Promising HIV Vaccine Strategies: Where We Have BeenWhere We Are Going

Barton Haynes
September 11, 2011 Bangkok, Thailand

HIV Vaccine Development

Virus discovered 1983 Cause of AIDS 1984
Vaccine development began 1984
2

HIV Vaccine Development

Hepatitis B virus vaccine is the outer coat (envelope)
1984- take the outer coat of HIV gp120 (envelope) and make the vaccine
3

HIV Vaccine Development

Protection from viruses antibodies that block (neutralize) virus

HIV Envelope gp120 made into AIDSVAX B/B and AIDSVAX B/E vaccines
330 300

N E S R I I

A K T N N T I L I

310

K S R V V I N C T

320

S I T I R T G T P

I
200

E E A L S G N L L L
290

T P G 260 F Y I L P S S V Q 270 A E D C N C T V H D H G C K N I V C Y N K 250 T P K 240 H L N I I A Y G A Q D 210 P K 190 S I K P E S I K D D Y Q V 230 R S F L E P S R I 220 T C K T T P L L K V N M T I N C C P P N K C P 180 F L 130 T V 140 L S S 170 H Q N I T N C C G D E V R D I 120 T W I Q E N M D V L N Q I S A E S V N V 150 L M 110 N N K W M N F N E T V N T N K E T 160 90 N A R L 100 L N N P V W A T H A P T V N T D C V H N D PN Q E I 80 L A A V A C F Y D S L T K E D A A 70 S L T N G T K D K M A A E W R A D H R P 40 V E G H L N N G V R K 60 I V F E V R W 50 F L G K D V L L PV L D Q L L E V P I Y V 500 K A G L R NH2 A A A G G M V N K

K L D I

N G

V2

Q T 280 S V V K P

V1

T I I C E T G N C N N F L G F 410 R N N I T 380 N T T K P I L 430 I N P F C Q C Y S P P K GG I K F D Q I F 390 L I 400 E E N 440 G I T MH H F N C R M W V C N I N S 460 I Q T T G G I G A L G S 450 L A Q I Y M T P A R D 470 P G G A T N N 490 T D K I N 480 N G G N G P R F T E

C Y A I E K R N 350 G T E W 360 N K A L K Q V T E K 370 H E K L

I D G I

T I D G

G Q V F Y

V3

340

420

A N G

V4

V5

510

G V

YK V V Q I E P

A P T

A K R R

R R E K V E

COOH

520

Amino acid sequence inside circles represents A244 gp120 gD(+). (adapted from Leonard, et al.,J.Biol. Chem. 265, 10373, 1990).

HIV Vaccine Development

HIV mutatesdiverse --strains we used in the laboratory not like strains in field --Lab cultured strains easy to neutralize while field strains difficult

HIV Vaccine Development

Vaccines induce antibodies against regions of the envelope that neutralize the easy to neutralize HIV strains but do not neutralize field HIV strains.

V2,V3 Quaternary (conformational) CD4 binding site CD4 binding site

V3 Loop

Carbohydrate

V1V2 Loops Membrane proximal

V2,V3 Quaternary (conformational) CD4 binding site CD4 binding site

V3 Loop

Carbohydrate

V1V2 Loops Membrane proximal

V2,V3 Quaternary (conformational) CD4 binding site CD4 binding site

V3 Loop

Carbohydrate

V1V2 Loops
Membrane proximal

V2,V3 Quaternary (conformational) CD4 binding site CD4 binding site

V3 Loop

Carbohydrate

V1V2 Loops
Membrane proximal

HIV Envelope gp120 made into AIDSVAX B/B and AIDSVAX B/E vaccines
330 300

N E S R I I

A K T N N T I L I

310

K S R V V I N C T

320

S I T I R T G T P

I
200

E E A L S G N L L L
290

T P G 260 F Y I L P S S V Q 270 A E D C N C T V H D H G C K N I V C Y N K 250 T P K 240 H L N I I A Y G A Q D 210 P K 190 S I K P E S I K D D Y Q V 230 R S F L E P S R I 220 T C K T T P L L K V N M T I N C C P P N K C P 180 F L 130 T V 140 L S S 170 H Q N I T N C C G D E V R D I 120 T W I Q E N M D V L N Q I S A E S V N V 150 L M 110 N N K W M N F N E T V N T N K E T 160 90 N A R L 100 L N N P V W A T H A P T V N T D C V H N D PN Q E I 80 L A A V A C F Y D S L T K E D A A 70 S L T N G T K D K M A A E W R A D H R P 40 V E G H L N N G V R K 60 I V F E V R W 50 F L G K D V L L PV L D Q L L E V P I Y V 500 K A G L R NH2 A A A G G M V N K

K L D I

N G

V2

Q T 280 S V V K P

V1

T I I C E T G N C N N F L G F 410 R N N I T 380 N T T K P I L 430 I N P F C Q C Y S P P K GG I K F D Q I F 390 L I 400 E E N 440 G I T MH H F N C R M W V C N I N S 460 I Q T T G G I G A L G S 450 L A Q I Y M T P A R D 470 P G G A T N N 490 T D K I N 480 N G G N G P R F T E

C Y A I E K R N 350 G T E W 360 N K A L K Q V T E K 370 H E K L

I D G I

T I D G

G Q V F Y

V3

340

420

A N G

V4

V5

510

G V

YK V V Q I E P

A P T

A K R R

R R E K V E

COOH

520

Amino acid sequence inside circles represents A244 gp120 gD(+). (adapted from Leonard, et al.,J.Biol. Chem. 265, 10373, 1990).

HIV Vaccine Development

AIDSVAX B/B 2 clade B envelopes (Western hemisphere)trial did not protect AIDSVAX B/E 1 clade B and 1 clade AE (Thailand)trial did not protect

13

HIV Vaccine Development

Army, Thai Ministry of Health, NIAID, sanofi-pasteur
ALVAC (canary pox) carrying HIV genes including an envelope + AIDSVAX B/E Low risk subjects
14

ALVAC gp120 92TH023-TM construct

V3: green 17b-site: purple cd4bs: yellow

V1V2: pink
light blue: glycans gp120 N-terminus: dark blue gp120 C-terminus: red TM domain lipid membrane
core: 15 of 16 glycans built v1v2: 6 of 8 v3: 1 of 1 v4v5: included in core

top view

P. Huang, B. Schief

HIV Envelope gp120 made into AIDSVAX B/B and AIDSVAX B/E vaccines
330 300

N E S R I I

A K T N N T I L I

310

K S R V V I N C T

320

S I T I R T G T P

I
200

E E A L S G N L L L
290

T P G 260 F Y I L P S S V Q 270 A E D C N C T V H D H G C K N I V C Y N K 250 T P K 240 H L N I I A Y G A Q D 210 P K 190 S I K P E S I K D D Y Q V 230 R S F L E P S R I 220 T C K T T P L L K V N M T I N C C P P N K C P 180 F L 130 T V 140 L S S 170 H Q N I T N C C G D E V R D I 120 T W I Q E N M D V L N Q I S A E S V N V 150 L M 110 N N K W M N F N E T V N T N K E T 160 90 N A R L 100 L N N P V W A T H A P T V N T D C V H N D PN Q E I 80 L A A V A C F Y D S L T K E D A A 70 S L T N G T K D K M A A E W R A D H R P 40 V E G H L N N G V R K 60 I V F E V R W 50 F L G K D V L L PV L D Q L L E V P I Y V 500 K A G L R NH2 A A A G G M V N K

K L D I

N G

V2

Q T 280 S V V K P

V1

T I I C E T G N C N N F L G F 410 R N N I T 380 N T T K P I L 430 I N P F C Q C Y S P P K GG I K F D Q I F 390 L I 400 E E N 440 G I T MH H F N C R M W V C N I N S 460 I Q T T G G I G A L G S 450 L A Q I Y M T P A R D 470 P G G A T N N 490 T D K I N 480 N G G N G P R F T E

C Y A I E K R N 350 G T E W 360 N K A L K Q V T E K 370 H E K L

I D G I

T I D G

G Q V F Y

V3

340

420

A N G

V4

V5

510

G V

YK V V Q I E P

A P T

A K R R

R R E K V E

COOH

520

Amino acid sequence inside circles represents A244 gp120 gD(+). (adapted from Leonard, et al.,J.Biol. Chem. 265, 10373, 1990).

HIV Vaccine Development

Army, Thai Ministry of Health, NIAID, sanofi-pasteur
ALVAC (canary pox) carrying HIV genes including an envelope + AIDSVAX B/E Low risk subjects 31% protection

17

V2,V3 Quaternary (conformational) CD4 binding site CD4 binding site

V3 Loop

Carbohydrate

V1V2 Loops
Membrane proximal

The RV144 ALVAC/HIV Prime, rgp120 B/E Trial: Immune Correlates Analysis

Barton Haynes
For the RV144 Immune Correlates Working Group September 13, 2011

19

Objectives of the Study

RV144 Estimated Vaccine Efficacy = 31% (95% CI, 1.1 to 52.1, P=0.04)

Objective: To carry out a correlates analysis to begin to identify how the vaccine might work.

20

Stratified Squamous Epithelium

HIV-1 2 Mucus Layer 1

Columnar Epithelium
HIV-1-infected cells 1

3 4 Langerhan/ dendritic cells CD4 T cells

47 CD4 CCR5

CD4 T cells

5-9

HIV-1- CD4 interactions

Macrophage FcR-mediated phagocytosis of virions and ADCC of virus infected CD4 T cells. NK Cell NK cell FcR-mediated ADCC

10,11

Definitions
Correlate of Risk- an immune response that predicts whether vaccinees become HIV-1 infected.

It may be causally related to protection from infection, or may be only a surrogate marker for another factor.
22

Hypothesis Generating Study

Goal of the statistical analysis is to discover correlates of risk

Such discoveries would generate hypotheses about the immune responses that contributed to protection

23

Case Control Study

Measured immune responses from: 41 Infected Vaccinees 205 Uninfected Vaccinees 40 Placebo Recipients Question: What are the immunologic measurements in vaccinees that predict HIV-1 infection over 3 year follow-up? Sample Time point: 2 weeks (peak immunogenicity) after final vaccination: Cryopreserved specimens: 2.5 ml plasma and 24 2 vials of cells

HIV Vaccine Development-Field is doing Two Things

Figure out how ALVAC/HIV AIDSVAX B/E worksthen make it better
Figure out how to induce the antibodies against Achilles Heels of envelope that the body doesnt normally want to make.

25

V2,V3 Quaternary (conformational) CD4 binding site CD4 binding site

V3 Loop

Carbohydrate

V1V2 Loops
Membrane proximal