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An AIDS vaccine: challenges and progress
Christine White-Ziegler
Kahn Institute Fellow,“Biotechnology and World Health”
Global estimates for adults and children
end 2004

People living with HIV

New HIV infections in 2004

Deaths due to AIDS in 2004
http://www.who.int/hiv/facts/en/
39.4 million [35.9 – 44.3 million]
4.9 million [4.3 – 6.4 million]
3.1 million [2.8 – 3.5 million]
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
Vaccine

Works post-infection

Prevents infection

Ongoing cost for medication

Minimal number of treatments

Lifetime treatment

Lifetime immunity

Side effects

Minimal side effects

NoncomplianceDecreased efficacy, drug
resistant mutants

Efficacy, immune evasion, viral subtypes

Resources for production and distribution

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?
 Immune system studies
 Vaccine strategy choice
 Animal testing
Review:
Food and Drug Administration,
Institutional Review Board
 Phase I/II clinical trials
 Phase III clinical trials
http://www.iavi.org/science/testing.asp
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
Evaluating a vaccine: Clinical trials

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.
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 Indostan
and the HIV vaccine elephant
(After the Indian fable by the American Poet John Godfrey Saxe, 1816-1887)

The problem
is CTL
induction!
Absolutely no.
the problem is too
many disincentives
for industry!
No, it is the
quality of
neutralizing
antibodies!
It is the
genetic
variability
of HIV!
Actually,
the problem
is the lack of
good field
sites!
It is all of the above!
The problem
is lack of
coordination!
And these men of Indostan
Disputed loud and long
Each 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
Epidemic
started
Adults & children Adults & children
newly infected
living with HIV/AIDS
with HIV
% of HIVMain mode(s) of
Adult
positive
prevalence adults who transmission for those
rate *
are women living with HIV/AIDS **
8.8%
58%
Hetero
29.4 million
3.5 million
North Africa & Middle East
late ’70s
early ’80s
late ’80s
550 000
83 000
0.3%
55%
Hetero, IDU
South and South-East Asia
late ’80s
6.0 million
700 000
0.6%
36%
Hetero, IDU
East Asia & Pacific
late ’80s
1.2 million
270 000
0.1%
24%
IDU, Hetero, MSM
late ’70s
early ’80s
late ’70s
early ’80s
early ’90s
1.5 million
150 000
0.6%
30%
MSM, IDU, Hetero
440 000
60 000
2.4%
50%
Hetero, MSM
1.2 million
250 000
0.6%
27%
IDU
late ’70s
early ’80s
late ’70s
early ’80s
late ’70s
early ’80s
570 000
30 000
0.3%
25%
MSM, IDU
980 000
45 000
0.6%
20%
MSM, IDU, Hetero
15 000
500
0.1%
7%
42 million
5 million
1.2%
50%
Sub-Saharan Africa
Latin America
Caribbean
Eastern Europe & Central Asia
Western Europe
North America
Australia & New Zealand
TOTAL
MSM
* 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
Global estimates for adults and children
end 2002

People living with HIV/AIDS

New HIV infections in 2002

42 million
5 million
Deaths due to HIV/AIDS in 2002
3.1 million
Estimated number of adults and children
newly infected with HIV during 2002
North America
45 000
Caribbean
60 000
Latin America
150 000
Western Europe
30 000
North Africa
& Middle East
Eastern Europe
& Central Asia
250 000East Asia & Pacific
270 000
South
83 000
Sub-Saharan
Africa
& South-East Asia
700 000
3.5 million
Total: 5 million
Australia
& New Zealand
500
Estimated adult and child deaths
from HIV/AIDS during 2002
North America
15 000
Caribbean
42 000
Latin America
60 000
Western Europe
8 000
Eastern Europe &
Central Asia
25 000
North Africa
& Middle East
37 000
Sub-Saharan
Africa
East Asia & Pacific
45
South
& South-East Asia
000
440 000
2.4 million
Total: 3.1 million
Australia
& New Zealand
<100
Children (<15 years) estimated to be living
with HIV/AIDS as of end 2002
North America
10 000
Caribbean
20 000
Latin America
45 000
Western Europe
5 000
Eastern Europe &
Central Asia
16 000
North Africa
& Middle East
40 000
sub-Saharan
Africa
East Asia & Pacific
4
South
& South-East Asia
000
240 000
2.8 million
Total: 3.2 million
Australia
& New Zealand
< 200
Estimated deaths in children (<15 years)
from HIV/AIDS during 2002
North America
< 100
Caribbean
7 000
Latin America
5 000
Western Europe
< 100
North Africa
& Middle East
6 800
Eastern Europe &
Central Asia
< 100
East Asia & Pacific
2
South
& South-East Asia
sub-Saharan
Africa
550 000
Total: 610 000
000
43 000
Australia
& New Zealand
< 100
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
End-2002 global HIV/AIDS estimates
Children (<15 years)

Children living with HIV/AIDS

New HIV infections in 2002

Deaths due to HIV/AIDS in 2002
3.2 million
800 000
610 000
End-1999 global HIV/AIDS estimates
Children (<15 years)

Children living with HIV/AIDS

New HIV infections in 1999

Deaths due to HIV/AIDS in 1999
1.3 million
620 000
480 000

Cumulative number of deaths due to HIV/AIDS
3.8 million
Spread 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 time
in 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
with HIV/AIDS as of end 1999
North America
900 000
Caribbean
360 000
Latin America
1.3 million
Eastern Europe
Western Europe & Central Asia
520 000 420 000
North Africa
& Middle East
220 000
sub-Saharan
Africa
East Asia & Pacific
530
South
& South-East Asia
000
5.6 million
24.5 million
Total: 34.3 million
Australia
& New Zealand
15 000
End-1999 global HIV/AIDS estimates
Children and adults

People living with HIV/AIDS

New HIV infections in 1999

Deaths due to HIV/AIDS in 1999
34.3 million
5.4 million
2.8 million

Cumulative number of deaths due to HIV/AIDS
18.8 million
About 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
been orphaned by AIDS* at age 14 or younger
at the end of 1999
North America
70 000
Caribbean
85 000
Latin America
110 000
Western Europe
9 000
Eastern Europe &
Central Asia
500
North Africa
& Middle East
15 000
sub-Saharan
Africa
East Asia & Pacific
5
South
& South-East Asia
850 000
12.1 million
Total: 13.2 million
* Children who have lost their mother or both parents to AIDS before the age of 15 years
600
Australia
& New Zealand
< 500
Estimated annual number of new HIV
infections by region, 1980 to 1999
4,000,000
Highly industrialized countries
New infections
3,500,000
3,000,000
2,500,000
North Africa & Middle East
Eastern Europe & Central asia
Sub-Saharan Africa
Latin America & the Caribbean
Southern & Eastern Asia
2,000,000
1,500,000
1,000,000
500,000
80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99
Different modes of transmission
Epidemic
started
Sub-Saharan Africa
Adults & children Adults & children
newly infected
living with HIV/AIDS
with HIV
Adult
prevalence
rate *
% HIVpositive
women
Main mode(s) of
transmission for those
living with HIV/AIDS **
24.5 million
4 million
8.57%
55%
Hetero
North Africa & Middle East
late ’70s–
early ’80s
late ’80s
220 000
20 000
0.12%
20%
Hetero, IDU
South and South-East Asia
late ’80s
5.6 million
800 000
0.54%
35%
Hetero, IDU
East Asia & Pacific
late ’80s
530 000
120 000
0.06%
13%
IDU, Hetero, MSM
1.3 million
150 000
0.49%
25%
MSM, IDU, Hetero
360 000
60 000
2.11%
35%
Hetero, MSM
420 000
130 000
0.21%
25%
IDU
520 000
30 000
0.23%
25%
MSM, IDU
900 000
45 000
0.58%
20%
MSM, IDU, Hetero
15 000
500
0.13%
10%
MSM
34.3 million
5.4 million
1.07%
47%
Latin America
late ’70s–
early ’80s
late ’70s–
Caribbean
early ’80s
Eastern Europe & Central Asia early ’90s
Western Europe
North America
Australia & New Zealand
TOTAL
late ’70s–
early ’80s
late ’70s–
early ’80s
late ’70s–
early ’80s
* 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
10/02
Ongoing Trials
Protocol Number
Status as of 9/02
Prime
Class
Boost
Producer
Product
Adjuvant
Class
Producer
Product
Adjuvant
Name
Name
HIVNET 026
Immuniza-tions
Canary-pox
Aventis
ALVAC
Protein
(n=160)
completed
vector (clade B
Pasteur
vCP205
subunit (clade
hydrox-
B Env)
ide/thim-
Env, Gag, Pro)
VaxGen
gp120 MN
Alum-inum
erosol
HVTN 039
Immuniza-tions
Canary-pox
Aventis
ALVAC
(n=110)
completed
vector (clade B
Pasteur
vCP1452
Env, Gag, Pro,
(high-dose)
RT, Nef)
HVTN 041
Immuniza-tions in
Protein (clade B
Glaxo-Smith-
NefTat +
(n=87)
progress
Nef-Tat fusion
Kline
gp120W61D
AS02A
protein + clade
B Env subunit)
HVTN 203
Immuniza-tions
Canary-pox
Aventis
ALVAC
Protein
(n=330)
completed
vector
Pasteur
vCP1452
http://chi.ucsf.edu/vaccines
VaxGen
AIDSVAX B/B
Alumi-num
subunit (clade
(gp120 MN,
hydrox-ide gel
B Env)
gp120 GNE8)
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
NFkB, NF-AT=
-production/activity
upregulated in Ag
activated T cells or
Mf
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-a

Malignancies
– Kaposi sarcoma (HHV-8)

AIDS Dementia Complex
– Hypotheses: cytokines, Mf, 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