise rapidly
Treatment vs. vaccine for HIV infection
Treatment
Works post-infection
Ongoing cost for medication
Lifetime treatment
Side effects
NoncomplianceDecreased efficacy, drug
resistant mutants
Resources for production and distribution
Vaccine
Prevents infection
Minimal number of treatments
Lifetime immunity
Minimal side effects
Efficacy, immune evasion, viral subtypes
Resources for production and distribution
Goals of an ideal AIDS vaccine
Activate protective responses-CTL, antibodies
Works at mucosal epithelia
Provide long term, sterilizing immunity
Simple administration
A good vaccine prevents HIV attachment and entry into cells
Protective correlates: What are they?
Immune response is activated, but does not clear infection
– Antibody production:• Most antibodies not neutralizing• Need broad base of neutralizing antibodies• Immune evasion allows escape of neutralizing antibodies
– Cytotoxic T lymphocytes• Critically important for early control of viremia• Immune evasion later in infection
– Role of other aspects of the immune system?
http://www.iavi.org/science/testing.asp
Animal testing
Phase I/II clinical trials
Phase III clinical trials
Immune system studies
Vaccine strategy choice
Review: Food and Drug Administration, Institutional Review Board
Evaluating a vaccine: Animal models
Animal model systems:
Human HIV-1 in chimpanzees
Simian immune deficiency virus (SIV) in maques
SHIV recombinant virus in macques
Problems:
Cost/care of monkeys
Fewer numbers of test subjects for vaccine
Ethics/increased regulation for experimenting on non-human primates
Testing alternate routes of vaccine delivery: mucosal vs. intravenous
Phase I trials: – tested in a small number of people (20-80) – healthy, low-risk, uninfected volunteer– determine safety, dosage and immunization schedule
Phase II trials:– conducted in larger numbers (up to a few hundred) of people– healthy, uninfected volunteer– further establish safety, refine dosage and immunization schedules
Phase III trials(1):– much larger-scale trial involving thousands of people– uninfected, high-risk individuals to determine the protective efficacy of the vaccine– requires the use of a placebo, an inactive substance given to some individuals to compare the effect
of the vaccine.
Evaluating a vaccine: Clinical trials
http://www.iavi.org/science/trials.asp
Clinical trials for HIV vaccine
30 vaccine candidates in 60 phase I/II trials since 1987
Takes optimistically 6-9 years (phase I through phase III)
Only two phase III trials completed, both using AIDSVAX
Vaccine strategies
Attenuated- live, but non-virulent, virus (e.g. influenza)
Inactivated- killed, whole virus (e.g. polio)
Subunit- protein(s) derived from virus (e.g. AIDSVAX)
Viral vectors- canary pox:HIV hybrid (e.g ALVAC)
http://chi.ucsf.edu/vaccines/vaccines
AIDSVAX vaccine by VAXGEN
AIDSVAX by VAXGEN
Only vaccine in phase III clinical trials
61 sites worldwide
Participants from high risk groups in:
– United States/Canada/Netherlands • HIV-1 subtype B, 5400 participants (5100 gay men, 300 women)
– Thailand • HIV-1 subtype E, 2500 participants (IDU)
Immunization every 6 months for total of 7 shots
Monitoring:– Neutralizing Ab production– Progression of disease– Effectiveness against HIV-1
http://www.vaxgen.com/products/AIDSV_clinical_trials.html
Results for AIDSVAX: Dismal
US/Puerto Rico/Canada/Netherlands:
– Completed February 2003– HIV-infection rate in volunteers who received AIDSVAX not
significantly different than the HIV-infection rate in the placebo group– HIV infected individuals not control virus any better than placebo group– Possible vaccine protection in racial subgroups and women
Thailand
– Completed November 2004– No significant efficacy in preventing infection
Prime-Boost Vaccinations
Aventis-Pasteur/Merck
– Adenovirus: “DNA vaccine”
– Canarypox: Recombinant live vaccine
Aventis-Pasteur/Vaxgen
– Canarypox: Recombinant live vaccine
– Recombinant GP 120 protein
Financial investment in AIDS vaccine research
Global investment in AIDS vaccine research ~US$ 500 million
Investment for AIDS vaccine more than all other vaccines
combined
10-15 year time frame, US $100-200 million to bring vaccine to
market
HIV genome
Challenges for vaccine development
Biological
Ethical
Financial
Social
Political
Gp120 binds to two receptors- CD4 and a chemokine receptor (CCR-5 or CXCR-4)
Wyatt and Sodroski. Science 280, 1884 (1998).
HAART treatment decreases virus levels
The six blind men of Indostanand the HIV vaccine elephant
(After the Indian fable by the American Poet John Godfrey Saxe, 1816-1887)
It is all of the above!
The problem is lack of coordination!
The problemis CTL induction!
No, it is thequality ofneutralizingantibodies!
It is the genetic variabilityof HIV!
Actually,the problem is the lack ofgood field sites!
Absolutely no.the problem is toomany disincentivesfor industry!
And these men of IndostanDisputed loud and longEach in his own opinion
Exceeding stiff and strong, Though each was partly in the right
And all were in the wrong!
A vaccine that confers partial immunity?
Decrease disease transmission Increase risk behaviors for
transmission
Delay progression to AIDS, not
prevention
AIDS vaccine development costs
Primary markets are poorest countries in the world
The role of CD8 T cells
Opportunistic infections of AIDS
Testing for HIV
Detection of antibodies in the blood
– Rapid immunoassay– ELISA– Western blotting
Detection of virus in the blood
– PCR
CD4 T cell counts in peripheral blood
Factors in vaccine development
Animal model
Testing in humans
Different strains of HIV around world
Immune evasion by virus
Inducing:
– Mucosal immunity– CD8 T cells– Long term immunity– Neutralizing antibodies
Regional HIV/AIDS statistics and features, end of 2002
* The proportion of adults (15 to 49 years of age) living with HIV/AIDS in 2002, using 2002 population numbers ** Hetero: heterosexual transmission – IDU: transmission through injecting drug use – MSM: sexual transmission among men who have sex with men
Sub-Saharan Africa
North Africa & Middle East
South and South-East Asia
East Asia & Pacific
Latin America
Caribbean
Eastern Europe & Central Asia
Western Europe
North America
Australia & New Zealand
TOTAL
late ’70searly ’80s
late ’80s
late ’80s
late ’80s
late ’70searly ’80s
late ’70searly ’80s
early ’90s
late ’70searly ’80s
late ’70searly ’80s
late ’70searly ’80s
29.4 million
550 000
6.0 million
1.2 million
1.5 million
440 000
1.2 million
570 000
980 000
15 000
42 million
8.8%
0.3%
0.6%
0.1%
0.6%
2.4%
0.6%
0.3%
0.6%
0.1%
1.2%
58%
55%
36%
24%
30%
50%
27%
25%
20%
7%
50%
Hetero
Hetero, IDU
Hetero, IDU
IDU, Hetero, MSM
MSM, IDU, Hetero
Hetero, MSM
IDU
MSM, IDU
MSM, IDU, Hetero
MSM
Epidemic started
Adults & childrenliving with HIV/AIDS
Adult prevalence
rate *
% of HIV-positive
adults who are women
Main mode(s) of transmission for those living with HIV/AIDS **
Adults & children newly infected
with HIV
3.5 million
83 000
700 000
270 000
150 000
60 000
250 000
30 000
45 000
500
5 million
Global estimates forGlobal estimates for adults and childrenadults and childrenend 2002end 2002
People living with HIV/AIDS
New HIV infections in 2002
Deaths due to HIV/AIDS in 2002
42 million
5 million
3.1 million
Estimated number of adults and childrenEstimated number of adults and childrennewly infected with HIV during 2002newly infected with HIV during 2002
Total: 5 million
Western Europe
30 00030 000North Africa & Middle East
83 00083 000Sub-Saharan
Africa
3.5 million3.5 million
Eastern Europe & Central Asia
250 000250 000East Asia & Pacific
270 000270 000South & South-East Asia
700 000700 000
Australia & New Zealand
500500
North America
45 00045 000Caribbean
60 00060 000
Latin America
150 000150 000
Estimated adult and child deaths Estimated adult and child deaths from HIV/AIDS during 2002from HIV/AIDS during 2002
Total: 3.1 million
Western Europe
8 0008 000North Africa & Middle East
37 00037 000Sub-Saharan
Africa
2.4 million2.4 million
Eastern Europe &Central Asia
25 00025 000East Asia & Pacific
45 00045 000South & South-East Asia
440 000440 000
Australia & New Zealand
<100<100
North America
15 00015 000Caribbean
42 00042 000
Latin America
60 00060 000
ChildrenChildren (<15 years)(<15 years) estimated to be living estimated to be living with HIV/AIDS as of end 2002with HIV/AIDS as of end 2002
Western Europe
5 0005 000North Africa & Middle East
40 00040 000sub-Saharan
Africa
2.8 million2.8 million
Eastern Europe &Central Asia
16 00016 000East Asia & Pacific
4 0004 000South & South-East Asia
240 000240 000
Australia & New Zealand
< 200< 200
North America
10 00010 000Caribbean
20 00020 000
Latin America
45 00045 000
Total: 3.2 million
Estimated deaths in children (<15 years) from HIV/AIDS during 2002
Western Europe
< 100< 100North Africa & Middle East
6 8006 800sub-Saharan
Africa
550 000550 000
Eastern Europe &Central Asia
< 100< 100East Asia & Pacific
2 0002 000South & South-East Asia
43 00043 000
Australia & New Zealand
< 100< 100
North America
< 100< 100Caribbean
7 0007 000
Latin America
5 0005 000
Total: 610 000
About 14 000 new HIV infections a day in 2002
More than 95% are in developing countries
2000 are in children under 15 years of age
About 12 000 are in persons aged 15 to 49 years,
of whom:— almost 50% are women— about 50% are 15–24 year olds
Children living with HIV/AIDS
New HIV infections in 2002
Deaths due to HIV/AIDS in 2002
End-2002 global HIV/AIDS estimatesChildren (<15 years)
3.2 million
800 000
610 000
Children living with HIV/AIDS
New HIV infections in 1999
Deaths due to HIV/AIDS in 1999
Cumulative number of deaths due to HIV/AIDS
End-1999 global HIV/AIDS estimatesEnd-1999 global HIV/AIDS estimatesChildren Children (<15 years)(<15 years)
1.3 million
620 000
480 000
3.8 million
Spread of HIV over time in Asia, 1984 to 1999Spread of HIV over time in Asia, 1984 to 1999
2.0% – 5.0% 1.0% – 2.0% 0.5% – 1.0% 0.1% – 0.5% 0.0% – 0.1%trend data unavailable
outside region
Spread of HIV over timeSpread of HIV over timein sub-Saharan Africa, 1984 to 1999in sub-Saharan Africa, 1984 to 1999
Estimated percentage of adults
(15–49) infected with HIV 20.0% – 36.0%10.0% – 20.0% 5.0% – 10.0% 1.0% – 5.0% 0.0% – 1.0%trend data unavailable
outside region
Adults and children estimated to be living Adults and children estimated to be living with HIV/AIDS as of end 1999with HIV/AIDS as of end 1999
Western Europe
520 000520 000North Africa & Middle East
220 000220 000sub-Saharan
Africa
24.5 million24.5 million
Eastern Europe & Central Asia
420 000420 000
South & South-East Asia 5.6 million5.6 million
Australia & New Zealand
15 00015 000
North America
900 000900 000Caribbean
360 000360 000
Latin America
1.3 million1.3 million
Total: 34.3 millionTotal: 34.3 million
East Asia & Pacific
530 000530 000
End-1999 global HIV/AIDS estimatesEnd-1999 global HIV/AIDS estimates Children and adultsChildren and adults
People living with HIV/AIDS
New HIV infections in 1999
Deaths due to HIV/AIDS in 1999
Cumulative number of deaths due to HIV/AIDS
34.3 million
5.4 million
2.8 million
18.8 million
About 15 000 new HIV infections a day in 1999About 15 000 new HIV infections a day in 1999
More than 95% are in developing countries
1 700 are in children under 15 years of age
About 13 000 are in persons aged 15 to 49 years, of whom:
— almost 50% are women
— about 50% are 15–24 year olds
Cumulative number of children estimated to have Cumulative number of children estimated to have been orphaned by AIDS* at age 14 or youngerbeen orphaned by AIDS* at age 14 or younger
at the end of 1999at the end of 1999
Western Europe
9 0009 000North Africa & Middle East
15 00015 000sub-Saharan
Africa
12.1 million12.1 million
Eastern Europe &Central Asia
500500 East Asia & Pacific
5 6005 600South & South-East Asia
850 000850 000
Australia & New Zealand
< 500< 500
North America
70 00070 000Caribbean
85 00085 000
Latin America
110 000110 000
Total: 13.2 millionTotal: 13.2 million * Children who have lost their mother or both parents to AIDS before the age of 15 years
New
in
fect
ion
s
-
500,000
1,000,000
1,500,000
2,000,000
2,500,000
3,000,000
3,500,000
4,000,000
80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99
Highly industrialized countries
North Africa & Middle EastEastern Europe & Central asiaSub-Saharan AfricaLatin America & the Caribbean
Southern & Eastern Asia
Estimated annual number of new HIV Estimated annual number of new HIV infections by region, 1980 to 1999infections by region, 1980 to 1999
Different modes of transmission
Sub-Saharan Africa
North Africa & Middle East
South and South-East Asia
East Asia & Pacific
Latin America
Caribbean
Eastern Europe & Central Asia
Western Europe
North America
Australia & New Zealand
TOTAL
late ’70s–early ’80slate ’80s
late ’80s
late ’80s
late ’70s–early ’80slate ’70s–early ’80searly ’90s
late ’70s–early ’80slate ’70s–early ’80slate ’70s–early ’80s
24.5 million
220 000
5.6 million
530 000
1.3 million
360 000
420 000
520 000
900 000
15 000
34.3 million
8.57%
0.12%
0.54%
0.06%
0.49%
2.11%
0.21%
0.23%
0.58%
0.13%
1.07%
55%
20%
35%
13%
25%
35%
25%
25%
20%
10%
47%
Hetero
Hetero, IDU
Hetero, IDU
IDU, Hetero, MSM
MSM, IDU, Hetero
Hetero, MSM
IDU
MSM, IDU
MSM, IDU, Hetero
MSM
Epidemic started
Adults & childrenliving with HIV/AIDS
Adult prevalence
rate *
% HIV-positive women
Main mode(s) of transmission for those living with HIV/AIDS **
* The proportion of adults (15 to 49 years of age) living with HIV/AIDS in 1999 ** Hetero: heterosexual transmission – IDU: transmission through injecting drug use – MSM: sexual transmission among men who have sex with men
Adults & children newly infected
with HIV
4 million
20 000
800 000
120 000
150 000
60 000
130 000
30 000
45 000
500
5.4 million
Protocol Number Status as of 9/02 Prime Boost
Class Producer Product
Name
Adjuvant Class Producer Product
Name
Adjuvant
HIVNET 026
(n=160)
Immuniza-tions
completed
Canary-pox
vector (clade B
Env, Gag, Pro)
Aventis
Pasteur
ALVAC
vCP205
Protein
subunit (clade
B Env)
VaxGen gp120 MN Alum-inum
hydrox-ide/thi
m-erosol
HVTN 039
(n=110)
Immuniza-tions
completed
Canary-pox
vector (clade B
Env, Gag, Pro,
RT, Nef)
Aventis
Pasteur
ALVAC
vCP1452
(high-dose)
HVTN 041
(n=87)
Immuniza-tions in
progress
Protein (clade B
Nef-Tat fusion
protein + clade
B Env subunit)
Glaxo-Smith-
Kline
NefTat +
gp120W61D
AS02A
HVTN 203
(n=330)
Immuniza-tions
completed
Canary-pox
vector
Aventis
Pasteur
ALVAC
vCP1452
Protein
subunit (clade
B Env)
VaxGen AIDSVAX B/B
(gp120 MN,
gp120 GNE8)
Alumi-num
hydrox-ide gel
Ongoing Trials
10/02
http://chi.ucsf.edu/vaccines
Coreceptor trophism
Early in infection
– Macrophage trophic strains– Bind CD4 and CCR5
Later in infection
– T cell trophic strains– Bind CD4 and CXCR4– Correlated to progression of disease to AIDS
HIV slow and nonprogressors
Non-progressors:
– 32 bp deletion in CCR5 chemokine receptor gene– Efficient proliferation and perforin expression CD8 cells– -CD8 Noncytotoxic activity
Slow progressors
– SDF overexpression, binds to CXCR4, prevents HIV attachment– Unknown mechanism for other slow progressors
• Group 1= seroconversion, low levels of virus, no progression• Group 2= no seroconversion, CD8 T cells to HIV
HIV transcribed in infected, activated cells
HIV not transcribed in quiescent cells
– Latent infections– Reservoir in lymphoid tissues
• Monocytes, T cells, dendritic cells
– Brain as a reservoir• Microglia, astrocytes
HIV transcribed in activated cells
– Macrophages, T cells– Activated by Ag binding, cytokines
HIV long terminal repeats (LTR) initiate HIV transcription
NFB, NF-AT=
-production/activity upregulated in Ag activated T cells or M
s HIV transcription
Protease cleaves polyproteins
HIV protease a target of HIV therapy
Other HIV proteins
Vpu and Nef
– downregulation of CD4– downregulation of MHC class I expression– Nef: increase in FasL
Vpr
– Transport of DNA to nucelus Vif
– Unknown– Affects viral infectivity
Models for loss of CD4 T cells
Virus directly kills CD4 cells (a small component!)
Apoptosis of CD4 cells– CTL, NK cells kill infected CD4 cells
– Gp120 binding to cells
– Increase FasL by Nef allows infected cells to kill uninfected cells
Immune exhaustion
Viral interference with replication/development of new T cells
AIDS related diseases
Wasting– Weight loss of 10% or more– Chronic diarrhea/fever for 30 days or more– Possible cause: TNF-
Malignancies
– Kaposi sarcoma (HHV-8)
AIDS Dementia Complex
– Hypotheses: cytokines, M, HIV glycoproteins
Reverse transcriptase (RT)
RNA-dependent DNA polymerase
– Found only in viruses– Target of HIV inhibitors
• Nucleoside analogs (AZT, 3TC) terminate mRNA elongation• Nonnucleoside inhibitors (nevirapine) bind and inhibit function of RT
Error prone
– High mutation rate of virus– Drug resistance– Immune escape variants=
• “Quasi -species” in a single individual• Escape presentation in MHC class I