Preventive HIV Vaccines at the Crossroads

1
Preventive HIV Vaccines at the Crossroads
Scott M. Hammer, MD Professor of
MedicineColumbia University College of
Physicians and Surgeons
The International AIDS SocietyUSA
SM Hammer, MD. Presented at IASUSA New York
Course, March 14, 2008.
2
HIV Prevention Landscape

• Behavioral modification and proven interventions
• Drugs for prevention
• pMTCT
• Treatment of discordant () partner
• Post-exposure prophylaxis (PEP)
• Pre-exposure prophylaxis (PrEP)
• Microbicides
• Male circumcision
• Treatment/prevention of genital ulcer disease
• Especially HSV-2
• Vaccine

3
Goals of an Effective HIV Vaccine

• Protective immunity
• Sterilizing immunity
• Abortive infection
• Viremic control and amelioration of disease
  
• Reduction of HIV transmission
  in the population

Garber DA et al Lancet Inf Dis 20044397-413
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Datasets Which Drive HIV Vaccine Concepts

• Acutely HIV infected patients
• Long-term non-progressors
• Especially, elite suppressors (controllers)
• Those who spontaneously suppress viral load to
  lt50 copies/ml
• Exposed but uninfected
• Non-human primate models

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Role of CTLs in Control of Viremia
Letvin N Walker B Nature Med 20039861-866
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HIV Vaccine Scientific Challenges

• Viral diversity
• Complex molecular epidemiology
• Induction of broadly reactive neutralizing
  antibodies
• Definition of immune correlates of protection
• Potential for viral escape
• HIV coinfection and superinfection
• Need for protection against mucosal and blood
  challenges
• Multiple candidate immunogens and adjuvants
• Dose, regimens, combinations
• Vector immunity
• Influence of varied HLA backgrounds

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A, B, AB recombinant
A
CRF02_AG, other recombinants
Insufficient data
B
CRF01_AE, B
C
B, BF recombinant
F,G,H,J,K,CRF01 other recombinants
D
B, C, BC recombinant
GLOBAL DISTRIBUTION OF HIV-1 SUBTYPES AND
RECOMBINANTS
Courtesy F. McCutchan
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Structures and Targets of Broadly Neutralizing
Antibodies for HIV
HIV Virion
Viral Membrane
gp41
Viral Spike
gp120
Broadly NeutralizingAntibodies
2F5
2G12
b12
4E10
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Immunogen Delivery Approaches

• Protein subunits
• Primarily induce antibody responses
• Recombinant peptide-based
• Can be modified to improve immunogenicity
  clustering of conserved epitopes, lipopeptide
  formulations, etc.
• DNA-based
• Primarily induce cell mediated responses
• Responses may be improved with adjuvants, and
  prime-boost approaches
• Vector-based
• Can induce both cell mediated and antibody
  responses
• Viral
• Bacterial
• Fungal
• Virus-like particles

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Potential Vaccine Vectors
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The T Cell Vaccine Concept
A combination of broad and potent CD4- and
CD8-mediated T-cell immune responses will prevent
HIV infection or control HIV disease through
cytolysis of virus producer cells, the
elaboration of anti-viral cytokines, or through
yet undefined mechanisms.

• External Viral Protein
• Envelope

Recognition of degraded viral peptide
HIV-infected cells

• Internal Viral Proteins
• Gag
• Protease
• Reverse Transcriptase
• Integrase, Nef

CD4
CD8
Provirus
T cellreceptor
Processedpeptides
Class I MHC
Courtesy G. Nabel
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Efficacy Results from the Step Study (Merck V520
Protocol 023/HVTN 502)A Phase II
Test-of-Concept Trial of the MRKAd5 HIV-1
Gag/Pol/Nef Trivalent Vaccine

• Susan Buchbinder, Michael Robertson, et al.
• 15th CROI
• February 5, 2008
• Boston, MA

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MRKAd5 trivalent vaccine

• Vaccine 111 admixture of 3 Ad5 vectors
• Encoded transgenes codon-optimized,
  near-consensus clade B HIV-1 sequences
• Placebo vaccine dilution buffer without Ad5

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STEP Study sites
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• Viral Load Set-Points Ad5 ? 200
• Planned interim analysis

Per-protocol
MITT
1-tailed p-value (benefit) 0.528 (for VEVLgt0)
1-tailed p-value (benefit) 0.656 (for VEVLgt0)
There was 1 female infection VLS 20,207 c/mL
(4.31 log10 c/mL)
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Cumulative Number of HIV Infections MITT
population (males), Ad5 200
1-tailed p-value 0.322 (for VEINF lt 0) 2-tailed
p-value 0.581 (for VEINF ? 0)
Cases accrued as of Oct 17, 2007
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Cumulative Number of HIV Infections MITT
population (males)
Overall
Ad5 gt 200
1-tailed p-value 0.044 (for VEINF lt 0)
2-tailed p-value 0.077 (for VEINF ? 0)
1-tailed p-value 0.020 (for VEINF lt 0)
2-tailed p-value 0.029 (for VEINF ? 0)
Cases accrued as of Oct 17, 2007
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Cumulative Number of HIV Infections MITT
Population
Cases accrued as of Oct 17, 2007
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Vaccine Research Center Vaccine Hypothesis
An AIDS vaccine can control or prevent
replication of relevant diverse HIV isolates
through antiviral CD4 and/or CD8 T cell responses
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VRC 6-Plasmid DNA HIV Vaccine
VRC-HIVDNA016-00-VP
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VRC rAd5 HIV Vaccine
VRC-HIVADV014-00-VP
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DNA/rAd5 Immunization Reduces Early Virus
Replication in SIVmac251 Infection
Mattapallil J, Roederer M, et al, J Exp Med 2006.
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Vaccine Efficacy Statistically Significant
Survival Advantage in Vaccinated Monkeys
100
75
Survival
50
25
P
0.0019
0
0
200
400
600
800
Days Post-Challenge
Vaccinated
Control
N. Letvin, et al., Science 2006
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VRC Candidate HIV Vaccine
0
1
2
12
Months
3
6
9
CMV-R promoter
rAd5
Env A Env B Env C gag B pol B nef B
Env A Env B Env C gag/pol B
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Differences in VRC and Merck Clinical Products
VRC
0
1
2
12
Months
3
6
9
Only common constituent Ad Gag-Pol (no Nef) lt1
of 22 injected components
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Comparison of VRC and Merck Vaccines
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AIDS Vaccine The Next Decade
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
2017
Merck rAdGag, Pol, Nef
VRC DNA/rAd Gag, Pol, Nef, Env A, B, C
Nab Vaccine
Test of T Cell Vaccine Concept
Next GenerationCombined by Mucosal/Innate
Test of Ab Vaccine Concept
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Redefining the Way Forward in HIV Vaccine
Research
National Institute of Allergy and Infectious
Diseases Summit on HIV Vaccine Research and
Development   Bethesda North Marriott Hotel
Conference Center Bethesda, MD   March 25, 2008
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HIV Vaccine Elements of Success

• Science
• Empiricism
• Luck!

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Acknowledgements

• Susan Buchbinder, UCSF
• Barney Graham, VRC/NIAID/NIH
• Francine McCutchan, HJF/USMHRP
• Gary Nabel, VRC/NIAID/NIH
• Michael Robertson, Merck