TOWARDS AN HIV VACCINE
why is it so hard to make an HIV vaccine and where are we now?
Neal Nathanson, MD Emeritus Professor Department of Microbiology University of Pennsylvania School of Medicine
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Estimated number of persons living with HIV/AIDS, December, 2004
1 million
8 million
26.8 million Global total: 39.4 million
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TOWARDS AN HIV VACCINE
g g g g g g g
Why is it so hard to make an AIDS vaccine? ‘Sterilizing’ or ‘partial’ immunity? Immune correlate of protection? Cellular immunity: provides protection? Neutralizing antibody: a daunting challenge Cross-clade immunity? Current status of AIDS vaccines?
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TOWARDS AN HIV VACCINE
WHY IS IT SO HARD TO MAKE AN AIDS VACCINE?
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TOWARDS AN HIV VACCINE
RESEARCH EXPERIENCE
• • • • • •
HIV env protein fails to induce neutralizing Ab Live attenuated SIVs protect but cause AIDS First HIV infection may not attenuate a second HIV infection? Persistence of HIV and progression to AIDS Immunobiological questions must be addressed Mechanisms of vaccine protection?
BIOLOGICAL ISSUES
IMPLICATION
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TOWARDS AN HIV VACCINE
VAXGEN TRIAL OF rgp120 multiple immunizations, 3 year cumulative infection percentage Science 2003, 299: 1290
GROUP TOTAL
TREATMENT PLACEBO VACCINE PLACEBO VACCINE PLACEBO VACCINE
SUBJECTS 1679 3330 1508 3003 171 327
INFECTIONS 98 191 81 179 17 12
PERCENT 5.8% 5.7% 5.4% 6.0% 9.9% 3.7%
WHITE, HISPANIC BLACK, ASIAN, OTHER
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TOWARDS AN HIV VACCINE
FIRST HIV INFECTION MAY NOT PROTECT AGAINST SECOND INFECTION? HIV INFECTION IN SEX WORKERS, NAIROBI, KENYA CASE # 3 OVERBAUGH ET AL, 2005, UNPUBLISHED
HIV-1 viral RNA levels
4.5 4.0
D
3.9
A
2.4 1.7
4.1
log10 copies/ml
3.5 3.0 2.5 2.0 1.5 1.0 0.5 Estimated days since infection
101
485
-50 0
150
350
550
750
950
1150
126 2
0.0
1350
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TOWARDS AN HIV VACCINE
THE DAUNTING TRIAD: FAILURE TO PREVENT INFECTION; PERSISTENCE; LOSS OF CD4 T CELLS
DYNAMICS OF HIV INFECTION ILLUSTRATING PROBLEMS IN PRE-EXPOSURE IMMUNIZATION 6 5 4 3 2 1 0 0 4
WEEKS HIV TRANSIENT INFECTION HIV (IMMUNIZED)
VIREMIA (LOG10 PER ML)
?
8
5
YEARS
10
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TOWARDS AN HIV VACCINE
“STERILIZING” OR “PARTIAL” IMMUNITY?
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TOWARDS AN HIV VACCINE
“STERILIZING” OR “PARTIAL” IMMUNITY? For viruses causing acute infections, subjects who have been adequately immunized usually undergo an abortive infection when exposed to a potentially virulent wildtype virus Will such ‘partial’ protection confer adequate resistance to an HIV challenge or is ‘absolute’ protection (‘sterilizing’ immunity) needed? Do studies of immunized monkeys challenged with SIV provide a useful reference? Do studies of viral set points and survival curves in HIV-infected humans provide a useful predictor? 10
TOWARDS AN HIV VACCINE
PROTECTION OF RHESUS MACAQUES AGAINST SIV SM E660 IV CHALLENGE BY RECOMBINANT VACCINIA (MVA) IMMUNIZATION Ourmanov, J Virology, 2000, 74: 2740
CONTROL RAPID PROGRESSORS 2 PROGRESSORS 3
RNA COPIES PER ML PLASMA GEOMETRIC MEAN
6 5 4 3 2 1 0 4 8
MVA gag-pol-env PROGRESSORS 1 NONPROGRESSORS 5
12
16
WEEKS AFTER CHALLENGE
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VIRUS SETPOINT DETERMINES THE COURSE OF THE INFECTION
Mellors et al, Science, 1996, 272: 1167; Whittle et al, COI, 1998, 10: 382.
100 90
<0.5
HIV-2
PERCENT SURVIVING
80 70 60 50 40 30 20 10 0 0 2 4 6 8 10 VIRAL SETPOINT 4-12 0.5-4
HIV-1
12-29 29-250 12 14 16 18
YEARS OF STUDY
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TOWARDS AN HIV VACCINE
IMMUNE CORRELATES OF PROTECTION?
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TOWARDS AN HIV VACCINE
CORRELATE HYPOTHESIS? Does protection correlate with a specific immune response parameter, such as antibody, CTL killing, or CD4+ proliferation? BARRIER HYPOTHESIS? Might a combination of antibody plus CTLs plus associated cytokine responses act in concert to constitute a sufficient barrier? Could different immunizing protocols protect by a different mix of immune defenses?
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CELLULAR IMMUNITY PROVIDES PARTIAL PROTECTION
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CD8 CELLULAR IMMUNE RESPONSE GOVERNS VIRUS SETPOINT Schmitz et al, Science 1999, 238: 857.
VIRAL RNA (COPIES PER ML)
7 6
MONKEY A
7 6 MONKEY B 5 4 3
5 4 3 -10 -5 0 5 10 15 20 25 30
CD8 DEPRESSED
DAYS AFTER IMMUNOSUPPRESSION
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TOWARDS AN HIV VACCINE
VACCINE FAILURE DUE TO ESCAPE FROM A SINGLE CD8 EPITOPE recombinant env-gag DNA/IL-2 vaccine; SHIV challenge
Barouche et al, Nature 2002, 415: 335.
LOG10 mRNA PER ML PLASMA
7
SHIV ESCAPE MUTANT (p11C DOMINANT EPITOPE)
6
1200
4
800
3
2 0 10 20 30 40 50
400
WEEKS AFTER INFECTION
CD4 PER µL
5
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NEUTRALIZING ANTIBODY: A DAUNTING CHALLENGE
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NEUTRALIZING ANTIBODY INFLUENCES VIRUS SETPOINT
chimp anti-HIV passive antibody; challenge: iv virulent SHIV (matched gp120)
Shibata et al, Nature Medicine, 1999, 5: 204; Nishimura et al, JV, 2002 76: 2123
SHIV DNA (LOG 10 COPIES PER 105 PBMC)
3 CONTROL (4) N AB TITER <2
2
1
PARTIAL (4) N AB TITER 2.5-4
0 COMPLETE (2) N AB TITER 5-8 -1 0 20 40 60 80 100 120
DAYS AFTER INFECTION
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TOWARDS AN HIV VACCINE
PASSIVE ANTIBODY PROTECTS MONKEYS AGAINST SUBSEQUENT CHALLENGE WITH VIRULENT SHIV Nishimura, 2002
PERCENT PROTECTION AGAINST SHIV CHALLENGE
100
80
60
40
20
0 0 20 40 60 80 100 120
SERUM DILUTION (1/X) PROVIDING 99% NEUTRALIZATION IN CELL CULTURE
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TOWARDS AN HIV VACCINE
MHC II
SIV
gp120
THE NEUTRALIZING ANTIBODY ENIGMA Using gp120, it is difficult to raise neutralizing antibody Using MHC Class II, anti-SIV neutralizing antibody can be readily induced INFERENCE? the problem lies with gp120 and not in any intrinsic ability of SIV to resist neutralization Query: is SIV gp120 a poor target for neutralization? Do gp120 neutralization escape mutants play a role?
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TOWARDS AN HIV VACCINE
HIV INFECTION INDUCES AUTOLOGOUS NEUTRALIZING ANTIBODY THAT SELECTS FOR ESCAPE VARIANTS
Richman et al, PNAS 2003, 100: 4144 PLASMA NEUTRALIZING TITER MONTHS AFTER INFECTON
0 0
VIRUS MONTHS
6 675 <100 <100 <100
12 2670 1769 <100 117
18 2190 2247 556 122
<100 <100 <100 <100
6 12 18
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THE NEUTRALIZING ANTIBODY ENIGMA
gp120
CD4 binding site
CD4 ligand domain
IgG binding domain targets near the CD4 binding site permitting viral escape mutants
if CD4 can dock why can’t IgG block attachment?
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TOWARDS AN HIV VACCINE
Influenza virus has a receptor site on each trimer head and can be neutralized by antibodies that bind to any of four different sites that are near the receptor binding site. Viral escape mutants can be selected for each of these neutralizing antibody sites
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CROSS CLADE IMMUNITY?
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THERE ARE ABOUT 10 DISTINCT CLADES (GENOTYPES) OF HIV-1
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ARE THE ~10 CLADES DISTINCT IMMUNOTYPES?
• • • •
Will neutralizing antibody cross clades? Will cellular immunity cross clades? Relevance of conserved vs variable epitopes? Are multivalent HIV-1 vaccines needed?
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TOWARDS AN HIV VACCINE
MULTICLADE VACCINE IS EQUAL TO MONOCLADE VACCINE
Rhesus monkeys immunized with env DNA @ 0, 4, 8 wks; rAdV env DNA @ 26 wks Tested 1 week post vaccine Letvin et al, 2003
env IMMUNOGEN BY CLADE mg DNA A 1.5 B 4.5 1.5 C 4.5 1.5
env RESPONSES BY CLADE IFN ELISPOT/106 PBL A 1200 1500 2500 B 2900 1200 2200 C 1300 2700 2600
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CURRENT STATUS OF AIDS VACCINES
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vaccine provides partial protection in SIV model
rDNA plus rAdv (SIV239 gag, pol, env) immunization iv SIV 251 (heterologous) challenge Letvin et al, unpublished, 2005
100
Vaccinated
% Survival
80
60
40
20
(n = 24)
Control
(n = 6)
p=0.007
0
0
50
100
150
200
250
300
350
400
Days Post-SIVmac251 Challenge
P=0.007 p=0.007
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TOWARDS AN HIV VACCINE
lessons from poliovirus vaccine
“In 1945, Professor Burnet of Melbourne wrote ‘While I was in America recently I had good opportunity to meet with most of the men actively engaged on research in poliomyelitis…The part played by acquired immunity to poliomyelitis is still completely uncertain, and the practical problem of preventing infantile paralysis has not been solved. It is even doubtful whether it ever will be solved.’ …most of us doing research on poliomyelitis in 1945 were mainly motivated by curiosity, rather than by the hope of a practical solution in our lifetime.” David Bodian, 1976
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