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Thursday, 06/21/2007 9:33:34 PM

Thursday, June 21, 2007 9:33:34 PM

Gates AIDS Vaccine Grants include P.Thorpe, via Duke’s B.Haynes.

A Spring 2007 course, “Biotechnology & the Law - H570”, taught by Prof. Sean O’Connor of the Univ. of WASH, featured a 4-24-07 lecture by Erik H. Iverson, Associate Gen. Counsel of the Bill & Melinda Gates Foundation (BMGF), titled, “Establishing Collaborative Structures & Licensing Strategies to Ensure Global Access of a Product”.
Here is his 13-pg. PDF slide presentation:
http://www.law.washington.edu/courses/oconnor/H570_Sp07/Documents/PowerPoints/4-24_UWLS_BiotechCours...

In the 1st 6 pgs., Iverson gives an overview of the Gates Foundation and the “Global Health Program” in particular. Beginning on pg. 7, he begins going thru 6 case studies of various types of grants. Then, in case study #7 (pgs. 10-13) he details the BMGF ‘Collaboration for AIDS Vaccine Discovery (CAVD)’ project. On pg. 12, there’s a big mapping of all the 16 CAVD Gates grants (“$287mm over 5 yrs”). P.Thorpe is on the left side in the “VDAC” (Vaccine Discovery Antibody Consortia) clump, with 7 other researchers (V.Chalwie, B.Chackerian, R.Musonda, T.Kepler, S.Harrison, P.Thorpe, L.Spicer, G.Kelsoe), all of which point to Duke’s B.Haynes. Recall that Dr. Barton Haynes is the Director of CHAVI (NIAID) and the Director of Duke’s Human Vaccine Institute (DHVI).

Note: Iverson’s talk squares with Dr. Haynes’ Duke Human Vaccine Institute (DHVI) website, which as of 6-21-07 states:

HAYNES VDC MISSION & GOALS (added 4-4-07)
“The goal of the Haynes Vaccine Discovery Consortia is to acquire proof of concept data that manipulation of the immunoregulatory controls of B cell immune responses to HIV-1 Env, coupled with enhanced immunogen design, can lead to safe induction of broadly reactive neutralizing antibody responses… First, the Kelsoe, Haynes and Thorpe laboratories are developing immunogen formulations that trigger B cells normally tolerant to the desired Envelope epitopes and regions… Haynes is determining the role of tolerance mechanisms, T regulatory cells and TLR signaling on control of broadly reactive B cell activation, and Philip Thorpe is determining the role of lipid binding of anti-HIV antibodies and anti-phosphatidylserine(PS) autoantibodies to protection from HIV infection. With Philip Thorpe, studies are planned to determine if anti-lipid antibodies can prevent infection or early viral destruction of the immune system in acute SIV infection…” [see complete Haynes webpage text below]
http://humanvaccine.duke.edu/modules/grant_spt/index.php?id=11

MORE ON BMGF’S CAVD FROM IVERSON’S 4-24-07 PRESENTATION:

CAVD: Science & Organization (Collab. for AIDS Vaccine Disc.)
• Represents the first major contribution of the Foundation to the Global HIV Vaccine Enterprise.
• Conceived in the Enterprise spirit of: “Working in an open, collaborative fashion, sharing data and reagents in a collegial fashion, with the appropriate balance between productive competition and collaboration.”
• CAVD consortia grants target 2 of the major priorities identified in the Enterprise Scientific Plan:
. . . . » Vaccine Discovery [‘VDC’ = Vaccine Discovery Consortia]
. . . . » Laboratory Standardization
• Launched in July 2006 with 16 research consortia
. . . . » Design new candidate vaccines
. . . . » Improve and standardize immunologic evaluations
. . . . » Linked in a collaborative alliance
• $287 million over 5 years

CAVD: Philosophy of the Grants
• Focus mainly on “maturational” or translational research to bridge a strategic gap between basic discovery and product development and manufacturing.
• Key aim to create a collaborative network in which:
. . . . » Approach of different research groups is independent and complementary, but
. . . . » common tools are used to compare results, and
. . . . » information is shared to allow for an iterative process of knowledge-building and problem-solving.

CAVD: Structure of the Consortia
• More than 165 investigators in 22 countries
. . . . » 16 Principal Investigators: 11 in US, 5 in Europe
• 11 Vaccine Discovery Consortia
. . . . » 5 focused on neutralizing antibodies <<< incl. B.Haynes
. . . . » 6 focused on cell mediated immunity
• 5 Central Service Facilities
. . . . » 2 Vaccine immune Monitoring Centers
. . . . » 1 Mouse Immunology Lab
. . . . » 1 Specimen repository
. . . . » 1 Statistical Center
• Alliance Management Contract

= = = = = IF YOU’RE CONFUSED ABOUT CHAVI VS. CAVD, AS I INITIALLY WAS:

The Big Picture in the Global War on HIV…

GLOBAL HIV VACCINE ENTERPRISE http://www.hivvaccineenterprise.org
Comprised of 2 “implementation projects”:
1. CHAVI = NIAID - Center for HIV/AIDS Vaccine Immunology http://www.chavi.org
. . . . . . $300mm over 7 years from NIAID to CHAVI (Dir=B.Haynes).
2. CAVD = BMGF - Collaboration for AIDS Vaccine Discovery http://www.cavd.org
. . . . . . $287mm over 5 years from BMGF to CAVD ($15mm to B.Haynes).

Dr. Barton Haynes, Immunologist, Duke Univ., Dept. of Medicine
Director, CHAVI http://www.chavi.org
Director, Duke Human Vaccine Institute (DHVI) http://humanvaccine.duke.edu
Interests: Human immunity, Tcell function, HIV/AIDS vaccines
http://humanvaccine.duke.edu/modules/haynes/index.php?id=1

HAYNES VDC MISSION & GOALS (4-4-07)
The goal of the Haynes Vaccine Discovery Consortia [funded by BMGF CAVD, 1 of 11 VDC’s] is to acquire proof of concept data that manipulation of the immunoregulatory controls of B cell immune responses to HIV-1 Env, coupled with enhanced immunogen design, can lead to safe induction of broadly reactive neutralizing antibody responses. We are using a two armed approach to the problem of induction of antibodies that broadly neutralize HIV.

First, the Kelsoe, Haynes and Thorpe laboratories are developing immunogen formulations that trigger B cells normally tolerant to the desired Envelope epitopes and regions. Garnett Kelsoe is determining the origins, development, physiology, and fates of marginal zone, transitional and B1 B cell populations in animal models, including mice and non-human primates. To do this, the Kelsoe group has develop a “Marginal Zone B Cell Mouse” that is a reconstituted mouse that contains predominantly all MZ B cells for immunization and immunoregulation studies. Haynes is determining the role of tolerance mechanisms, T regulatory cells and TLR signaling on control of broadly reactive B cell activation, and Philip Thorpe is determining the role of lipid binding of anti-HIV antibodies and anti-phosphatidylserine(PS) autoantibodies to protection from HIV infection. With Philip Thorpe, studies are planned to determine if anti-lipid antibodies can prevent infection or early viral destruction of the immune system in acute SIV infection.

Second, the Harrison, Alam, Spicer, Shaw, Robinson and Hahn laboratories are developing immunogens that are more “native” and will preferentially induce the desired antibody types. These include HIV Env immunogens with a spectrum of affinities for binding to broadly reactive neutralizing antibodies, and immunogens with low entropic barriers to Mab binding and therefore are thermodynamically stable. Steve Harrison and group are expressing and characterizing single-chain Fvs from 4E10, 2F5 and 2G12 Mabs. With these genes he is carrying out directed mutation of single-chain Fvs and dissecting lipid and protein contributions to binding and Mab neutralization. He will use the Fvs in co-crystallization efforts with trimeric gp120/gp41 constructs. Munir Alam is designing gp41 peptide lipid conjugates using 4E10 and 2F5 epitpes peptides. He is characterizing the binding kinetics, and thermodynamic properties of 4E10 and 2F5 binding to peptide-lipid conjugates. Haynes is characterizing the carbohydrates of HIV-1 Env produced in T cells and macrophages, and is determining methods for making these “autoantigens” immunogenic. Spicer is studying the lipid-peptide conjugates for their structures by NMR. George Shaw and Beatrice Hahn have constructed HIV-1/HIV-2 chimeras with HIV-2 neutralizing determinants in HIV-1 scaffolds, to study the neutralization of HIV-2. They are constructing novel immunogens with HIV-1 and 2 scaffolds and virus like particles for formulation with adjuvants developed in this VDC by Haynes and colleagues.
http://humanvaccine.duke.edu/modules/grant_spt/index.php?id=11

= = = = = = = = = =
PEREGRINE’S PUBLIC STATEMENTS RE: DUKE/GATES HIV COLLAB…

10-24-05 Annual SHM http://tinyurl.com/c9bnq
“Tulane & Duke are working on Tarvacin for the treatment of HIV” [The first mention of Duke & Tarvacin]

12-15-05 CFO P.Lytle, N.Y. Sec. Analysts BioDefense Conf., http://tinyurl.com/raxu5
”Regarding HIV, we know that we have positive binding to both HIV1 & HIV2. There are plans underway for important collaborations in HIV, and we expect announcements during 1H-2006.”

2-15-06 CEO S.King, BIO-CEO Investors Conf.”, NYC http://tinyurl.com/a7842
“We’re also studying the potential for HIV. We know we have pos. binding for HIV1, HIV2, SIV, and SHIV. We have active collab’s at Duke and Tulane…”

9-11-06 Qtly. Conf. Call (King/Lytle): http://tinyurl.com/k7uo6
“BAVI HIV INITIATIVE: HIV is currently our primary area of interest for potential new AV indications... We have already generated positive data supporting the fact that Bavi recognizes both HIV virus and HIV infected cells. In order to fully evaluate the potential of Bavi in HIV therapy, we have expanded our collaborations in the HIV area. Our curr. collaborators include investigators at Tulane National Primate Research Center, Duke Univ., as well as contract research labs. Some of our collaborators at Duke recently received funding from The Gates Foundation for studies related to their HIV Vaccine Initiative. As part of these studies, we will be working with these researchers to assess phospholipids as a potential target for combating HIV. Because the program is being conducted by the researchers at Duke, we are not able to discuss the details at this time, but needless to say, we are very pleased to be involved in this collaboration, in increasing recognition that phospholipids may be an attractive target in HIV infection. We will provide an update on these studies as mutually agreed upon with our collaborators or at appropriate times for data generated internally, or at contract research institutions. It is important to remember that Univ. collaborators can be a very valuable asset to Peregrine, bringing us world-class expertise, access to cutting-edge researchers and facilities, and the potential for eventual support from key opinion leaders. At the same time, these researchers operate on their own timetables, and we have limited control concerning when the study results are completed and when they can be made public. These studies are proceeding and we will report on the results in due course.”

10-24-06 Annual SHM, incl. Thorpe presentation on Bavi AC/AV http://tinyurl.com/vmasl
“On the pre-clinical front, we are continuing our collab’s for AV applications, with the primary focus on HIV. Approx. 40% of HCV patients are HIV-positive as well, obviously representing a large part of the market. Those studies are ongoing at Tulane & Duke, as well as at contract labs.”

3-12-07 Qtly. Conf. Call (King/Lytle): http://tinyurl.com/2dtmca
Expanding the patient population we are treating to potentially include HCV/HIV co-infected individuals is a 3rd focus area… Our interest in this patient population has been further stimulated by solid evidence, thru our collab’s at Duke, that Bavi binds to HIV virus, binds to HIV-infected cells, and may have potent neutralizing effects on the virus. We plan to lay out our plans for each of these studies over the upcoming weeks as protocols are finalized and initiated.
Richard Feracusa, ML: Earlier you had mentioned the progress that Duke University had made with regard to HIV. It was quite impressive, and I know that they have received Gates Foundation money for HIV trials. Do you anticipate that they would conduct clinical trials, or you, or both?
SK: ”One thing to keep in mind is the goal of the group at Duke is to develop vaccines for HIV. Our drug, again, one of the areas of focus they have is, they believe these phospholipids, phosphatidylserine [PS] in particular, may be a very promising target for vaccine development. So the funding that's coming out of there is actually funding a lot of studies that are being done with bavituximab as a model for them to develop later on - vaccines, which would clearly take quite a long time. So whether or not they would support clinical trials is somewhat questionable. Those would probably be trials we would run, and clearly, as we're able to initiate this coinfected patient population we'll start to get some glimpses of at least how our drug interacts with the HIV infection, in an HCV setting. And so, I think from our standpoint, we're just viewing this as a real net-positive. They've given us access to data that we otherwise would not have been able to generate. We clearly, and I know that everyone would love to see the data from the Duke collaboration out there, we're obviously as anxious as anyone. The collaboration is going extremely well, the data we're generating is really helping us in the way we think about our development of bavituximab for HCV & HIV, so it's been a real successful collaboration, and we do look forward to hopefully a little bit later this year getting that data out there and really showing the progress, but in the meantime they're a very conservative group. We're more than happy to comply with their wishes as far as data release, although we certainly do take every opportunity to prod along the release of data when we get a chance.”

= = = = = = = = = =
THE BILL & MELINDA GATES FOUNDATION has provided 16 grants totaling $287mm over 5 years to establish an international network of HIV vaccine discovery consortia, supported by central labs and data analysis facilities. The goal of this new network is to overcome major scientific obstacles facing HIV vaccine research, and accelerate the development of an effective vaccine that could help bring the global AIDS epidemic under control. The 16 grants, known collectively as the Collaboration for AIDS Vaccine Discovery (CAVD), include:
A. Vaccine Discovery Consortia: 11 grants establish large-scale vaccine discovery consortia to pursue a range of innovative strategies for designing an effective HIV vaccine
1. Neutralizing antibodies: 5 consortia will focus on designing vaccine candidates capable of eliciting effective neutralizing antibodies against HIV
2. Cellular immunity: 6 consortia will focus on overcoming significant shortcomings with current vaccine candidates designed to elicit effective cellular immunity
B. Central facilities: 5 grants establish central facilities to support comparative evaluations of the vaccine candidates created by the discovery consortia…
Following are descriptions of each of the 16 BMGF grants:

VACCINE DISCOVERY CONSORTIA
A. Neutralizing Antibodies [5 grants, incl. Duke/Haynes #3 below]
5 grants establish large-scale vaccine discovery consortia to address one of the biggest scientific obstacles currently facing HIV vaccine development: designing novel vaccine candidates capable of eliciting effective neutralizing antibodies. Virtually all licensed vaccines are believed to work, at least in part, by stimulating the immune system to produce neutralizing antibodies that bind to vulnerable regions on the infection-causing agent – much like a lock and key. But traditional approaches for eliciting effective antibodies have mostly failed for HIV. A major challenge is that HIV has a high level of genetic variability, and an effective vaccine will need to elicit antibodies that can neutralize a broad range of HIV strains.
The 5 grants focused on Neutralizing Antibodies include:
1. Vaccines to Neutralize HIV-1 $25.3mm - Robin Weiss, Univ. College London…
2. Discovery of Novel HIV Neutralizing Epitopes and Their Optimal Presentation Though Computational Design of Small Protein Immunogens $19.4mm - Leo Stamatatos, Seattle Biomedical Research Institute…
3. (((( Broadly Reactive Neutralizing Antibodies: Novel Strategies for Vaccine Design $15mm - Barton Haynes, Duke Univ. - Previous studies by Dr. Haynes and colleagues have suggested that the immune system is naturally capable of producing effective antibodies against HIV, but suppresses these antibodies from being generated. The investigators hypothesize that critical areas on HIV’s outer coat mimic a person’s own “self” molecules, and the immune system therefore does not attack HIV with effective antibodies – a phenomenon known as immune tolerance. The consortium’s goal is to identify vaccine strategies to “switch on” the immune system’s ability to make effective antibodies against HIV, either by interrupting immune tolerance, or by making altered versions of the outer coat of HIV that can stimulate different but effective antibodies. As part of this research, the consortium will collaborate with scientists in Zambia to study a less virulent type of HIV, called HIV-2. By understanding how antibodies are more easily able to neutralize HIV-2, the investigators hope to uncover new strategies for effective vaccine design. ))))
4. The V3 Loop: A Conserved Structure of gp120 That Can Induce Broadly Neutralizing Antibodies Against HIV-1 $8.4mm - Susan Zolla-Pazner, New York Univ. School of Medicine…
5. Allogenic HIV Vaccine Strategy Utilizing Innate and Adaptive Immunity $5.6mm - Thomas Lehner, Kings College London…
B. Cellular Immunity [6 grants]
In addition to neutralizing antibodies, an effective HIV vaccine may need to induce cellular, or Tcell, immunity. Cellular immunity and neutralizing antibodies work in concert – while antibodies bind to viruses to prevent them from infecting cells, cellular immunity locates and destroys infected cells. 6 grants establish large-scale consortia to address critical challenges in designing vaccine candidates capable of eliciting strong and long-lasting protective cellular immune responses against HIV. To date, several HIV vaccine candidates designed to elicit cellular immunity have been tested in clinical trials, although all have significant shortcomings. The 6 grants focused on cellular immunity include:
1. Novel Recombinant Adenovirus and Mycobacteria Vector-Based Vaccines for HIV-1 - Norman Letvin, Harvard Univ. and Beth Israel Deaconess Medical Center $18mm
2. Optimization and Efficacy of a Transcutaneous “Stealth” Adenovirus Vector Vaccine for Mucosal Protection Against HIV - Steven Patterson, Imperial College London $9.2mm
3. Poxvirus T-Cell Vaccine Discovery Consortium - Giuseppe Pantaleo, Centre Hospitalier Universitaire Vaudois $15.3mm
4. T-Cell Vaccine R&D Consortium - Timothy Zamb, International AIDS Vaccine Initiative $23.7mm
5. Harnessing Dendritic Cells and Innate Immune Activation Signals to Guide HIV-1 Vaccine Development - David Ho, Aaron Diamond AIDS Research Center $24.7mm
6. Harnessing Innate Immunity to Enhance the Immunogenicity of HIV Vaccines - M. Juliana McElrath, Fred Hutchinson Cancer Research Center $30.1mm
C. CENTRAL FACILITIES [5 grants]
5 grants will create central facilities to support the vaccine discovery consortia described above. These facilities will help consortia members share data in a timely manner, and use standardized protocols and benchmarks to compare results. The 5 grants for central facilities include:
1. Comprehensive Antibody Vaccine Immune Monitoring Consortium - David Montefiori, Duke Univ. $31.5mm
2. Comprehensive T-Cell Vaccine Immune Monitoring Consortium - Richard Koup, Dale & Betty Bumpers Vaccine Research Center, U.S. NIH Grant recipient $33.3mm - Dr. Montefiori will establish an intl. network of laboratories to evaluate neutralizing antibody responses elicited by HIV vaccine candidates created by the vaccine discovery consortia, and Dr. Koup will establish a complementary network of laboratories to evaluate cellular immune responses…
3. Mouse Immunology Laboratory - Phil Greenberg, Univ. of Washington $10mm
4. Consortium on Global HIV Vaccine Research Cryorepository - Hagen Von Briesen, Fraunhofer-Institut für Biomedizinische Technik $7.5mm
5. Vaccine Immunology Statistical Center - Steven Self, Fred Hutchinson Cancer Research Center $9.9mm
http://www.hivvaccineenterprise.com/_dwn/news/HIVVaccineGrants_Backgrounder.pdf

CHAVI CENTER FOR HIV-AIDS VACCINE IMMUNOLOGY
VACCINE DESIGN DISCOVERY TEAM
The Vaccine Design Discovery Team is led by Dr. Barton Haynes of Duke University. Investigators in vaccine design will work in the Vector Development Core to design vectors, inserts and composite immunogens for testing in the Non-Human Primate Core. Viable immunogens resulting from these immunogenicity studies will be considered for vaccine development.
http://www.chavi.org/modules/chavi_teams/index.php?id=1
http://www.chavi.org/modules/chavi_contact/index.php?id=3#Haynes

Barton Haynes, MD, CHAVI Director
Dec.22, 2006 CHAVI Y02 Fall Progress Report
…including…
STRUCTURAL BIOLOGY OF ENVELOPE
• What are the HIV-1 envelope glycoprotein epitopes recognized by broadly and potently neutralizing antibodies?
• Do complement-mediated or ADCC-mediated “neutralizing” antibodies recognize the same or different epitopes as the standard in vitro assay neutralizing antibodies?
• What are the conformations of the HIV-1 envelope in the un-liganded state and bound to antibodies of different neutralizing potency? How does the structure change when CD4 and co-receptor bind?
• What conformations are sampled by the envelope variable loops and carbohydrate?
• What is the structure of the native HIV-1 trimer?
• What special features characterize the envelope of transmitted HIV-1?
http://www.hivvaccineenterprise.com/_dwn/CHAVI_Progress_Report_20061227.pdf

CHAVI = “Center for HIV AIDS Vaccine Immunology”
The Center for HIV/AIDS Vaccine Immunology (http://www.chavi.org) is currently one of two implementation projects under the Global HIV Vaccine Enterprise, the other being the recently funded Collaboration for AIDS Vaccine Discovery (CAVD http://www.cavd.org) by grants from the BILL AND MELINDA GATES FOUNDATION. In July 2005, the NIAID awarded the CHAVI grant to a consortium of investigators from Duke University, the Dana-Farber Cancer Institute, Beth Israel Deaconess Medical Center, Oxford University, and the University of Alabama-Birmingham, led by Dr. Barton Haynes. The CHAVI will test new vaccine strategies to overcome key immunological roadblocks in HIV vaccine design. These roadblocks include a lack of understanding of the correlates of protective immunity to HIV-1 and a lack of vectors and immunogens that can induce protective, durable immune responses at mucosal sites. The CHAVI will study the transmitted virus, and the biological events that occur during transmission. The CHAVI will work to define protective innate and adaptive host defenses against HIV in humans and SIV in primates.

The overall goals of the CHAVI include:
• Determine the viral and immunological events and host genetic factors associated with HIV transmission, infection and (partial) containment of virus replication
• Develop novel HIV-1 vectors, immunogens and adjuvants that suppress viral replication and elicit persistent mucosal and/or systemic immune responses
• Use SIV infection in primates as a model for HIV infection in humans and determine the factors that lead to mucosal protection from SIV in primates
• Test novel HIV-1 vaccine candidates in phase I clinical trials
http://www.chavi.org/modules/chavi_reports/index.php?id=5
http://www.chavi.org/modules/chavi_about/index.php?id=1
http://humanvaccine.duke.edu/modules/grant_spt/index.php?id=2