TOWARDS AN HIV VACCINE - University of Pittsburghsuper7/19011-20001/19611.pdf · TOWARDS AN HIV...

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TOWARDS AN HIV VACCINEwhy is it so hard to make an HIV vaccine and where are we now?

Neal Nathanson, MDEmeritus Professor

Department of MicrobiologyUniversity of Pennsylvania

School of Medicine

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Estimated number of persons living with HIV/AIDS, December, 2004

Global total: 39.4 million

26.8 million

8 million

1 million

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TOWARDS AN HIV VACCINE

g Why is it so hard to make an AIDS vaccine?g ‘Sterilizing’ or ‘partial’ immunity?g Immune correlate of protection?g Cellular immunity: provides protection?g Neutralizing antibody: a daunting challengeg Cross-clade immunity?g Current status of AIDS vaccines?

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WHY IS IT SO HARD TO MAKE AN AIDS VACCINE?

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RESEARCH EXPERIENCE• HIV env protein fails to induce neutralizing Ab• Live attenuated SIVs protect but cause AIDSBIOLOGICAL ISSUES• First HIV infection may not attenuate a second HIV infection?• Persistence of HIV and progression to AIDSIMPLICATION• Immunobiological questions must be addressed• Mechanisms of vaccine protection?

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VAXGEN TRIAL OF rgp120multiple immunizations, 3 year cumulative infection percentage

Science 2003, 299: 1290

GROUP TREATMENT SUBJECTS INFECTIONS PERCENT

TOTAL PLACEBO 1679 98 5.8%VACCINE 3330 191 5.7%

WHITE, PLACEBO 1508 81 5.4%HISPANIC VACCINE 3003 179 6.0%

BLACK, PLACEBO 171 17 9.9%ASIAN, OTHER VACCINE 327 12 3.7%

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0.0-50 150 350 550 750 950 1150 1350

1262

3.9

2.4

1.7

4.1

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

HIV

-1 v

iral R

NA

leve

ls

log1

0 co

pies

/ml

Estimated days since infection

0

101

485

AD

TOWARDS AN HIV VACCINEFIRST HIV INFECTION MAY NOT PROTECT AGAINST SECOND INFECTION?

HIV INFECTION IN SEX WORKERS, NAIROBI, KENYACASE # 3

OVERBAUGH ET AL, 2005, UNPUBLISHED

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VIR

EMIA

(LO

G10

PER

ML)

0

1

2

3

4

5

6

HIV TRANSIENT INFECTIONHIV (IMMUNIZED)

4 80 5 10WEEKS YEARS

?

DYNAMICS OF HIV INFECTION ILLUSTRATINGPROBLEMS IN PRE-EXPOSURE IMMUNIZATION

THE DAUNTING TRIAD: FAILURE TO PREVENT INFECTION; PERSISTENCE; LOSS OF CD4 T CELLS

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“STERILIZING” OR “PARTIAL” IMMUNITY?

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“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 auseful reference?

Do studies of viral set points and survival curves in HIV-infected humans provide a useful predictor?

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PROTECTION OF RHESUS MACAQUES AGAINST SIV SM E660 IV CHALLENGE

BY RECOMBINANT VACCINIA (MVA) IMMUNIZATIONOurmanov, J Virology, 2000, 74: 2740

WEEKS AFTER CHALLENGE

0 4 8 12 16

RN

A C

OPI

ES P

ER M

L PL

ASM

AG

EOM

ETR

IC M

EAN

1

2

3

4

5

6

MVA gag-pol-envPROGRESSORS 1NONPROGRESSORS 5

CONTROLRAPID PROGRESSORS 2PROGRESSORS 3

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YEARS OF STUDY0 2 4 6 8 10 12 14 16 18

PER

CEN

T SU

RVI

VIN

G

0102030405060708090

100

0.5-4

4-12

12-2929-250

VIRALSETPOINT

<0.5HIV-2

HIV-1

VIRUS SETPOINT DETERMINES THE COURSE OF THE INFECTIONMellors et al, Science, 1996, 272: 1167; Whittle et al, COI, 1998, 10: 382.

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IMMUNE CORRELATES OF PROTECTION?

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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.

DAYS AFTER IMMUNOSUPPRESSION-10 -5 0 5 10 15 20 25 30

VIR

AL

RN

A (C

OPI

ES P

ER M

L)

3

4

5

6

7

3

4

5

6

7MONKEY A

MONKEY B

CD8 DEPRESSED

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TOWARDS AN HIV VACCINEVACCINE FAILURE DUE TO ESCAPE FROM A SINGLE CD8 EPITOPE

recombinant env-gag DNA/IL-2 vaccine; SHIV challengeBarouche et al, Nature 2002, 415: 335.

WEEKS AFTER INFECTION0 10 20 30 40 50

LOG

10 m

RN

A P

ER M

L PL

ASM

A

2

3

4

5

6

7

400

800

1200

CD

4 PE

R µ

L

SHIVESCAPE MUTANT(p11C DOMINANT EPITOPE)

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NEUTRALIZING ANTIBODY: A DAUNTING CHALLENGE

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TOWARDS AN HIV VACCINENEUTRALIZING 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

DAYS AFTER INFECTION

0 20 40 60 80 100 120SHIV

DN

A (L

OG

10

CO

PIES

PER

105 P

BM

C)

-1

0

1

2

3

CONTROL (4)N AB TITER <2

PARTIAL (4)N AB TITER 2.5-4

COMPLETE (2)N AB TITER 5-8

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SERUM DILUTION (1/X) PROVIDING 99% NEUTRALIZATION

IN CELL CULTURE

0 20 40 60 80 100 120

PER

CEN

T PR

OTE

CTI

ON

AG

AIN

ST S

HIV

CH

ALL

ENG

E

0

20

40

60

80

100

PASSIVE ANTIBODY PROTECTS MONKEYS AGAINST SUBSEQUENT CHALLENGE WITH VIRULENT SHIV

Nishimura, 2002

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SIVMHC II

gp120

THE NEUTRALIZING ANTIBODY ENIGMAUsing gp120, it is difficult to raise neutralizing antibodyUsing 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 neutralizationQuery: is SIV gp120 a poor target for neutralization? Do gp120 neutralization escape mutants play a role?

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TOWARDS AN HIV VACCINEHIV INFECTION INDUCES AUTOLOGOUS NEUTRALIZING

ANTIBODY THAT SELECTS FOR ESCAPE VARIANTSRichman et al, PNAS 2003, 100: 4144

PLASMA NEUTRALIZING TITERMONTHS AFTER INFECTON

VIRUSMONTHS

0 6 12 18

0 <100 675 2670 2190

6 <100 <100 1769 2247

12 <100 <100 <100 556

18 <100 <100 117 122

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THE NEUTRALIZING ANTIBODY ENIGMA

CD4liganddomain

IgG bindingdomain targets near the CD4 binding sitepermitting viral escape mutants

gp120CD4

bindingsite

if CD4 can dock why can’t IgG block attachment?

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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 VACCINEMULTICLADE VACCINE IS EQUAL TO MONOCLADE VACCINE

Rhesus monkeys immunized with env DNA @ 0, 4, 8 wks; rAdV env DNA @ 26 wksTested 1 week post vaccine

Letvin et al, 2003

env IMMUNOGENBY CLADE

mg DNA

env RESPONSESBY CLADE

IFN ELISPOT/106 PBLA B C A B C

--

1.5

4.5-

1.5

-4.51.5

120015002500

290012002200

130027002600

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CURRENT STATUS OF AIDS VACCINES

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TOWARDS AN HIV VACCINEvaccine provides partial protection in SIV modelrDNA plus rAdv (SIV239 gag, pol, env) immunization

iv SIV 251 (heterologous) challengeLetvin et al, unpublished, 2005

0 50 100 150 200 250 300 350 4000

20

40

60

80

100Vaccinated

Control

Days Post-SIVmac251 Challenge

% S

urvi

val (n = 24)

(n = 6)

p=0.007P=0.007

p=0.007

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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 themen 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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