An AIDS vaccine: challenges and progress

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An AIDS vaccine challenges and progress

• Christine White-Ziegler
• Kahn Institute Fellow,Biotechnology and World
  Health

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Global estimates for adults and childrenend 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

• People living with HIV
• New HIV infections in 2004
• Deaths due to AIDS in 2004

http//www.who.int/hiv/facts/en/
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HIV infection and progression to AIDS
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HIV virus structure
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HIV life cycle
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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

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http//www.who.int/hiv/facts/en/
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http//www.who.int/hiv/facts/en/
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Biological challenges to vaccine development

• Different subtypes of HIV
• Difficulties in raising neutralizing antibodies
• Quick evolution of virus
• No animal model for testing

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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
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Most antibodies to gp120 are not neutralizing
Wyatt and Sodroski. Science 280, 1884 (1998).
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HIV mutants arise rapidly
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Treatment vs. vaccine for HIV infection

• Treatment
• Works post-infection
• Ongoing cost for medication
• Lifetime treatment
• Side effects
• Noncompliance?Decreased 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

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Goals of an ideal AIDS vaccine

• Activate protective responses-CTL, antibodies
• Works at mucosal epithelia
• Provide long term, sterilizing immunity
• Simple administration

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A good vaccine prevents HIV attachment and entry
into cells
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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?

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? 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
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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

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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.

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http//www.iavi.org/science/trials.asp
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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

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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 poxHIV hybrid (e.g ALVAC)

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http//chi.ucsf.edu/vaccines/vaccines
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AIDSVAX vaccine by VAXGEN
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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

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http//www.vaxgen.com/products/AIDSV_clinical_tria
ls.html
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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

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Prime-Boost Vaccinations

• Aventis-Pasteur/Merck
• Adenovirus DNA vaccine
• Canarypox Recombinant live vaccine
• Aventis-Pasteur/Vaxgen
• Canarypox Recombinant live vaccine
• Recombinant GP 120 protein

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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

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HIV genome
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Challenges for vaccine development

• Biological
• Ethical
• Financial
• Social
• Political

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Gp120 binds to two receptors- CD4 and a chemokine
receptor (CCR-5 or CXCR-4)
Wyatt and Sodroski. Science 280, 1884 (1998).
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HAART treatment decreases virus levels
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The six blind men of Indostanand 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!
Actually, the problem is the lack of good field
sites!
It is the genetic variability of HIV!
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!
It is all of the above!
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A vaccine that confers partial immunity?

• Decrease disease transmission

• Increase risk behaviors for transmission
• Delay progression to AIDS, not prevention

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AIDS vaccine development costs
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• Primary markets are poorest countries in the world

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The role of CD8 T cells
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Opportunistic infections of AIDS
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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

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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

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Regional HIV/AIDS statistics and features, end of
2002
of HIV-positive adults who are women
Main mode(s) of transmission for those living
with HIV/AIDS
Adults children newly infected with HIV
Epidemic started
Adults children living with HIV/AIDS
Adult prevalence rate
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
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 80s late 80s late 80s late
80s late 70s early 80s late 70s early
80s early 90s late 70s early 80s late
70s early 80s late 70s early 80s
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
3.5 million 83 000 700 000 270 000 150
000 60 000 250 000 30 000 45 000 500 5
million
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
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Global estimates for adults and childrenend 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
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Estimated number of adults and childrennewly
infected with HIV during 2002
Eastern Europe Central Asia 250 000
Western Europe 30 000
North America 45 000
East Asia Pacific 270 000
North Africa Middle East 83 000
South South-East Asia 700 000
Caribbean 60 000
Sub-Saharan Africa 3.5 million
Latin America 150 000
Australia New Zealand 500
Total 5 million
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Estimated adult and child deaths from HIV/AIDS
during 2002
Eastern Europe Central Asia 25 000
Western Europe 8 000
North America 15 000
East Asia Pacific 45 000
North Africa Middle East 37 000
South South-East Asia 440 000
Caribbean 42 000
Sub-Saharan Africa 2.4 million
Latin America 60 000
Australia New Zealand lt100
Total 3.1 million
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Children (lt15 years) estimated to be living with
HIV/AIDS as of end 2002
Eastern Europe Central Asia 16 000
Western Europe 5 000
North America 10 000
East Asia Pacific 4 000
North Africa Middle East 40 000
South South-East Asia 240 000
Caribbean 20 000
sub-Saharan Africa 2.8 million
Latin America 45 000
Australia New Zealand lt 200
Total 3.2 million
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Estimated deaths in children (lt15 years) from
HIV/AIDS during 2002
Eastern Europe Central Asia lt 100
Western Europe lt 100
North America lt 100
East Asia Pacific 2 000
North Africa Middle East 6 800
South South-East Asia 43 000
Caribbean 7 000
sub-Saharan Africa 550 000
Latin America 5 000
Australia New Zealand lt 100
Total 610 000
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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 1524 year olds

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End-2002 global HIV/AIDS estimatesChildren (lt15
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
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End-1999 global HIV/AIDS estimatesChildren (lt15
years)

• 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

1.3 million 620 000 480 000 3.8 million
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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
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Spread of HIV over timein sub-Saharan Africa,
1984 to 1999
Estimated percentage of adults (1549) 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
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Adults and children estimated to be living with
HIV/AIDS as of end 1999
Eastern Europe Central Asia 420 000
Western Europe 520 000
North America 900 000
East Asia Pacific 530 000
North Africa Middle East 220 000
South South-East Asia 5.6 million
Caribbean 360 000
sub-Saharan Africa 24.5 million
Latin America 1.3 million
Australia New Zealand 15 000
Total 34.3 million
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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
• Cumulative number of deaths due to HIV/AIDS

34.3 million 5.4 million 2.8 million 18.8 million
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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 1524 year olds

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Cumulative number of children estimated to have
been orphaned by AIDS at age 14 or youngerat
the end of 1999
Eastern Europe Central Asia 500
Western Europe 9 000
North America 70 000
East Asia Pacific 5 600
North Africa Middle East 15 000
South South-East Asia 850 000
Caribbean 85 000
sub-Saharan Africa 12.1 million
Latin America 110 000
Australia New Zealand lt 500
Total 13.2 million
Children who have lost their mother or both
parents to AIDS before the age of 15 years
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Estimated annual number of new HIV infections by
region, 1980 to 1999
New infections
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Different modes of transmission
Main mode(s) of transmission for those living
with HIV/AIDS
Adult prevalence rate
HIV-positive women
Adults children newly infected with HIV
Adults children living with HIV/AIDS
Epidemic started

• 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

late 70s early 80s late 80s late 80s late
80s late 70s early 80s late 70s early
80s early 90s late 70s early 80s late
70s early 80s late 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
4 million 20 000 800 000 120 000 150
000 60 000 130 000 30 000 45 000 500 5.4
million
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
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10/02
Ongoing Trials
Protocol Number Status as of 9/02 Prime Prime Prime Prime Boost Boost Boost Boost
Class Producer Product Name Adjuvant Class Producer Product Name Adjuvant
HIVNET 026 (n160) 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/thim-erosol
HVTN 039 (n110) Immuniza-tions completed Canary-pox vector (clade B Env, Gag, Pro, RT, Nef) Aventis Pasteur ALVAC vCP1452 (high-dose)
HVTN 041 (n87) Immuniza-tions in progress Protein (clade B Nef-Tat fusion protein clade B Env subunit) Glaxo-Smith-Kline NefTat gp120W61D AS02A
HVTN 203 (n330) 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
http//chi.ucsf.edu/vaccines
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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

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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

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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

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HIV long terminal repeats (LTR) initiate HIV
transcription
NFkB, NF-AT -production/activity upregulated in
Ag activated T cells or Mf ?????????s HIV
transcription
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Protease cleaves polyproteinsHIV protease a
target of HIV therapy
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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

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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

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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

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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