HIV Vaccine Research

Dina Kovarik, M.S., Ph.D.Program Manager, NWABR

May 16, 2009

www.uhaweb.hartford.edu/bugl/images/HIV_bud2.jpg

The HIV/AIDS Pandemic

http://www.abc.net.au/reslib/200707/r163084_600500.jpg

http://www.chicagobooth.edu/magazine/29/2/images/AIDS.jpg

http://www.deza.admin.ch/pictures/E_Bereich/Factsheets_SOSA/south_africa/ZAFwomanandchild_1.jpg

http://www.workofwomen.org/images/orphanedchildren.JPG

Report on the Global AIDS Epidemic. Executive Summary. 2007. www.unaids.org

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http://lowposts.com/wp-content/uploads/2009/03/fat_magic.jpg

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www.lincolncountyhealth.com. www.mlm.nih.gov

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Human Immunodeficiency Virus (HIV)

Burton et al. 2005. PNAS 102:14943. http://www.rhodes.edu/biology/glindquester/viruses/pagespass/hiv/attachment.jpg

gp120

gp41

TM

gag

tatpol

vif

vpuvpr

rev

nefenv

Immune Responses to Infection

Antigen Presenting Cell (APC, Phagocyte)

Virion

Immune Responses to Infection

Antigen Presenting Cell (APC, Phagocyte)

Virion

Kill Infected

Cells

CD8+ T Cell

Killer T Cells

Immune Responses to Infection

Antigen Presenting Cell (APC, Phagocyte)

Virion

B Cell

CD8+ T Cell

Killer T Cells

Antibodies Coat

Pathogen

Kill Infected

Cells

Immune Responses to Infection

Antigen Presenting Cell (APC, Phagocyte)

Virion

B Cell

CD4+ T CellT

Helper

Cells

CD8+ T Cell

Killer T Cells

Immune Correlates and HIV Infection

CD8+ T Cells

Antibodies

Neutralizing Abs

CD4+ T Cells

Weeks Months Years

T C

ell C

ount

or

Ant

ibod

y T

iter

RN

A C

opie

s pe

r M

illili

ter

Time Post-Infection

Peak Virus Load

Y YX

Binding Antibodies (BAbs)

Neutralizing Antibodies (NAb)

Binding Versus Neutralizing Antibodies

Adapted from Wendy Blay Puryear, Ph.D.

Nonhuman primate models for AIDS

• HIV-1: only replicates in chimpanzees--disease in 10 years

• Simian Immunodeficiency Virus (SIV): causes AIDS in months to years

• Simian Human Immunodeficiency Virus (SHIV): chimera with HIV env gene in the backbone of SIV; disease progression similar to SIV

http://www.theprimata.com/macaca_nemestrina.jpghttp://upload.wikimedia.org/wikipedia/commons/9/9f/Macaca_fascicularis.jpg

Macaca nemestrinaMacaca fascicularisMacaca mulatta

http://www.aaas.org/news/releases/2007/images/0416macaque_lone.jpg

Antibodies and HIV: Passive Transfer Studies

• Passive transfer of SIV-specific neutralizing antibodies (NAbs) one and 14 days after SIV infection reduced viral load and prolonged healthy life. (Shibata et al.1999. Nat Med 5:204)

• Passive transfer of high-dose NAbs 6 hours before, but not 24 hours after, virus challenge can prevent infection. (Nishimura et al. 2003. PNAS 100:15131.)

• Administration of NAbs after infection can accelerate the de novo antibody response. (Haigwood et al. 2004. J Virol78:5883)

The Role of CD8+ T Cells in HIV Infection

• A rise in CD8+ T cells early in HIV infection is associated with a reduction in viral load. (Koup et al. 1994. J Virol 68:4650)

• A decrease in CD8+ T cells numbers late in HIV infection correlates with an increase in viral load. (Walker et al. 1987. Nature

328:345; Ogg et al.1998.Science 279:2103.)

• Depletion of CD8+ T cells in SIV-infected macaques resulted in immediate increases in viral load, while CD8+ T cell restoration resulted in virus control. (Schmitz et al.1999.Science

283:857; Jin et al. 1999. J Exp Med 189:991.)

If antibodies and T cells protect from HIV infection or disease, why don’t we have

an effective HIV vaccine?

• Timing is everything

• The devil is in the details

The Power of Immune Memory

1st Infection 2nd Infection

Str

eng

th o

f R

esp

on

se

Primary Response

Memory Response

Vaccination 1st Infection

Str

eng

th o

f R

esp

on

se

Primary Response

Memory Response

The Race to Catch HIV

Mattapallil et al. 2005. Science 434:1093.Brenchley et al. 2004. J Exp Med 200:749.

But HIV Keeps Running Away…

+ = patient serum able to neutralize patient virus

Virus Time Point

0 1 2 3 4 5 6

Ser

um

Tim

e P

oint

0

1

2

3

4

5

6

- - - - - - -- - - - - - -

+ - - - - - -+ + - - - - -+ + + - - - -

+ + + + - - -+ + + + + - -

Richman et al. 2003. PNAS 100:4144.

If antibodies and T cells protect from HIV infection or disease, why don’t we have

an effective HIV vaccine?

• Timing is everything

• The devil is in the details

Diversity Within the Individual

Average 1 mutation per replicated genome

Homogeneous new infection

Replicates ~ 24hrs

Produces 1010 new virions a day

Rapidly develop a “quasispecies”

Wendy Blay Puryear, Ph.D.

HIV-1 Diversity WorldwideHIV-1 group M:

- 9 subtypes (>30% difference) - several circulating recombinant forms

ABCDF, G, H, J. KCRF01_AE

other

CRF02_AGCRF03_AB

Subtype

Hemelaar et al. 2004. WHO/UNAIDS.

Comparative Genetic Diversity of HIV and Influenza

Weiss. 2003. Nat Med. 9:887, adapted from Korber et al. 2001. Brit Med Bull 58:19.

Components of a Potentially Successful HIV Vaccine

• Target multiple HIV antigens – Overcome viral resistance and diversity

• Cell Mediated Immunity– CD4+ T Helper Cells– CD8+ “Killer” T Cells

• Humoral Immunity / Antibodies– Binding antibodies Antibody-dependent cellular cytotoxicity– Neutralizing antibodies (NAbs) Block infection of target cells

Vaccines in Clinical Use

Strategy Agent / Pathogen(s)

Live-Attenuated Smallpox Tuberculosis (BCG)

Polio (OPV / Oral, Sabin) Varicella (chickenpox)

Measles, Mumps, Rubella (MMR) Yellow Fever

Inactivated (Killed) Polio (IPV / injected, Salk) Hepatitis A Virus

Influenza Rabies

Cholera Plague

Toxoid Tetanus toxoid Diphtheria toxin

Pertussis toxin

Virus-Like Particles Hepatitis B Virus Human Papillomavirus (HPV)

Component Haemophilus influenzae type b (Hib) Pneumococcal conjugate vaccine

A Brief History of HIV Vaccines

gp120

gp140trimers

Recombinant Proteins

Peptides

Moderately Potent NAbs

http://www.aids.harvard.edu/images/laboratories/figure_virionstructure.jpg

Live Infection

Vector Viruses(Adenovirus, Poxvirus)

Attenuated HIV

Safety (HIV) and Efficacy (Merck)

Other Approaches

Plasmid DNA Virus-Like Particles (VLPs)Inactivated Virions

Variables in HIV Vaccine Development

Vaccine Modality Gene Model Virus Whole, killed env Mouse SHIVSF162

Attenuated gag Rabbit SHIV89.6/P

DNA pol Guinea Pig SIVmac239/251Recombinant Proteins nef Ferret SIV E660Peptides tat Monkey SIV mneVirus-like particles rev Macaca nemestrina

Mimetopes vif Macaca fascicularis

Vectors: vpr Macaca mulatta

Vaccinia vpu Modified Vaccinia AnkaraFowlpoxCanarypox

Adenovirus Herpes simplex virusRabies virusVesicular Stomatitis Virus Semiliki Forest VirusAdeno-associated virusOPVSalmonellaMoloney Leukemia virusHepatitis B virusListeria monocytogenes

Adapted from Nancy Haigwood, Ph.D.

Adjuvant AdminitrationAlum DoseCytokines RoutePulsed DC TimingCo-stimulatoryQS-21CpG oligosPROPRIETARY

Stages of Vaccine Clinical Trials

Phase Objective Number of Volunteers

1 Evaluate Vaccine Safety 20-50

2Test Immunogenicity of Vaccine (production of antibodies and/or T cells)and Obtain Additional Safety Information

100s

3 Test Effectiveness of Vaccine (i.e. ability to prevent infection and/or disease)

1000s

Clinical HIV Trial Sponsors

• National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH)– Vaccine Research Center (VRC),

– HIV Vaccine Trials Network (HVTN)

• International AIDS Vaccine Initiative (IAVI)

• Center for HIV/AIDS Vaccine Immunology (CHAVI)

• South African AIDS Vaccine Initiative (SAAVI)

Pharmexa-Epimmune Aventis-Sanofi Pasteur/ANRS

Bavarian Nordic Therion

Aaron Diamond AIDS Research Center Chrion

Wyeth VaxGen

GeoVax Merck

Endpoints:Prevention of HIV InfectionReduction in Viral LoadMaintenance of CD4+ T cells

AIDSVAX: Targeting gp120

World’s First Phase III Trial of an AIDS Vaccine

N=5,400 in USA, Canada, Netherlands (5,100 MSM) and N=2,500 in Thailand

Sponsors: VaxGen, a spin-off of Genetech run by Dr. Don Francis, formerly of the CDC

Study Design:

VaxGen’s AIDSVAX, two forms of rgp120 from clade B (B/B) or one from clade B and one from clade E (B/E)

Immunize @ 0, 1, 6, 12, 18, 24 & 30 months

Follow up for 3 years (1998-2001)

BB

Protective Effectiveness less than 30% (or indeterminant)

However, the vaccine was safe, and the trial itself was a success

BE

Nitayaphan et al. 2004. J Infect Dis 190:702.

Endpoints:Prevention of HIV InfectionReduction in Viral LoadMaintenance of CD4+ T cells

Thai Prime-Boost Study

N = 16,000 volunteers ages 20-30

Sponsors: Thai Government, Aventis Pasteur, VaxGen, US Military

Study Design:

Prominent clade in Thailand is CRF01_AE

VaxGen’s AIDSVAX rgp120 from clades B and E

Prime @ 0, 1, 3 & 6 months with ALVAC canarypox vaccine (vCP1521, Aventis Pasteur); contains HIV genes gag, pol, and nef, clade B

Co-administer AIDSVAX B/E at 3 and 6 months

Started in 2003, 6 year study

http://www.primeboost3.org/eng/

BE

Thai Prime-Boost Study

“We have a concern about the wisdom of the U.S. government’s sponsoring a recently initiated phase III trial in Thailand…Multiple phase I and II clinical trial have revealed that the ALVAC vector is poorly immunogenic. The gp120 component as now been proven in phase III trials in the United States and Thailand to be completely incapable of prevention or ameliorating HIV-1 infection.

Society expects the scientific community to develop a vaccine to counter the AIDS pandemic, but there are adverse consequences to conducting large-scale trials of inadequate HIV-1 vaccines….

…One price for repetitive failure could be crucial erosion of confidence by the public and politicians in our capability of developing an effective AIDS vaccine collectively…

…The decision about whether or not to proceed with mounting a phase III HIV-1 vaccine trial needs to take into account the likelihood of success and the consequences of failure, the value of what can realistically be learned, and the human and financial costs involved.”

Burton et al. 2004. Science 303:316.

Trial Cost: $119 million

Cost of rgp120: $3 million

2007 Interim Analysis: No safety concerns

Final results expected by the end of 2009.

http://www.iavireport.org/

Endpoints:

Prevention of HIV Infection

Reduction of Viral Load: Delayed onset of AIDS, reduced transmission

V520: The STEP & Phambili Trials

N = 3,000 volunteers (STEP, begin in 2004); 801 (Phambili).

Sponsors: HIV Vaccine Trials Network (HVTN) & Merck

Study Design:

Ad5 is a replication-defective adenovirus (common cold virus)

Three doses of Clade B Ad5-gag, Ad5-pol & Ad5-nef

Doses at 0, 1 and 6 months

Target cellular immune responses

Started in 2004

Sites: North & South America, Australia (STEP); South Africa (Phambili)

STEP Trial Efficacy Analyses: HVTN Full Group Meeting. Nov 7, 2007.

2007 Interim Analysis:

Modified intent-to-treat (MITT) population includes all participants who received at least one study injection

Per protocol (PP) population includes all participants who received at least the first 2 study injections

STEP Interim Analysis

Vaccine Placebo

Total MITT Cases 24 / 741 = 3.2% 21 / 762 = 2.8%

Cases included in PP Efficacy Analysis 19 / 672 = 2.8% 11 / 691 = 1.6%

STEP Trial Efficacy Analyses: HVTN Full Group Meeting. Nov 7, 2007.

HIV Infection Associated with Pre-existing Ad5 Antibodies

Baseline Ad5 Titer

Vaccine V

PlaceboP

Relative Incidence (V:P)

< 18* 4.0 4.0 1.0

19-200 4.4 2.2 2.1

201-1000 6.1 3.0 2.0

> 1000 4.4 1.2 3.5

Incidence (%) of HIV Infection MITT Population (males)

*Note: 18 is the limit of detection for the Ad5 assay.

http://www.iavireport.org/Issues/Issue11-5/Step.asp

USA: Approximately half population Ad5+

East Africa: 95% population Ad5+

Immediate Implications for Future Studies: PAVE

STEP

Partnership for AIDS Vaccine

Evaluation (PAVE)

Steinbrook. 20057 NEJM 357:2653.

According to Anthony Fauci, the director of the NIAID, "To be brutally honest with ourselves, we have to leave open the possibility . . . that we might not ever get a vaccine for HIV.

People are afraid to say that because they think it would then indicate that maybe we are giving up. We are not giving up. We are going to push this agenda as aggressively and energetically as we always have. But there is a possibility — a clear finite possibility — that that's the case."

The longest journey begins with a single step, and then another, and then another….

Vaccine Time from Bench to Clinic

Human Papillomavirus 14 years

Rotavirus 15 years

MMR (combination vaccine) 16 years

FluMist® nasal flu vaccine 27 years

Chickenpx (VARIVAX®) 33 years

Source: Stefan Kappe, Ph.D. Seattle Biomedical Research Institute. 2007.

Development of Clinical Vaccines

Questions?