rv144 clinical development plans n.
Download
Skip this Video
Loading SlideShow in 5 Seconds..
RV144: Clinical Development Plans PowerPoint Presentation
Download Presentation
RV144: Clinical Development Plans

Loading in 2 Seconds...

play fullscreen
1 / 38

RV144: Clinical Development Plans - PowerPoint PPT Presentation


  • 108 Views
  • Uploaded on

RV144: Clinical Development Plans. Nelson L. Michael, M.D., Ph.D Colonel, Medical Corps, U.S. Army Director US Military HIV Research Program (MHRP) Walter Reed Army Institute of Research. IAS 2012, Washington, DC USA

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'RV144: Clinical Development Plans' - alyssa


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
rv144 clinical development plans
RV144: Clinical Development Plans

Nelson L. Michael, M.D., Ph.D

Colonel, Medical Corps, U.S. Army

Director

US Military HIV Research Program (MHRP)

Walter Reed Army Institute of Research

IAS 2012, Washington, DC USA

The views expressed are those of the presenter and should not be construed to represent the positions of the U.S. Army or DoD

past hiv vaccine concepts
Past HIV Vaccine Concepts
  • Although only three concepts have undergone clinical efficacy testing to date, each HIV vaccine efficacy trial has yielded unexpected outcomes that have transformed the HIV landscape.

2003

2005

2007

2009

  • 2003: AIDSVAX
  • VaxGenEnv gp120
  • Humoral Immunity
  • Phase III studies in high-risk subjects in the US/Thailand
  • Elicited type-specific Abs but not broadly reactive NAbs
  • No efficacy
  • 2007: STEP-PHAMBILI STUDIES
  • Merck Ad5-Gag/Pol/Nef
  • Cellular Immunity
  • Phase IIb study in high-risk subjects in North/South America
  • Elicited cellular immunity by IFN-γ ELISPOT assays
  • No efficacy, possible increased HIV-1 acquisition
  • 2009: RV144
  • Sanofi ALVAC prime, AIDSVAX gp120 boost
  • Humoral and Cellular Immunity
  • Phase III study in low-risk subjects in Thailand
  • 31% reduction in HIV-1 acquisition with no viral load effect

Advancing HIV vaccine candidates to efficacy trials will accelerate progress in the field, bringing us closer to an effective global vaccine.

2

rv 144 demonstrated efficacy for hiv acquisition
RV 144 demonstrated efficacyfor HIV acquisition

C. Modified Intention-to-Treat Analysis*

1.0

0.9

Placebo

0.8

0.7

0.6

Probability of HIV Infection (%)

0.5

Vaccine

0.4

0.3

0.2

0.1

0.0

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

Years

N=16,395

51 vaccine, 74 placebo HIV infected

Est. VE = 31% 95% CI 1-51% (p=0.04)

Rerks-Ngarm et al. (2009, NEJM)

what we have learned rv 144
What we have learned—RV 144
  • Protection among low incidence heterosexual Thais, VE 31.2% at 42 months
  • No effect on post-infection viremia or CD4 count
  • Relatively monophyletic circulating variants CRF01_AE
  • Efficacy appears to be early and non-durable
  • Evoked binding Ab but not measurable, primary isolate Nab— BAb appeared early and decreased by > 10 fold over 6 months
  • CD4+ Env responses, but not CD8 responses
  • Correlate/surrogate studies limited by samples and endpoints
what we would want next
What we would want next
  • Extend the observation of early 60% efficacy by increasing the durability of immune responses
    • Additional vaccine boosts
    • Improved adjuvants
    • Improved vaccines
  • Elucidate correlates of risk of infection.
    • Adequately powered studies
    • Adequate sample collections
  • Public health implementation--establish protection in higher incidence populations (additional boosts/improved adjuvants)
    • Heterosexuals in sub-Saharan Africa
    • MSM in Africa and Asia
rv 144 correlates discovery effort
RV 144 Correlates Discovery Effort

ADVISORY GROUPS

PA H Steering Committee

Product

Development Advisory

Group

Clinical Development

MHRP - DAIDS Steering Committee

Humoral & Innate Immunity

RV144 Steering Committee

Cellular Immunity

Scientific Steering Committee

Host

Genetics

Correlates

Animal

Models

Scientific Advisory Groups

multivariate logistic regression quantitative variables
Multivariate Logistic Regression: Quantitative Variables

All 6 variables together in multivariate analysis, P=0.08

Only a-EnvIgA and IgG gp70:V1V2 binding, p = 0.009 (log reg), 0.012 (Cox)

2 individual variables were significant:

  • gp70 V1V2 inversely correlates with infection [q = 0.08]
    • Estimated 43% reduction in infection rate (per SD)
  • Plasma IgAdirectly correlates with infection [q = 0.08]
    • Estimated 54% increase in infection rate (per SD)
slide12

Case control analysis of microarray shows trend to inverse correlation at tip of V2 and in CD4 binding site

sieve analysis of v2
Sieve Analysis of V2
  • Comparison of viruses from HIV-1 infected vaccine versus HIV-1 infected placebo recipients
  • These are not transmitted/founder viruses—the mean time to last negative visit was ~ 3 months.
  • V2 was a major focus of analysis.
  • Analysis—collaboration between Dr. Morgane Rolland (MHRP), Dr. Jim Mullins (UW), SCHARP
results sites 169 and 181 separately
Results: Sites 169 and 181 Separately
  • For each site, VE significantly differs against match vs. mismatched infection
    • vaccine reduced infection rate 3.77 times more for 181-mm than 181-m
  • Positive VE for 169-matched infection and181-mismatched infection
  • The sieve analysis suggests that the vaccine selectively blocked acquisition with 169-matched and with 181-mismatched virus; but conferred no protection against 169-mismatched or 181-matched virus
correlates of risk of infection
Correlates of Risk of Infection
  • WARNING—it is textbook (Stan Plotkin’s) knowledge that different vaccines for the same pathogen can have different correlates of risk/protection.
  • Will correlate of risk for ALVAC-AIDSVAX B/E in RV 144 generalize to….
    • These products in Thai MSM?
    • ALVAC-gp120 engineered for heterosexuals in Africa?
    • Other HIV vaccines such as DNA/Ad5 (HVTN 505 phase IIb), Ad26-MVA, etc?
  • We want all subsequent efficacy trials to seek correlates—now more than ever. This impacts clinical design.
collaborators
Collaborators

Duke

Bart Haynes

Larry Liao

Georgia Tomaras

Nathan Vandergrift

Garnett Kelsoe

David Montefiori

Thomas Kepler

Marcella Sarzotti-Kelsoe

Munir Alam

Bill and Melinda

Gates Foundation

Nina Russell

Francine McCutchan

HVTN

Peter Gilbert

Nicole Frahm

Julie McElrath

UMDNJ

Abe Pinter

NYU/VA

Susan Zolla-Pazner

Harvard

Joseph Sodroski

Steve Harrison

Norm Letvin

IHV

George Lewis

Tony DeVico

  • NIH VRC
  • Gary Nabel
  • Peter Kwong
  • John Mascola
  • Marie Pancera
  • Jason McLellan
  • Thai Ministry of Public Health
mhrp s product development plan
21MHRP’s Product Development Plan
  • MHRP’s vaccine development strategy emphasizes regional and global approaches.

1

BUILDING ON RV144

REGIONAL VACCINE STRATEGY

Building on the RV144 outcome and lessons learned, conduct efficacy trials of the prime-boost concept in:

Thai MSM populations

High-risk populations in Southern Africa

2

DIVERSIFYING AND REFINING THE PORTFOLIO

GLOBAL VACCINE STRATEGY

Pursuing diverse platforms (e.g. vectors, multi-valent constructs or mosaic inserts) that build on the prime-boost concept and readily translate to multi-clade testing and a globally effective vaccine.

slide23
Planned studies are mutually reinforcing and will amplify public health impact and regional relevance.

Focus on regional public health impact

Precedent for vaccine efficacy

Future amplification of global reach

THAILAND

High Risk MSM

Mutually reinforcing studies strengthen and support public health benefit in target populations and the translation of the platform globally.

US/EUROPE

SOUTHEAST ASIA

RV144

SOUTHERN AFRICA

Republic of South Africa(RSA)

High Risk Heterosexual

  • Strategy for achieving potential licensure in target markets and having the broadest public health impact.

23

May 2011

timeline
Timeline

Go/No-Go

short term development objectives
Short-term Development Objectives
  • Characterize vaccine immune responses using samples collected
    • In sufficient amounts
    • At the right times
    • From systemic as well as mucosal sites
  • Improve magnitude and durability of vaccine-induced responses
research strategy
Research Strategy

Three Exploratory Phase II immunogenicity trials in Thailand

  • Collections: serum, plasma, cells, genital fluids
  • Special collections: leukapheresis, gut biopsy, cervical biopsy, bone marrow aspiration (except RV305)
  • Broad array of humoral and cellular assays
bridging study from aidsvax alum to delta 11 mf59
Bridging Study—from AIDSVAX/alum to delta 11/MF59
  • ALVAC-HIV prime as before
  • gp120 boost comparison:
    • One B and one E, both gD negative, C1 delta 11
    • Novartis process and MF59 adjuvant
    • Part A Open Label safety assessment in the U.S. for Novartis product:

A=ALVAC-HIV, N=Novartis rgp120B/E

bridging study part b thailand compare aidsvax alum vs novartis gp120 mf59
Bridging Study Part B Thailand—compare AIDSVAX/alum vs Novartis gp120/MF59

A=ALVAC-HIV, AVX=AIDSVAX B/E, N=Novartis rgp120B/E

*Possibly use RV306 samples

slide31

Pox-Protein Development Plan

S. Africa ph2b

Research

Population: Heterosexual, high-risk

Products: DNA + NYVAC (sanofi) + gp140 (Polymun)/MF59 (NVD)

vs. NYVAC (sanofi) + gp140 (Polymun)/MF59 (NVD)

Objective: Extend results & accelerate evaluation of other products using adaptive trial design and first available protein

Partners/Funders: NIH, HVTN, sanofi pasteur, Novartis, BMGF

Ongoing RV144 Follow-up in Thailand

  • Studies:
  • RV144i immune correlates studies
  • RV305 protein boosting study
  • RV306 expanded immunogenicity study
  • Objective:
  • Determine correlate of protection
  • for use in future trials; optimize the regimen
  • Partners/Funders:
  • US Army, Thai Gov’t, NIH, sanofi pasteur, BMGF

Thailand ph2b

Population: MSM, high-risk

Products: ALVAC (sanofi) + gp120/MF59 (NVD)

Objective: Confirm result & demonstrate efficacy in target population with potential for licensure

Partners/Funders: US Army, Thai Gov’t, NIH, sanofi, BMGF?

Licensure

Africa ph2b

Candidate selection

Population: Heterosexual, high-risk

Products: ALVAC (sanofi) + gp120/MF59 (NVD)

Objective: Extend result & translate vaccine to Africa, other high-risk groups

Partners/Funders: NIH, HVTN, sanofi, Novartis, BMGF, RSA?

  • ALVAC is default vector prime
  • Proteins boosts TBD
  • RV144 immune correlates
  • Immune grid
  • Cost, product availability

31

slide33

Nature 482, 89–93 (02 February 2012)

100

80

DNA/MVA

60

MVA/MVA

% Uninfected

Ad26/MVA

40

MVA/Ad26

20

Sham

0

0

2

4

6

8

Number of IR Challenges

mva ad26 and ad26 mva regimens lower early setpoint viral loads following sivmac251 infection
MVA/Ad26 and Ad26/MVA Regimens Lower Early Setpoint Viral Loads Following SIVmac251 Infection

Sham

MVA/MVA

DNA/MVA

6.09

5.75

Log SIV RNA

5.47

Days Following Infection

Days Following Infection

Days Following Infection

Ad26/MVA

3x resistance to infection

4/8 : viremia blunted 1 log

3/8 : rapid virologic control

1/8 : persistently uninfected

MVA/Ad26

Log SIV RNA

4.55

3.83

Days Following Infection

Days Following Infection

protection against acquisition of ir sivmac251 by ad35 ad26 sivsme543gagpolenv vaccine
Protection Against Acquisition of IR SIVmac251 by Ad35/Ad26-SIVsmE543GagPolEnv Vaccine
ad26 mva correlates analysis
Ad26-MVA correlates analysis
  • Acquisition endpoint.
    • envelope binding antibody r= .79 p<.0001.
    • neutralization antibody r=.50 p=.0034
    • ADCC r=.38 p=.034 (trend)
  • set point viral load endpoint, Many correlates (N=27);
    • prechallenge gag elispot count and gag elispot breadth were both correlated (r=-.50 p=.006 and r=-.64 p=.0002, respectively) with the endpoint.
    • peak envelope binding antibody r=-.70 followed by prechallengeneutralizing antibody r=.67.
summary
Summary
  • RV 144 demonstrated that vaccines can provide HIV acquisition protection.
  • Correlates of risk of infection were discovered in RV 144.
  • Correlates of risk of infection in Ad26-MVA (and other) vaccines have been discovered in NHP models.
  • We must educate (and remind) ourselves that correlates of risk may or may not generalize.
  • There is great value (but at a cost) to seek correlates of infection risk in future HIV vaccine trials.
  • Product development and scientific rationale must communicate with each other.
acknowledgements
Acknowledgements

Supported by:

Collaboration for AIDS Vaccine Discovery Grant From the Bill and Melinda Gates Foundation

HVTN, DAIDS, NIAID

With Collaborations with the MHRP and Thai Ministry of Public Health

  • National Institute of Allergy and Infectious Diseases (NIAID)
  • National Institutes of Health (NIH)
  • Division of AIDS (DAIDS)
  • U.S. Department of Health and Human Services (HHS)

Center for HIV/AIDS Vaccine Immunology (CHAVI) # U19 AI067854-06

HVTN