Larry Corey MD Principal Investigator NIAID supported HIV Vaccine Trials Network HVTN Past President and Director Fred Hutchinson Cancer Research Center Professor Laboratory Medicine and ID: 796807
Download The PPT/PDF document "Progress in the HIV Vaccine Field" is the property of its rightful owner. Permission is granted to download and print the materials on this web site for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.
Slide1
Progress in the HIV Vaccine Field
Larry Corey, MD
Principal Investigator, NIAID supported HIV Vaccine Trials Network (HVTN)
Past President and Director, Fred Hutchinson Cancer Research Center
Professor
, Laboratory Medicine and
Medicine, University
of Washington
Seattle, Washington USA
Slide2Disclosures
None
Slide3HVTN as an organization, especially my colleagues: Scott Hammer, Glenda Gray, Julie McElrath, Peter Gilbert, Jim Kublin and Susan Buchbinder
The HVTN’s major pharmaceutical and
institutional collaborators: Sanofi, GSK, Janssen, VRC, IAVI and CHAVI programs The HVTN’s community members and advisory boardsIts funders: NIAID and BMGF
Acknowledgements
Slide4Special AcknowledgementTony
Fauci
, MD
Slide5HIV: Still the World’s Most
Important Global
H
ealth Problem
US still over 45,000 new cases yearlyGlobally more than 2 million new infections occur per year
Number of people living with HIV increasing yearly
Long way from an AIDS
F
ree Generation
Slide6Indiana HIV outbreak: geographic distribution
Scott County pop. 24,000; Austin, IN pop. 4,200
Adams, NEJM 2015;373:1379-1380
Adams, NEJM
2015;373:1379-1380
Scott County
Slide7Slide8Commentary on HIV Prevention Strategies
While many prevention strategies have high efficacy in clinical trials, their extended effectiveness
requires continuous adherence, which often results in
decreased effectiveness over time.
They also require high saturation in a community and
hence their long term effects on population based
incidence in country’s with generalized epidemics is uncertain:
Condoms; PrEP; vaginal rings; PEP; circumcision, all deserve support and increased uptake
Test and Treat very effective for the individual; eventual population effect will be achieved
Slide9With asymptomatic acquisition, prolonged subclinical infection, and sexual transmission, getting to an AIDS Free Generation
will
require a
vaccine.
Larry’s definition of an AIDS Free Generation; 95% reduction in incident cases annually:
USA < 2,500 incident cases yearly
Globally < 100,000 cases yearly
7/19/2016
9
The Need for an HIV Vaccine
Slide10“Ultimately, we believe, the only guarantee of a sustained end of the AIDS
pandemic lies in a combination of non-vaccine prevention methods and
the development and deployment of a safe and effective HIV vaccine.”
Slide11The Two Major Scientific Questions
Facing
the
HIV Vaccine Field
:Can non-neutralizing antibodies be potent enough to achieve desirable vaccine efficacy (VE >50%) for at least 2 years?
Can this be achieved by designing better recombinant proteins and adjuvants
?
By eliciting better T helper responses to drive higher and more durable antibody production
?
Is neutralization, as we currently measure it, associated with vaccine protection and will this protection be of a sufficient magnitude to overshadow other vaccine design approaches?
Slide12HIV Vaccine Field at the Time of the Durban Conference in July 2000
HIV vaccines not on the main stage:
No vaccine studies in RSA
HVTN just being organized (1999)
Several phase 1 trials of recombinant proteins were underway, including a phase 1 vaccine study in Uganda
Period of first generation vaccines (1984 – 2004):
Recombinant envelope vaccines all directed at trying to induce neutralizing antibodies
Large number of gp120, gp140, gp145, gp160 manufactured and tested
All immunogenic
Narrow (strain specific) neutralization
Poor durability
Slide13VaxGen
USA (gp120)
VaxGen
IDU Thai Trial (gp120)
Step Trial/
Phambili
Trials (Ad5 gag/pol/
nef
)
RV144 Thai Trial (ALVAC/gp120)
Trial start/end
Trial analysis/results
Immune correlates
1995
2000
2005
2010
1 year
1 year
HVTN 505 (DNA/Ad5
env
/gag/pol
2015
AMP Trial (VRC-01)
HVTN 702 (Clade C ALVAC/gp120)
A Pictorial History of HIV-1 Vaccine Efficacy Trials
IAS Durban
AMP
702
Slide14Second Generation Vaccines: T
Cell
Based Vaccines
Post-
VaxGen, HIV vaccine field turned to “T cell based” vaccines
CD8+ T cells were what differentiated elite controllers from progression and it was hoped that vaccines that would induce such responses would be effective in either reducing acquisition or post-acquisition viral load.
Hypothesis: the more potent T cell responses, the better the vaccine:
Ad5 vector based vaccine much more effective in inducing CD8+ T cell responses than ALVAC
Slide15VaxGen
USA (gp120)
VaxGen
IDU Thai Trial (gp120)
Step Trial/
Phambili
Trial (Ad5 gag/pol/
nef
)
RV144 Thai Trial (ALVAC/gp120)
Trial start/end
Trial analysis/results
Immune correlates
1995
2000
2005
2010
1 year
1 year
HVTN 505 (DNA/Ad5
env
/gag/pol
2015
AMP Trial (VRC-01)
HVTN 702 (Clade C ALVAC/gp120)
A Pictorial History of HIV-1 Vaccine Efficacy Trials
IAS Durban
AMP
702
Slide16Ad5 HIV Vaccines
Step and
Phambili
Trials with the MRK Ad5 gag/pol/
nef:No efficacy in either post infection viremia or reduced acquisition despite a high prevalence and reasonable magnitude of CD8+ T cell responses Increased rate of acquisition of HIV-1 in both trials among men
Step: MSM Ad5 seropositive, uncircumcised men
Phambili
: heterosexual men, also Ad5 seropositive
Mechanism of increased acquisition is unclear, especially as the DNA prime Ad5 boost regimen used in HVTN 505 had no evidence of increased acquisition
:
The critical difference is the addition of HIV envelope in the DNA/Ad5 regimen
Envelope antibodies may be a factor in eliminating/negating the effects of increased mucosal T cells after Ad5 vaccination
Slide17The Good News for HIV Vaccine Development – September 2009 and the RV144 Trial
Regimen
of ALVAC priming followed by gp120 results in efficacy in large trial in Thailand
.
Results met with surprise and skepticism:ALVAC not as good as Ad vectors for T cell priminggp120
used had failed in IDU
trial
How could these two together all of a sudden produce efficacy?
Slide18Thai Trial (RV144) Primary Results
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Years
Probability of HIV Infection (%)
Placebo
Vaccine
Modified Intention-to-Treat Analysis*
Slide19Post-RV144
Massive scientific effort to understand how did RV144 work: correlates of risk/correlates of protection.
Pivot in the field from concentrating on novel vectors to understanding that it is the insert (HIV envelope gene ) and structure of the envelope antigen that one puts in the vector that is critical for vaccine design.
Slide20Concepts from the RV144 Correlates Program 2010 - 2014
No direct
correlation between neutralizing antibodies and HIV-1 acquisition
in RV144:None
of the sera from the RV144
vaccinees
neutralized a panel of 20 contemporaneous isolates of HIV-1 circulating in Thailand during the course of the
trial
The antibody related correlations associated with Vaccine Efficacy in RV144 were in the magnitude and the epitope specificity of non-neutralizing antibodies which exhibited virion binding or infected cell associated functions.
Slide21Correlation Between Antibodies to the V1V2 Loop and Vaccine Efficacy in RV 144
Antibodies to the conserved region of V2, previously almost completely ignored by the HIV vaccine field, were highly correlated with efficacy.
Slide22RV144 Correlates Observations
Sequencing studies of the viral envelope from persons on the trial revealed that distinct immunological pressure was observed in the crown of the V2 loop where vaccine immune responses were directed.
Distracting/inhibitory antibodies could be produced that reduced vaccine efficacy.
Slide23CD4+ T cell Responses to HIV envelope in RV144
Polyfunctional CD4+ T cell responses to HIV-1 envelope also independently contributed to VE.
The cytokine patterns of these helper T cell responses suggest that T helper responses that influence antibody development are important.
Slide24COMPASS:
Com
binatorial
P
olyfunctionality Analysis of Single-cell Subsets
COMPASS permits the
unbiased
characterization of
polyfunctional subsets
Expression
of 6 functional markers:
CD154
, IL-2, IFN-g, TNF-a, IL-17, IL-426=64 possible combinations / cell subsetsMany empty combinations → 15 considered
Slide25Env-specific CD4+ T cell p
olyfunctionality
score is an independent correlate of Vaccine Efficacy
The five-function CD4+ T subset remains significant (OR=0.59, p=0.010) when the V1V2 and IgA
Ab variables are also included in the model.
The effects of
the V1V2
IgG
correlate and the five-function subset are
additive
(no evidence of interaction).
VariableOR95% CIP-value5-function Env-specific CD4+ T cell subset0.590.40-0.890.011V1V2 IgG Ab primary
0.620.42-0.94
0.022
IgA Ab primary
1.761.2-2.60.003
(Lin L. et al, Nat Biotech. 2015 Jun;33(6):610-6.)
Slide262016/2017: 3 Novel Strategies
Slide272010 Formation of the P5 Partnership
Purpose:
To build on RV144 data and ultimately license a pox-protein based HIV vaccine with the potential for broad and timely public health impact.
Strategy:
Developed a partnership to extend the RV144 concept to Clade C regions of the world.
Use expert committees to select the strains and then use company expertise to manufacture these vaccines for immunogenicity, safety and efficacy.
Slide28The Strategy for the ALVAC/Protein
Phase
3
Program
Construction of Bivalent Subtype C gp120/MF59
Booster at
12 months
Construction of ALVAC-HIV-C
(vCP2438)
Optimize regimen by increasing potency and durability
Slide29HVTN Strategy for the Phase 3 Program
Slide30Meeting the “Go
” Criteria
: Immunogenicity from
HVTN 100
, a phase 1/2 randomized, double blind, placebo-controlled trial of clade C ALVAC- ® (vCP2438) and Bivalent Subtype C gp120/MF59® in HIV-uninfected South African adults.
Bekker LG, Laher F, Moodie Z, Tomaras G, Grunenberg N, Allen M, Daniels B, Innes C, Mngadi K, Malahleha M, Grant S, Gilbert P, Michael N,
Phogat
S, Diaz Granados C,
Kanesa
Thasan
N, Corey L, Gray G, McElrath J, for the HVTN 100 team.
LB xxxx
Slide31Boxplots of IgG binding
a
ntibody
t
iters
to
the gp120
Vaccine Antigens
used in
RV144
and HVTN
100
The midline of the box plot indicates the median.
The ends of the box indicate the 25
th
and 75
th percentiles.
Slide32S
ignificantly greater
polyfunctionality
scores in
HVTN 100 (P < 0. 00001)
Slide33HVTN 702
A pivotal phase 2b/3 multi-site, randomized, double-blind, placebo-controlled clinical trial to evaluate the safety and efficacy of ALVAC-HIV (vCP2438) and Bivalent Subtype C gp120/MF59 in preventing HIV-1 infection in adults in South
Africa
Scheduled
to start
Nov.
1, 2016
in
RSA
Glenda Gray, Chair
Co-Chairs:
Linda
Gail Bekker, Fatima Laher, Mookho Malahlela
Slide34Study Schema: HVTN 702
Estimated Total Study duration 72 months:
Stage 1: 60 months - 18 months for enrollment, 24 months of follow-up for HIV-1 uninfected individuals, 18 months follow up for HIV-1 infected individuals
Stage 2: an additional 12 months of follow up for uninfected individuals
N
(total 5400)
Primary Vaccine Regimen
Booster
Month 0
Month 1
Month 3
Month 6
Month 12
2700
ALVAC-HIV
(vCP2438)
ALVAC-HIV (vCP2438)ALVAC-HIV+ Bivalent Subtype C gp120/MF59
®ALVAC-HIV+ Bivalent Subtype C gp120/MF59
®
ALVAC-HIV+
Bivalent Subtype C gp120/MF59
®
2700
Placebo
Placebo
Placebo + Placebo
Placebo + Placebo
Placebo + Placebo
Slide352016/2017: 3 Novel Strategies
Slide36J&J HIV Vaccine Research Program:
BIDMC/Harvard
HVTN
IAVI
MHRP
NIAID
Ragon Institute
Slide37Prophylactic Vaccine
Aiming at
Protection
Against all Clades of
HIV-1
1
2
3
Mosaic inserts for global coverage
(Gag-Pol-Env)
Trimeric
env
proteins for improved humoral immunity
Vectors that elicit optimal immune responses
Slide38The Ad26/Ad26+Env HIV vaccine regimen provides substantial protection against SHIV
SF162P3
challenges in non-human primates
[
study
#13-19 designed
to mimic APPROACH trial (HIV-V-A004), “regimen selection trial”]
6x IR SHIV challenges
N = 12
per group
0
3
12
months
6
prime
boost
prime
boost
18
Per-Exposure
Risk Reduction
Full Protection after 6 challenges
Ad26/Ad26+Env
94%
66%
Ad26/
MVA+Env
87%
42%
Ad26/
Env
84%
33%
Slide392016/2017: 3 Novel Strategies
Slide40Behring together with his colleagues Wernicke (left) and
Frosch
(center) in Robert Koch's laboratory in
Berlin.
Photo
: Courtesy of Aventis
Behring
WWW.nobelprize.org
The Nobel Prize in Physiology or Medicine 1901
to Emil
von
Behring: “For
his work on serum therapy, especially its application against diphtheria, by which he has opened a new road in the domain of medical science and thereby placed in the hands of the physician a victorious weapon against illness and deaths".Nobel Prizes awarded for discoveries related to antibodies in infectious diseases:1901: Serum therapy for diphtheria (Behring),1908: Describing humoral immunity (Mechnikov, Ehrlich), 1972: Defining the chemical structure of antibodies (Edelman, Porter)1984: Production of
monoclonal antibodies (mAbs) (Jerne, Köhler, Milstein)
1987: Explaining the mechanism for antibody
diversity (Tonegawa)
Long History of
Antibodies
to Treat and
Prevent Infectious
Disease
(
Serum Therapy)
Pre-Antibiotic Era: Bering
and Paul
Ehrlich pioneered serum
therapy
for diseases such as
diphtheria
,
tetanus
,
streptococcal
infections
Slide41Active Vaccination
Passive
Immunization
Systemic IgG
Gene-based Ab (AAV)
Antibodies Teach Us About
HIV V
accine
D
evelopment
CD4bs
VRC01
Immune pathways of
antibody
evolution
(B cell biology)
10e8
MPER
PG9
V1V2 glycan
Trimer
11
PGT 128
V3 glycan
Slide42V1V2-Glycan – bind to trimer cap
V3-glycan, N332 supersite
gp41 MPER – near
membrane
gp120/41 interface – bind to parts of both gp120 and gp41
CD4 binding site of gp120 – where the virus attaches to CD4
Neutralizing
Ab
to HIV-1
V3-glycan
V1V2-glycan
CD4 binding site
gp41 MPER
gp120/41
interface
Christina
Corbaci
,
Andrew Ward
,
Only antibodies that have advanced the clinic (VRC01, 3BNC117)
Slide43VRC01 Blocks Attachment to CD4
CD4
gp120
trimer
CCR5
gp41
trimer
Target Cell
CD4 binding site on gp120 is
functionally conserved: All viruses must bind CD4
VRC01 neutralizes ~ 90% of diverse viral isolates
Slide445%
21%
36%
12%
3%
45%
How Potent is VRC01
In
Vitro
Neutralization (IC
80
)
Panel of 170 genetically diverse
Env-pseudoviruses
, representing all major clades
Line shows median IC value - based on results from all viruses, including those not neutralized.
% of viruses
resistant
to neutralization, IC
80
> 50µg/ml
Neutralizes 80%-90% of viruses (all major clades)
Mean IC
80
= 1.0
ug
/ml; potential to work at physiologically attainable levels.
Slide45VRC01 Mucosal Pharmacokinetics
in Rhesus Macaques
Slide46RECTAL CHALLENGE
VAGINAL CHALLENGE
VRC01 Protects
Against
Mucosal
SHIV-Challenge in
Non-Human
Primates
4/4 protected
0/4 protected
4/4 protected
1
/4 protected
20 mg/kg infusion of VRC01: Challenge with SHIV SF162P3
Pegu et al. Science
Transl
Med (2014)
Ko et al. Nature (2014)
Rudicell et al. J
Virol
(2014)
Slide47Passive Antibody Protection
NHP studies tell us that physiologically achievable levels of Ab could prevent HIV-1 infection
But
no direct proof in humans
Learn from Proof of Concept Trial in Humans:
What level of neutralizing Ab is needed to prevent infection?
Pertains to passive
bNAb
infusion or vectored delivery
Convert the
mAb
levels to serum level of neutralization needed to protect (e.g.,
neut titer 1:50, 1:500)Provides a benchmark for vaccine development; i.e. what antibody level does a vaccine need to achieve
Slide48Can a passively infused monoclonal antibody
prevent HIV-1 infection in high risk adults: MSM
in Americas
&
Hetersosexual
Women in sub-Saharan Africa
AMP = Antibody Mediated Prevention
Passive Antibody Prevention
Phase IIB Efficacy Studies
Chairs:
Lawrence Corey, HVTN
Mike Cohen, HPTN
Co-chairs:
Srilatha
Edupuganti
Nyaradzo
Mgodi
Slide49The AMP Studies:
Highlights
Placebo controlled trial of VRC01
mAb
(IV), given on q2 month schedule
Two cohorts:
2,400
MSM +
TG
in North & South America
1,500
Women in sub-Saharan
AfricaPowered to detect 60% efficacy; and to associate VRC01 plasma level with protectionBoth trials opened in April/May 2016
Slide50The AMP Studies:
Highlights
Cohort
IV Treatment
n=
Schedule
North + South American
MSM
(2400)
HVTN 704 / HPTN 085
VRC01
10
mg/kg
800
Every
8
wks
x 10 doses
VRC01
30
mg/kg
800
Placebo Control
800
Sub-Saharan
African women
(1500)
HVTN 703
/ HPTN 081
VRC01
10
mg/kg
500
Every
8
wks
x 10 doses
VRC01
30
mg/kg
500
Placebo Control
500
Two
different infusion
doses: Important to know if lower dose of 10 mg/kg can protect
Powered to associate mAb serum level
with protection
Slide51Rationale for the 2 Cohorts and 2 Dosing Regimens
Route of acquisition and genital tract immunology and anatomy may influence the distribution of VRC01 and potential efficacy.
Variation in the doses allows us to more precisely define what are the optimal concentrations of neutralizing activity associated with protection from acquisition.
Slide52Per protocol
Per protocol
(VRC01 30 mg/Kg)
(VRC01
10
mg/Kg)
Concentrations of Antibody in Serum in HVTN 104
Slide5362.5% PYRs
66% Overlap in Concentrations
Slide54Hypothesis: HIV acquisition will be rare in the
first 4 weeks post-infusion at either dose
Slide55HVTN 704/HPTN 085,
MSM + TG
HVTN 703/HPTN 081,
Women
AMP
Research Sites
Slide56Gaborone, Botswana
Kisumu, Kenya
Blantyre, Malawi
Lilongwe, Malawi
Maputo, Mozambique
Harare, Zimbabwe
(3
clinics
)
Cape Town, RSA
Durban, RSA (2 clinics
) Johannesburg, RSASoweto, RSAVulindlela, RSAMbeya, TanzaniaAMP sub-Saharan Africa Sites
Slide57MSM+TG AMP Sites
Atlanta,
GA (2
clinics)
Birmingham, AL
Boston, MA (2
clinics)
Chapel Hill, NC
Cleveland, OH
Los Angeles, CA
Nashville,
TN
Newark, NJNew York, NY (4 clinics) Philadelphia, PA Rochester, NY San Francisco, CASeattle, WA Washington, DCLima, Peru (3 clinics)Iquitos, PeruRio de Janeiro, Brazil
Slide58Concepts from the AMP Studies
Can lower levels of neutralization activity afford protection or does
in vivo protection require only high concentrations of CD4 binding site antibodies?
Are non-neutralizing effector functions as predictive of efficacy as neutralizing activity?
Defining the optimal concentration defining efficacy allows one to engineer a second generation product and delivery system that will provide protective levels in a way that can be delivered efficiently on a population basis.
Higher potency; longer half-life; cheaper delivery.
Slide59Protect against infection resulting from
intrapartum
exposure to HIV; i.e., during childbirth
Protect the infant during the course of breastfeeding (months)
Potential Role in Interruption of
Maternal to Child Transmission
Could HIV
mAbs
:
Slide60VaxGen
USA (gp120)
VaxGen
IDU Thai Trial (gp120)
Step Trial/
Phambili
Trials (Ad5 gag/pol/
nef
)
RV144 Thai Trial (ALVAC/gp120)
Trial start/end
Trial analysis/results
Immune correlates
1995
2000
2005
2010
1 year
1 year
HVTN 505 (DNA/Ad5
env
/gag/pol
2015
AMP Trial (VRC-01)
HVTN 702 (Clade C ALVAC/gp120)
A Pictorial History of HIV-1 Vaccine Efficacy Trials
AMP
702
IAS Durban
Janssen Trial
2020
First data available
Janssen Test of Concept
Slide6161
Slide6262
Slide63The HIV Vaccine Field is Open for Business
Three pivotal HIV vaccine related efficacy trials are either in progress (AMP) or soon to be initiated: HVTN 702 and Janssen POC trial in 2016 - 2017.
These pivotal efficacy studies will define if either or both neutralizing and/or non-neutralizing antibodies can be tweaked to provide reasonable vaccine efficacy in high risk Clade C regions of the world.
These studies will set the stage for the entire design and development of HIV vaccines for the next decade.
Slide64Using human clinical trials with intense evaluation of the Correlates of Protection is in the end - true “rational vaccine design”.
For
the first time, the basic science agenda
in HIV vaccine development will
be based on human clinical trials.
The HIV Vaccine Field is in
a Novel Space
Slide65Acknowledgments
HVTN Core, SDMC, EMT
Jim Kublin, Peter Gilbert, Glenda Gray, Susan Buchbinder, Scott Hammer,
Gepi
Pantaleo,
Shelly Karuna,
Nicole Grunenberg, Carter Bentley
Site Investigators
Study Volunteers
HVTN
Lab
ProgramJulie McElrath, Georgia Tomaras, Nicole Frahm, John Hural,David Montefiori, Steve DeRosa,Erica Andersen-Nissen, Lynn Morris DAIDS Vaccine Research ProgramCarl Dieffenbach, Mary Marovich, Dale Hu, Phil Renzullo, Pat D’Souza, Paul Kitsutani, Mary Allen, Jim Lane, Mike Pensiero
Bill and Melinda Gates Foundation
Emilio
Emini
, Nina Russell and teamUSMHRPNelson Michael, Robert O’Connell
CHAVI IDBart Haynes, Larry Liao and colleagues
JanssenFrank
Tomaka
, Maria Pau,
Hanneke
Schuitemaker
, Paul Stoffels
Sanofi Pasteur
Jim
Tartaglia
, Sanjay
Gurunathan
, Sanjay
Phogat
Slide66Collaborators - Africa
Glenda Gray
Linda Gail-Bekker
Gita
Ramjee
Cheryl
Louw
Kathy Mngadi
Graeme
Meintjes
Craig Innes
Nicole Hunt
Phillip KotzeFrancis MartinsonJani IleshStewart ReidLeonard
MabokoMaphoshane
Nchabeleng
Lungiswa
MtingiDumezweni Ntshangase
William BrumskineZvavahera Chirenje
Mookho Malahlela
Modulakgotla
Sebe
Slide67Mark Mulligan
Paul Goepfert
Ray Dolin
Lindsey Baden
Ken Mayer
Richard Novak
Benigno
Rodriguez
Spyros Kalams
Scott Hammer
Beryl
Koblin
Ian FrankMichael KeeferSusan BuchbinderJulie McElrathGepi Pantaleo
Jorge SanchezMartin
Casapia
Robinson Cabello
Collaborators - U.S., South America and Europe