Transcript HIV Vaccine Research Dina Kovarik, M.S., Ph.D. Program Manager, NWABR May 16, 2009 www.uhaweb.hartford.edu/bugl/images/HIV_bud2.jpg.

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
Report on the Global AIDS Epidemic. Executive Summary. 2007. www.unaids.org
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pg
www.lincolncountyhealth.com.
www.mlm.nih.gov
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Human Immunodeficiency Virus (HIV)
gp41
gp120
vif
gag
rev
pol
tat
vpr
http://www.rhodes.edu/biology/glindquester/viruses/pagespass/hiv/attachment.jpg
vpu
nef
env
TM
Burton et al. 2005. PNAS 102:14943.
Immune Responses to Infection
Virion
Antigen Presenting Cell
(APC, Phagocyte)
Immune Responses to Infection
Virion
CD8+ T Cell
Killer T
Cells
Antigen Presenting Cell
(APC, Phagocyte)
Kill
Infected
Cells
Immune Responses to Infection
Virion
CD8+ T Cell
Killer T
Cells
Kill
Infected
Cells
Antigen Presenting Cell
(APC, Phagocyte)
B Cell
Antibodies
Coat
Pathogen
Immune Responses to Infection
Virion
CD8+ T Cell
Killer T
Cells
CD4+ T Cell
T Helper
Cells
Antigen Presenting Cell
(APC, Phagocyte)
B Cell
Immune Correlates and HIV Infection
CD4+ T Cells
Antibodies
Neutralizing Abs
CD8+ T Cells
Weeks
Months
Years
Time Post-Infection
T Cell Count or Antibody Titer
RNA Copies per Milliliter
Peak Virus Load
Binding Versus Neutralizing Antibodies
Neutralizing
Antibodies (NAb)
Y
Binding
Antibodies (BAbs)
X
Adapted from Wendy Blay Puryear, Ph.D.
Nonhuman primate models for AIDS
Macaca fascicularis
Macaca mulatta
Macaca nemestrina
• 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://upload.wikimedia.org/wikipedia/commons/9/9f/
Macaca_fascicularis.jpg
http://www.aaas.org/news/releases/2
007/images/0416macaque_lone.jpg
http://www.theprimata.com/macaca_nemestrina.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
Memory Response
Primary Response
Strength of Response
Strength of Response
Memory Response
1st Infection
2nd Infection
Primary Response
Vaccination
1st Infection
The Race to Catch HIV
Brenchley et al. 2004. J Exp Med 200:749.
Mattapallil et al. 2005. Science 434:1093.
But HIV Keeps Running Away…
Virus Time Point
Serum Time Point
0
1
2
3
4
5
6
Richman et al. 2003. PNAS 100:4144.
0
1
2
3
4
5
6
-
-
-
-
-
-
-
+ - - + + - + + + -
-
-
-
+ + + + - + + + + + -
-
+ = patient serum able to
neutralize patient virus
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
Homogeneous new infection
Replicates ~ 24hrs
Produces 1010 new virions a day
Average 1 mutation per replicated genome
Rapidly develop a “quasispecies”
Wendy Blay Puryear, Ph.D.
HIV-1 Diversity Worldwide
HIV-1 group M:
- 9 subtypes (>30% difference)
- several circulating recombinant forms
Subtype
A
B
C
D
F, G, H, J. K
CRF01_AE
CRF02_AG
CRF03_AB
other
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
Polio (IPV / injected, Salk)
Hepatitis A Virus
Influenza
Rabies
Cholera
Plague
Tetanus toxoid
Diphtheria toxin
Inactivated (Killed)
Toxoid
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
Recombinant
Proteins
Moderately
Potent NAbs
gp120
Peptides
gp140
trimers
Safety (HIV)
and Efficacy
(Merck)
Live Infection
Attenuated HIV
Vector Viruses
(Adenovirus, Poxvirus)
Other Approaches
Plasmid DNA
Virus-Like Particles (VLPs)
Inactivated Virions
http://www.aids.harvard.edu/images/laboratories/figure_virionstructure.jpg
Variables in HIV Vaccine Development
Vaccine Modality
Whole, killed
Attenuated
DNA
Recombinant Proteins
Peptides
Virus-like particles
Mimetopes
Vectors:
Vaccinia
Modified Vaccinia Ankara
Fowlpox
Canarypox
Adenovirus
Herpes simplex virus
Rabies virus
Vesicular Stomatitis Virus
Semiliki Forest Virus
Adeno-associated virus
OPV
Salmonella
Moloney Leukemia virus
Hepatitis B virus
Listeria monocytogenes
Gene
env
gag
pol
nef
tat
rev
vif
vpr
vpu
Model
Mouse
Rabbit
Guinea Pig
Ferret
Monkey
Virus
SHIVSF162
SHIV89.6/P
SIVmac239/251
SIV E660
SIV mne
Macaca nemestrina
Macaca fascicularis
Macaca mulatta
Adjuvant
Alum
Cytokines
Pulsed DC
Co-stimulatory
QS-21
CpG oligos
PROPRIETARY
Adminitration
Dose
Route
Timing
Adapted from Nancy Haigwood, Ph.D.
Stages of Vaccine Clinical Trials
Phase
Objective
1
Evaluate Vaccine Safety
20-50
2
Test 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)
Number of Volunteers
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
Bavarian Nordic
Aaron Diamond AIDS Research Center
Wyeth
GeoVax
Aventis-Sanofi Pasteur/ANRS
Therion
Chrion
VaxGen
Merck
B
B
AIDSVAX: Targeting gp120
B
E
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)
Endpoints:
Prevention of HIV Infection
Reduction in Viral Load
Maintenance of CD4+ T cells
Nitayaphan et al. 2004. J Infect Dis 190:702.
Protective Effectiveness less
than 30% (or indeterminant)
However, the vaccine was safe,
and the trial itself was a success
B
Thai Prime-Boost Study
E
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
Endpoints:
Prevention of HIV Infection
Reduction in Viral Load
Maintenance of CD4+ T cells
http://www.primeboost3.org/eng/
Thai Prime-Boost Study
Trial Cost: $119 million
Cost of rgp120: $3 million
2007 Interim Analysis: No safety concerns
Final results expected by the end of 2009.
“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.
http://www.iavireport.org/
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)
Endpoints:
Prevention of HIV Infection
Reduction of Viral Load: Delayed onset of AIDS, reduced transmission
STEP Trial Efficacy Analyses: HVTN Full Group Meeting. Nov 7, 2007.
STEP Interim Analysis
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
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
Incidence (%) of HIV Infection MITT Population (males)
Baseline
Ad5 Titer
Vaccine
V
Placebo
P
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
USA: Approximately half population Ad5+
East Africa: 95% population Ad5+
*Note: 18 is the limit of detection for the Ad5 assay.
http://www.iavireport.org/Issues/Issue11-5/Step.asp
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….
Development of Clinical Vaccines
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.
Questions?