New Frontiers in HIV Vaccine
Development
Barney S. Graham, M.D., Ph.D.
Chief, Clinical Trials Core and Viral
Pathogenesis Laboratory, VRC, NIAID, NIH
March 9, 2011
Impact of Licensed Vaccines
Viral Disease
Year of Peak US
Prevalence
Peak Number of Cases
per Year in US
Number of Annual US
Cases in Modern
Vaccine Era (2009)
Diphtheria
1921
200,000
0
Hepatitis A
1971
59,606
2,585 (2008)
Hepatitis B
1985
26,654
4,033 (2008)
Measles
1958 – 1962
503,282
71
Mumps
1967
185,691
1,991
Pertussis
1934
265,269
17,000
Polio
1951 – 1954
16,316
0
Rubella
1966 – 1968
47,745
3
Smallpox
1900 – 1904
48,164
0
Source: CDC/MMWR, WHO
Classical
Vaccinology
The response to natural
infection provides the
proof of concept
HIV
Vaccinology
Biological Challenges for HIV
Vaccine Development
• Lack of natural immunity
– No evidence of viral clearance and recovery from HIV infection
– Evidence of superinfection
• Genetic diversity
– Antigen selection
– Immune escape
• Infection of immunologic “First Responders”
– Infection of antigen presenting cells
– Interference with antigen presentation
– Rapid destruction of memory CD4+ T lymphocytes
• Infection of immunoprivileged sites, sequestered virus,
and latency
• Difficult to induce neutralizing antibody
• Imperfect animal models
First Signal of Efficacy in HIV
Vaccine Clinical Trials
Human Efficacy Data are
Always Pivotal
1st Evidence of ARV Efficacy
Fischl M et al NEJM 1987
1st Evidence of HIV vaccine efficacy
Rerks-Ngarm et al NEJM 2009
Iterative Research Process
Discovery
Preclinical
Research &
Development
Clinical
Research
Does HIV have an Achilles heel?
Zhou et al. Nature 2007; 445:732
Sites of Vulnerability on gp160
Schief WR et al. Curr Opin HIV AIDS. 2009;4:431
The Atomic Structure of VRC01 in
Complex with HIV-1 gp120
Contact surface
gp120
inner domain
gp120
outer domain
bridging sheet
Chen et al. Science 2009; 326:1123
Wu et al. Science 2010; 329:856
Zhou et al. Science 2010; 329:811
HIV Vaccinology: Moving Forward
 Recent data and advancing technologies provide new hope that
vaccine development is possible
 Reducing HIV acquisition is primary goal of vaccination
 Followup of RV144
 Improved delivery vectors and modified antigens
 New study populations and novel trial designs
 Opportunity to define immune correlates
 Structure guided antigen development
 Findings enable development of vaccines for tuberculosis,
malaria, influenza, respiratory syncytial virus, and biodefense
agents
Vaccine Research Center
VRC.NIH.GOV
1 866 833-LIFE
vaccines@nih.gov