an aids vaccine: challenges and progress christine white-ziegler kahn institute...

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]



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

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



early ’90s




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


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


250 000250 000East Asia & Pacific

270 000270 000South & South-East Asia

700 000700 000


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


37 00037 000Sub-Saharan

Africa


Eastern Europe &Central Asia



440 000440 000


<100<100

North America


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


40 00040 000sub-Saharan

Africa





240 000240 000


< 200< 200

North America


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


Africa

550 000550 000


< 100< 100East Asia & Pacific


43 00043 000


< 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



End-2002 global HIV/AIDS estimatesChildren (<15 years)

3.2 million

800 000

610 000

Children living with HIV/AIDS



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



Africa



420 000420 000

South & South-East Asia 5.6 million5.6 million


15 00015 000

North America

900 000900 000Caribbean

360 000360 000

Latin America


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



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



Africa



500500 East Asia & Pacific


850 000850 000


< 500< 500

North America


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


Western Europe

North America


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

an aids vaccine: challenges and progress christine white-ziegler kahn institute...

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