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: [email protected]; 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