VACCINES AGAINST HIV-AIDS: 2011

1. General considerations

2. Therapeutic vaccines against HIV. Dendritic cells

3. Preventive vaccines against HIV. Other strategies for prevention

4. Final considerations

7000 M 30 M + (85% in developing countries)

Preventive vaccine ART for life Eradication Therapeutic vaccine (functional cure)

Per year: > 600 Catalunya >3000 Spain > 3 M World

VACCINES AGAINST HIV-AIDS: 2011

1. General considerations

2. Therapeutic vaccines against HIV. Dendritic cells -Functional cure 3. Preventive vaccines against HIV. Other strategies for

prevention

4. Final considerations

Wild type

I Res.

R Res.

Z Res.

I

I

I+R+P

THERAPEUTIC VACCINE AGAINST HERPES ZOSTER Vaccines againts rabies, tetanus and difteria are therapeutic

5

50

500

5000

50000

500000

5000000

5 10 15 20 25 30 35 40 45 50 55 60

months

pla

sm

a v

iral

load

HAART STOP HAART TV

The immune system is not able to “contain” VL rebound even after a long term successful suppressive ART Conversely, the aim of an immunogen or a therapeutic vaccine should be to avoid VL rebound after interruption of ART

VACCINES AGAINST HIV-AIDS: 2011

Therapeutic vaccines against HIV infection Felipe García, Agathe León, Josep M Gatell, Montserrat Plana, Teresa Gallart Hospital Clinic-HIVACAT, IDIBAPS, University of Barcelona. Barcelona. Spain Correspondence to: Dr. Felipe García, Infectious Diseases Unit, Hospital Clínic, Villarroel, 170, 08036 Barcelona, Spain. Phone: 34932275586, FAX: 34934514438, E-mail: fgarcia@clinic.ub.es; Acknowledgments: This study was partially supported by grants: FIS PS09/01297, TRA-094, EC10-153, FIS PI10/02984, SAF2006-26667-E, RIS*, HIVACAT**, ORVACS***. Dr Felipe García was recipient of a Research Grant from IDIBAPS****, Barcelona, Spain. Dr. M Plana was supported by contract FIS 03/0072 from the Fundació Privada Clínic per a la Recerca Biomèdica in collaboration with the Spanish Health Department

VACCINES AGAINST HIV-AIDS: 2011

Modalities of therapeutic vaccines tested in clinical trials -Whole inactivated virus: 1

-Subunit vaccines: 4

-Vaccines using DNA as vector: 4

-Viral vector vaccines: 12

-Dendritic cells based vaccines: 2

HIVACAT Second Period HIVACAT Current Period

2012 2013 2014 2015 2016 2011

Timelines Therapeutic Vaccines

11

DCV2 DCV2 2nd arm & trial data

Development of pNL4.3/ΔRT/ΔGag chimeras

Δ-RT/ Δ-Int +/- chimeras

Phase I clinical trial & data analysis MVA/chimp-adeno

In vitro production & characterization of NL4.3/ΔRT virions & chimeras NL4.3/ΔRT/ΔGag NL4.3/ΔRT/ΔNef, NL4.3/ΔRT/ΔEnv

Development of safe recombinant chimeras Nef & Env and double

chimeras

Characterization , immunogenicity studies & analysis

DCV trial development

RISVAC03- MVA Phase I clinical trial & trial data

Phase II clinical trial

DCV3 & trial data DCV3

ORVACS

MANON 03 STUDY

HAART

Pulsed DC (4x106 virions/vaccine)

PLASMAPHERESIS

CD4>500 cells/microL PVL>5000 copies/ml

-w246

PVL<20

-w90

w0 6w 12w 18w

-d8 -d8 -d8

STOP-2

w30

-d8

STOP-1

HAART

-w78

Blood sample (60-80 ml)

for DC generation

HAART PLUS THERAPEUTIC VACCINE WITH AUTOLOGOUS MONOCYTE-DERIVED

DENDRITIC CELLS (DC) LOADED WITH INACTIVATED AUTOLOGOUS HIV-1

-d8

24w

Non-Pulsed DC

s.c. DC injections

CASES N=12

CONTROLS N=6*

HAART

PVL<20

HAART *2 lost for follow-up

0 2 4 6 8 10 12 14 16 18 20 22 24 260.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

stop1

stop2

Weeks after HAART interruption

log

10 o

f p

lasm

a v

iral

load

(co

pie

s/m

l)

Patient #262

0 2 4 6 8 10 12 14 16 18 20 22 24 260

1

2

3

4

5

6

Stop 1

Stop 2

WEEKS AFTER HAART INTERRUPTION

Patient #207

0 2 4 6 8 10 12 14 16 18 20 22 24 260

1

2

3

4

5

6

Stop 1

Stop 2

WEEKS AFTER HAART INTERRUPTION

log

10 o

f p

lasm

a v

iral

load

(co

pie

s/m

l)

0 2 4 6 8 10 12 14 16 18 20 22 24 260.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5stop1

stop2

Weeks after HAART interruption

log

10 o

f p

lasm

a v

iral

load

(co

pie

s/m

l) Figure 3D Figure 3C

Figure 3B Figure 3A

Cases: n=12

Controls: n=4

DCV-1 study

HAART Stop HAART

-72 -32 -24 0 2 4 6 8 10 48 WEEK

Inclusion criteria

1. <20 copies/ml

2. Nadir >350 C

CD4+ T c/mm3

Doses of pulsed MD-DC

STOP 1

Virus culture

STOP 2

ARM III (N=12)

ARM V

CONTROL

GROUP (N=12)

Doses of NON- pulsed MD-DC

ARM IV (N=12)

-d7 Blood sample (120 ml)

for DC generation

Doses of pulsed MD-DC

DCV2-b study

DCV-2b study (submitted)

• __ ______ _________ __ _____ ____ __ ____ __ ___ ___ __________ _ ____ ________ __ _____ ___ _______ ___ ___

• __ ____ _________ ___ ___ ________ _ ___ ___ ___ ___ ______ ___ • ____ ___ __ ___________ ____ ___ ______ __ _____ ____ __ ____ __ ___ ___

___________ __ __________ _______

Figure 5. Pre-ART vs. Week 12 of STI Log Change in Viral Load

-6,00

-5,00

-4,00

-3,00

-2,00

-1,00

0,00

1,00

2,00

Log C

hange in V

iral L

oad

___ _________ __ _____ ____ ___ __________ _ __ ___

Routy et al.

5

50

500

5000

50000

500000

5000000

5 10 15 20 25 30 35 40 45 50 55 60

months

pla

sm

a v

iral

load

HAART STOP HAART TV

VACCINES AGAINST HIV-AIDS: 2011

1. General considerations

2. Therapeutic vaccines against HIV. Dendritic cells -Discordant CD4 response ? -Eradication (ERAMUNE study) ? -Reduce reservoirs (ERAMUNE study) ? -Minimize inflammation / immune activation ?

-Minimize needs of ART ?

3. Preventive vaccines against HIV. Other strategies for prevention

4. Final considerations

Patients off HAART

-6 0 2 4 48 WEEKS

Inclusion criteria

1. > 10000 c/ml

2. Nadir >350

CD4+ T c/mm3

1st 2nd 3rd doses of

pulsed MD-DC

VIRUS

CULTURE

ARM I (N=12)

ARM II

CONTROLS

(N=12)

-d7 Blood sample (120 ml)

for DC generation

1st 2nd 3rd doses of

non-pulsed MD-DC

PART 1

Garcia F et al. JID, 2011

0 4 8 12 16 20 24 28 32 36 40 44 48-0.4

-0.2

0.0

0.2

0.4

DC-PLACEBO

DC-HIV-1

DC-PLACEBO 12 12 12 12 11 11 11 9DC-HIV-1 10 10 10 10 8 8 8 7

0.08

0.03

0.04

AUC,

P= 0.06

WEEKS

Lo

g 10

PVL

(cop

ies/

ml)

VIRAL LOAD RESPONSES

IT WAS OBSERVED A MODEST DECREASE OF VL IN VACCINATED PATIENTS

5

50

500

5000

50000

500000

5000000

5 10 15 20 25 30 35 40 45 50 55 60

months

pla

sm

a v

iral

load

Therapeutic vaccine

5

50

500

5000

50000

500000

5000000

5 10 15 20 25 30 35 40 45 50 55 60

months

pla

sm

a v

iral

load

Therapeutic vaccine

Less ART ? Later ART ?

7000 M 30 M + (85% in developing countries)

Preventive vaccine ART for life Eradication Therapeutic vaccine (functional cure)

Per year: > 600 Catalunya >3000 Spain > 3 M World

VACCINES AGAINST HIV-AIDS: 2011

1. General considerations

2. Therapeutic vaccines against HIV. Dendritic cells 3. Preventive vaccines against HIV. Other strategies for

prevention

4. Final considerations

clinicaloptions.com/hiv

HIV/AIDS Highlights From Rome

Efficacy of HIV Prevention Strategies From

Randomized Clinical Trials

Abdool Karim SS, et al. Lancet. 2011;[Epub ahead of print].

100 0 20 40 60 80

Efficacy (%)

Study Effect Size, % (95% CI)

ART for prevention; HPTN 052, Africa, Asia, Americas

PrEP for discordant couples; Partners PrEP, Uganda, Kenya

PrEP for heterosexual men and women; TDF2, Botswana

Medical male circumcision; Orange Farm, Rakai, Kisumu

PrEP for MSMs; iPrEX, Americas, Thailand, South Africa

Sexually transmitted diseases treatment; Mwanza, Tanzania

Microbicide; CAPRISA 004, South Africa

HIV vaccine; RV144, Thailand

96 (73-99)

73 (49-85)

63 (21-84)

54 (38-66)

44 (15-63)

42 (21-58)

39 (6-60)

31 (1-51)

VACCINE AGAINST HIV-AIDS: 2005

Most efficient and cost effective intervention in the eradication (small pox, polio) or control of transmisible infectious diseases Most are preventive Some are “therapeutic”: rabies, difteria, tetanus, zoster

VACUNAS: COMPONENTE MAGICO

I.P.

VACCINE AGAINST HIV-AIDS: 2011

Most efective vaccines have been discovered by trial and error without knowing the correlates of immuneprotection of natural disease or to prevent or modify the evolution of the disease

deteccion

análisis

reacción

Anticuerpos no neutralizantes neutralizantes

Células citotóxicas (CD8, CTL´s)

uso diagnóstico

control de la infección vacunas

uso diagnóstico control de la infección rechazo de transplantes vacunas ?

VACCINE AGAINST HIV-AIDS: 2005

Immune system (innate, Ab, CMI, mucosal) is the natural tool to identify, protect, eradicate and/ or modulate the evolution of transmisible infectious diseases After a first contact is able to generate a quick memory response Limited varibility of ofending pathogens. Cross reactivity Remains intact during the course of most infections

deteccion

análisis

reacción

Anticuerpos no neutralizantes neutralizantes

Células citotóxicas (CD8, CTL s)

uso diagnóstico

control de la infección vacunas

uso diagnóstico control de la infección rechazo de transplantes vacunas ?

VACCINE AGAINST HIV-AIDS: 2011

VACCINE AGAINST HIV-AIDS: 2011

VACCINE AGAINST HIV-AIDS: 2011

VACCINE AGAINST HIV-AIDS: 2005

>= 20% variability

Diversidad

Walker B. NEJM. 1998

Pilcher CD. J Clin Invest. 2004.

Etapas tempranas de la infección por el VIH

Captación y transporte del virus

por células dendríticas.

Infección CD4+ en la lámina propia

y ganglios reginales

Diseminación masiva del VIH

-Organos linfoides

-Sistema nervioso central

-Establecimiento de reservorios

-Replicación persistente

-Latencia

2 dias

5 dias

RESPUESTA INMUNE 4-12

semanas

Batalla de Normandia. Instalación de cabezas de puente

6/6/1944

Costa de Normandía: playas de Utha, Ohama, Gold, Juno, Sword

VACCINE AGAINST HIV-AIDS: 2011

x

? ??

VACCINE AGAINST HIV-AIDS: 2011

Viral envelope

gp41

CD4bs

gp120

(Burton D. Human neutralizing antibodies and a vaccine for HIV-1.

XIV International AIDS Conference [Abstract nº201])

dominio de fusión

dominio interacción CD4

> 99 %

100 %

100 %

vacuna

Vacuna AIDSVax

Adenovirus

Buchbinder Lancet 2008

> 99 %

100 %

100 %

vacuna Vacuna MSD: Step trial

Rolland et al, Nat Med. 2011

Infecting HIV sequences Gag sequences differ genetically from

sequences contained in the vaccine

Gag Pol Nef Nef Pol Gag

STEP trial post-analyses

• Viruses in breakthrough infections (i.e. in vaccine group) are genetically further

apart from the vaccine sequence than viruses in the placebo-group

• This “sieve-effect” suggests that:

• the vaccine may have blocked the out-growth of HIV variants that were

most similar to the vaccine

• the vaccine induced immune response may have driven specific viral

evolution

• The differences in viral evolution or strain selection did NOT affect viral load, but

the observed selection effect indicates that the induced immunity was in some

way acting on the virus at least.

RV144 / “Thai trial”

Poxvirus (ALVAC)

Viral envelope

gp41

CD4bs

gp120

(Burton D. Human neutralizing antibodies and a vaccine for HIV-1.

XIV International AIDS Conference [Abstract nº201])

dominio de fusión

dominio interacción CD4

Total of 16402 individuals enrolled between vaccine and placebo group

Is there an early effect on HIV acquisition ?

P=0.01

Rerks-Ngarm NEJM 2009

> 99 %

100 %

30 % 70 %

vacuna Thai trial RV144

Post RV144 analyses

Barton Haynes, Bangkok AIDS Vaccine 2011, Sept 13th

Broadly Cross-Neutralizing Antibodies in HIV-1 Patients with Undetectable Viremia. Medina-Ramírez et al, J. Virology, in

press

V1 191 (A) NL4-3 (B) AC10 (B) 92BR025 (C) 92UG024 (D) CM244 (E) VSV

528-010 49.1±11.3 1.7±0.9 13.4±2.7 6.8±3.0 7.1±5.3 13.8±1.1 67.1±2.2

734-000 17.9±3.7 0.1±0.3 28.0±5.1 2.1±1.0 21.4±9.6 38.9±3.9 58.7±2.6

521-005 26.3±7.1 2.1±1.4 27.1±2.7 30.8±4.7 23.3±2.9 16.6±1.0 70.0±2.4

600-003 28.6±3.5 3.1±0.7 44.2±8.2 13.1±5.0 42.5±21.9 22.9±0.8 54.1±6.6

363-014 26.7±14.4 2.4±0.3 15.9±3.7 14.8±0.4 35.5±18.4 24.4±2.5 50.5±3.3

541-011 34.9±4.0 4.5±0.5 40.6±6.0 26.3±1.8 46.4±2.7 48.5±2.7 62.6±4.8

181-036 40.6±10.2 14.6±3.1 46.6±1.3 26.2±10.5 43.5±18.6 27.6±3.3 94.2±14.2

488-013 16.9±1.9 1.2±0.8 48.7±9.9 13.9±2.3 36.7±18.1 46.9±2.6 77.9±4.4

642-007 27.8±9.8 3.7±2.7 16.7±2.7 27.7±7.5 44.6±7.4 26.9±3.5 96.5±2.2

308-031 17.5±1.4 1.7±1.2 9.1±4.4 9.1±2.2 20.8±3.6 33.0±6.2 85.7±4.5

331-030 32.4±2.4 5.8±0.7 25.0±6.6 14.7±2.6 38.5±3.7 42.8±5.9 63.7±9.1

634-005 44.2±6.0 6.0±6.7 45.1±12.0 42.4±9.2 49.5±11.4 23.8±1.9 103.15.9

Viral envelope

gp41

CD4bs

gp120

(Burton D. Human neutralizing antibodies and a vaccine for HIV-1.

XIV International AIDS Conference [Abstract nº201])

dominio de fusión

dominio interacción CD4

> 99 %

100 %

30 % 70 %

vacuna

Thai trial RV144

100 %

90 % 10 %

vacuna Vacuna HIVACAT ??

HIVACAT Second Period HIVACAT Current Period

2012 2013 2014 2015 2016 2011

69

DNA Vectors Murine analysis, immunogenicity & GMP + Toxicology

Phase I clinical trial

VLP

Timelines Prophylactic Vaccines

BCG Vectors: rBCG:HIVA

Vector devel. Clade A murine analysis & toxicology

rBCG-2auxo-HIVconsv, -HIVACAT T-cell, -malaria+TB

BCG - synthesis vector for VLPs

Prime/boost

T and B cell immunogens in:

GMP + Toxicology

Phase I clinical trial

MVA Vectors

Cloning & expression, Murine analysis & immunogenicity

HSP Vectors

Loading & representation

Murine analysis, immunogenicity & GMP +Toxicology

Phase I clinical trial

RISVAC02- MVA Phase II clinical trial

Phase I clinical trial & trial data

Murine analysis, immunogenicity & GMP +Toxic<ology

Phase I clinical trial

Construction, stability & imm.

HIVACAT Second Period HIVACAT Current Period

2012 2013 2014 2015 2016 2011

70

New neutralizing Ab Isolation of human monoclonal Ab

Immunogen design for nAb

Library of mutant Env proteins

Ab secreting cells in STI Patients screening

Selected Env Seq. / nAb Refinement 1s t gen. B cell imm. & 2nd gen. B cell imm.

Timelines B cell immunogen

gp41 immunogens Murine & stability analysis

Design optimized strat. human immunization

Selection, phenotypic characterization and immunogenicity Studies of selected variants

Neutralization as.

nAb identification

Immunogenicity

VACCINES AGAINST HIV-AIDS: 2011

1. General considerations

2. Therapeutic vaccines against HIV. Dendritic cells 3. Preventive vaccines against HIV. Other strategies for

prevention

4. Final considerations

clinicaloptions.com/hiv

HIV/AIDS Highlights From Rome

Efficacy of HIV Prevention Strategies From

Randomized Clinical Trials

Abdool Karim SS, et al. Lancet. 2011;[Epub ahead of print].

100 0 20 40 60 80

Efficacy (%)

Study Effect Size, % (95% CI)

ART for prevention; HPTN 052, Africa, Asia, Americas

PrEP for discordant couples; Partners PrEP, Uganda, Kenya

PrEP for heterosexual men and women; TDF2, Botswana

Medical male circumcision; Orange Farm, Rakai, Kisumu

PrEP for MSMs; iPrEX, Americas, Thailand, South Africa

Sexually transmitted diseases treatment; Mwanza, Tanzania

Microbicide; CAPRISA 004, South Africa

HIV vaccine; RV144, Thailand

96 (73-99)

73 (49-85)

63 (21-84)

54 (38-66)

44 (15-63)

42 (21-58)

39 (6-60)

31 (1-51)

The Research Centres

73

Two internationally renowned centres of reference More than 60 investigators

Program Directors Scientific Dr

HIVACAT Strategic Committee