Vaccines and Microbicides: The Long Road to Success


"Failure informs future success." 
The HIV vaccine and microbicide researchers who took to the stage on
Monday to discuss the future of these experimental HIV prevention technologies
repeated this mantra throughout the symposium.  

The halted STEP vaccine study perhaps
best illustrates this point. Last year an interim analysis showed Merck’s
Ad-5 vaccine was ineffective and may have even enhanced risk of HIV
infection. But Susan Buchbinder, a STEP investigator, emphasized the
valuable lessons learned from the study: the utility of the test-of-concept
trial (Phase IIb) to give us quick answers; that we must recalibrate
the non-human primate model to better understand its applicability; and a wealth of data was mined, even leads on potential immune correlates.
Predicting a positive immune response remains an important yet elusive
goal in testing HIV vaccines.  

The panelists emphasized the need
for truly novel ideas in moving forward in vaccine discovery, some bordering
on weird science like reducing, not enhancing an immune response, promoting
more mutations, and using replicating viral vectors for vaccine delivery.
The Bill & Melinda Gates Foundation, characteristically leading
the charge, this year implemented its Grand Challenges Explorations,
a $100 million initiative to encourage bold and unconventional science.   

Although the microbicide research
field is no stranger to setbacks, Zeda Rosenberg, from the International
Partnership for Microbicides, spoke of the optimism around ARV-containing
candidates.  This new generation of microbicides is thought to
be more potent than its predecessor because of its known anti-HIV properties. 
Some microbicides contain combination ARVs, expected to offer multi-mechanism
protection.  

Learning from past trials, or what
some would loosely call "failures," consistent use of the microbicide
in the intervention arm has proved to be a challenge. Responding to
this finding, microbicides are being designed for longer protection
to make adherence easier. Prospects include a once-daily or even a 30-day
microbicide delivered via a vaginal ring.  

A robust pipeline to hedge against
failures is needed in both vaccine and microbicide pursuits, panelists
agreed. "Nine out of 10 drugs or vaccines end with failures," said
Tachi Yamada of the Gates Foundation. "Success is about long-term
investment, not about today or tomorrow, but sometime in our lifetime."

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    HIV – Phosphatidylserine Discovery

    August 28, 2008

    Last month’s announcement by NIAID Director Dr. Anthony Fauci to scrap the upcoming “PAVE-100″ HIV vaccine clinical trial, (following on the heels of the failed Merck “STEP” HIV vaccine trial), showed yet again how difficult and elusive the goal of an effective HIV vaccine remains.

    In the midst of these sobering developments, an important new insight was gained into why experimental HIV vaccines have failed to elicit an adequate immune response. The discovery, published in the August issue of the Journal of Virology (1), came from the leader of NIAID’s “CHAVI” organization, Dr. Barton Haynes of Duke University, who is also a principle investigator of the Gates Foundation HIV vaccine effort.

    In their paper, Haynes and colleagues discuss experiments showing that HIV weakens the immune system much faster than previously thought. The primary mechanism responsible for this immunosuppression is an overwhelming amount of what Haynes terms “microparticles”, which are tiny particles shed from the outer membranes of infected and dying cells. This cellular debris accumulates during early HIV infection, and circulates throughout the body blunting the functions of the immune cells that would ideally fight the virus. Popular news articles have discussed this aspect of the Duke researchers’ findings, but the details and broader implications of the team’s discovery have yet to be elucidated in the media.

    The paper explains that the microparticles contain the molecule phosphatidylserine (PS) exposed on their surface. PS is a lipid that normally lines the interior of the cell membranes of every cell in our body. As a cell dies, it loses the ability to maintain PS on the inside of the cell membrane. The PS flips to the exterior, where it is perceived by immune cells as a sign of a dying native cell. The Haynes team cite recent data showing how exposed PS appears to be the fundamental signal that shifts the behavior of immune cells into not mounting an antigen-specific attack, since PS is interpreted as a sign of “self” rather than a foreign invader (2). Other researchers have also recently illustrated the suppressive effects of PS on macrophages, the resulting cytokine environment, dendritic cells, and T cells (3-7). It is thus no surprise that recent research has also revealed exposed PS as a feature common to many diverse pathogens (8-22), as if they independently evolved to exploit a similar mechanism of evasion, since it provides the crucial advantage of triggering an inappropriate immune response, facilitating the pathogen’s survival and proliferation.

    A review of Haynes’ recent patent applications provides further details that have yet to be published in the journals. In one application, titled “Multicomponent Vaccine” (23), Haynes explains that any future successful HIV vaccine must interrupt this PS-mediated immunosuppressive signaling. A specific goal mentioned is for a vaccine to induce antibodies to PS (anti-PS), thereby blocking the overwhelming immune suppression seen in the Duke research, allowing the viral immunogen in the vaccine the chance to evoke T and B cells which effectively fight the virus.

    In yet another recent patent application, Haynes proposes using anti-PS as a promising treatment for people already infected with the virus (24). He discusses the ability of anti-PS monoclonal antibodies to bind to HIV and HIV-infected cells, saying anti-PS “can be safely used as a therapeutic Mab for treatment of HIV infected subjects”, and that it can “broadly neutralize HIV in an unprecedented manner”.

    Perhaps the most fascinating comment found in one of Haynes’ many recent patent applications is his suggestion that HIV’s method of immune evasion may be a general escape mechanism utilized by other pathogens (24), and that similar means of therapy may be effective against other diseases. Indeed, a review of the recent major journals corroborates this concept:

    * In April, the journal Science published experiments showing that the pox family of viruses, (vaccinia), utilize exposed PS to gain entry into cells (25).

    * In the March issue of the journal Clinical Cancer Research, scientists from Harvard University discuss experiments in which blocking PS signaling helped facilitate complete melanoma tumor regressions (26).

    * The protozoan parasites responsible for many of the deadly diseases affecting much of the developing world have been found to rely on exposed PS to successfully avoid the immune system of their host (16-22).

    * Several cancer researchers have recently published data which bears a striking resemblance to the new findings of the Haynes HIV group, showing a very similar method of systemic immune suppression caused by PS-exposing microparticles shed from tumor cells (29-34), (see also 27, 28).

    * In another recent Haynes patent application he also discusses PS-exposing microparticles as playing a role in the pathogenesis of several auto-immune diseases as well as atherosclerosis (35), (see also 36-40).

    Taken together, these discoveries suggest a new immunological perspective of pathogenesis in general. A paradigm appears to be emerging in which the necessary and admirable flexibility of the immune system has been exploited precisely where it is most vulnerable – when it must commit to a ‘friendly’ response. The recent HIV research by Haynes and colleagues, focusing on PS-induced immune suppression, and the safe therapeutic targeting of exposed PS with antibodies, carries implications of unprecedented broad therapeutic potential.

    References:

    1. Nancy Gasper-Smith, Deanna M. Crossman, John F. Whitesides, Nadia Mensali, Janet S. Ottinger, Steven G. Plonk, M. Anthony Moody, Guido Ferrari, Kent J. Weinhold, Sara E. Miller, Charles F. Reich III, Li Qin, Stephen G. Self, George M. Shaw, Thomas N. Denny, Laura E. Jones, David S. Pisetsky, and Barton F. Haynes, 2008, Induction of Plasma (TRAIL), TNFR-2, Fas Ligand, and Plasma Microparticles after Human Immunodeficiency Virus Type 1 (HIV-1) Transmission: Implications for HIV-1 Vaccine Design, The Journal of Virology, Vol. 82, No. 15

    2. Peter R. Hoffmann, Jennifer A. Kench, Andrea Vondracek, Ellen Kruk, David L. Daleke, Michael Jordan, Philippa Marrack, Peter M. Henson and Valerie A. Fadok, 2005, Interaction between Phosphatidylserine and the Phosphatidylserine Receptor Inhibits Immune Responses In Vivo. The Journal of Immunology, 174: 1393-1404.

    3. Lars-Peter Erwig and Peter M. Henson, 2007, Immunological Consequences of Apoptotic Cell Phagocytosis Am J Pathol. July; 171(1): 2–8.

    4. Xiao Chen, Kara Doffek, Sonia L. Sugg and Joel Shilyansky , 2004. Phosphatidylserine Regulates the Maturation of Human Dendritic Cells The Journal of Immunology, 173: 2985-2994.

    5. Celio G. Freire-de-Lima∗, Yi Qun Xiao, Shyra J. Gardai, Donna L. Bratton, William P. Schiemann, and Peter M. Henson, 2006, Apoptotic cells, through transforming growth factor-beta, coordinately induce anti-inflammatory and suppress pro-inflammatory eicosanoid and NOsynthesis in murine macrophages. J. Biol. Chem., Vol. 281, Issue 50, 38376-38384

    6. Satoshi Yotsumoto, Terutaka Kakiuchi and Yukihiko Aramaki, 2005, Negatively charged phospholipids suppress IFN-gamma production in T cells. Biochemical and Biophysical Research Communications, Volume 338, Issue 4,

    7. Dongmei Shi, Meng Fu, Pinshen Fan, Wei Li, Xinhui Chen, Chenxin Li, Xianlong Qi, Tianwen Gao and Yufeng Liu, 2007, Artificial phosphatidylserine liposome mimics apoptotic cells in inhibiting maturation and immunostimulatory function of murinemyeloid dendritic cells in response to 1-chloro-2,4-dinitrobenze in vitro . Archives of Dermatological Research Volume 299, Number 7

    8. Ryungsa Kim, Manabu Emi, Kazuaki Tanabe, 2005. Cancer Cell Immune Escape and Tumor Progression by Exploitation of Anti-Inflammatory and Pro-Inflammatory Responses. Cancer Biology & Therapy 4:9, 924-933

    9. Ryungsa Kim, Manabu Emi, Kazuaki Tanabe and Koji Arihiro, 2006, Tumor-Driven Evolution of Immunosuppressive Networks During Malignant Progression. Cancer Research 66, 5527-5536

    10. Melissa K. Callahan, Paul M. Popernack, Shigeki Tsutsui, Linh Truong, Robert A. Schlegel, and Andrew J. Henderson, 2003. Phosphatidylserine on HIV Envelope Is a Cofactor for Infection of Monocytic Cells The Journal of Immunology, 170: 4840-4845

    11. David A. Coil and A. Dusty Miller, 2005. Enhancement of Enveloped Virus Entry by Phosphatidylserine Journal of Virology, p. 11496-11500, Vol. 79, No. 17.

    12. Shawn J. Green, 2006. Could a vaccine to cholesterol cause a wrinkle in the HIV-1 envelope? Public Library of Science Journal of Biology, Published: November 22, 2006

    13. David A. Coil and A. Dusty Miller, 2005. Phosphatidylserine treatment relieves the block to retrovirus infection of cells expressing glycosylated virus receptors Retrovirology 2005, 2:49

    14. Ge Ma, Teresa Greenwell-Wild, Kejian Lei, Wenwen Jin, Jennifer Swisher, Neil Hardegen, Carl T. Wild, and Sharon M. Wahl, Secretory Leukocyte Protease Inhibitor Binds to Annexin II, a Cofactor for Macrophage HIV-1 InfectionJEM, Volume 200, Number 10, 1337-1346

    15. N Gasper-Smith, JF Whitesides, N Mensali, JS Ottinger, SG Plonk, MA Moody, G Ferrari, KJ Weinhold, CF Reich, DS Pisetsky and BF Haynes, 2007, Plasma FAS ligand, TNFR2, and TRAIL levels are elevated during the time of viral load ramp-up in acute HIV-1 infection AIDS Vaccine 2007 Conference, Seattle Washington, August 20-23, 2007, PO1-01.

    16. Shigetoshi Eda, Irwin Sherman, 2002, Cytoadherence of Malaria-Infected Red Blood Cells Involves Exposure of Phosphatidylserine Cell Physiol Biochem 12:373-384

    17. Sergio H. Seabra, Wanderley de Souza and Renato A. DaMatta, 2004, Toxoplasma gondii exposes phosphatidylserine inducing a TGF-beta1 autocrine effect orchestrating macrophage evasion. Biochemical and Biophysical Research Communications, Volume 324, Issue 2, pages 744-752.

    18. Desiree van der Kleij, Eicke Latz, Jos F. H. M. Brouwers, Yvonne C. M. Kruize, Marion Schmitz, Evelyn A. Kurt-Jones, Terje Espevik, Esther C. de Jong, Martien L. Kapsenberg, Douglas T. Golenbock, Aloysius G. M. Tielens, and Maria Yazdanbakhsh, 2002. A Novel Host-Parasite Lipid-Crosstalk J. Biol. Chem., Vol. 277, Issue 50, 48122-48129

    19. Renato A. DaMatta , Sergio H. Seabra, Poliana Deolindo, Andréa C. V. Arnholdt, Lauro Manhães, Samuel Goldenberg, Wanderley de Souza, 2007. Trypanosoma cruzi exposes phosphatidylserine as an evasion mechanism FEMS Microbiology Letters,Volume 266 Issue 1 Page 29-33

    20. Annalena Bollinger, 2005, Leishmania Major Promastigotes Use Phosphatidylserine For Silencing Of Polymorphonuclear Neutrophils Doctoral dissertation in partial fulfillment of the requirements for the degree of Doctor of Natural Sciences (Dr. rer. nat.) from the University of Lübeck – Faculty of Technology and Sciences

    21. J.L.M. Wanderley, A. Benjamin, F. Real, A. Bonomo, M.E.C. Moreira and M.A. Barcinski, 2005, Apoptotic mimicry: an altruistic behavior in host/Leishmania interplay Braz J Med Biol Res, June 2005, Volume 38(06) 807-812

    22. José Mario de Freitas Balanco, Maria Elisabete Costa Moreira, Adriana Bonomo, Patricia Torres Bozza, Gustavo Amarante-Mendes, Claude Pirmez and Marcello André Barcinski, 2001, Apoptotic mimicry by an obligate intracellular parasite downregulates macrophage microbicidal activity Current Biology, Volume 11, Issue 23, Pages 1870-1873

    23 HAYNES, Barton, F., SMITH, Nancy, G., ALAM, S., Munir GAO, Feng LIAO, Hua-Xin, Publication Date:29.05.2008, (WO/2008/063586) MULTICOMPONENT VACCINE, World Intellectual Property Organization patent application WO/2008/063586

    24. Haynes; Barton F., published March 6, 2008, Method of inducing neutralizing antibodies to human immunodeficiency virus, US patent application 20080057075

    25. Jason Mercer, Ari Helenius, 2008. Vaccinia Virus Uses Macropinocytosis and Apoptotic Mimicry to Enter Host Cells
    Science, 2008 Apr 25;320(5875):531-5.

    26. Catia Fonseca and Glenn Dranoff, 2008. Capitalizing on the Immunogenicity of Dying Tumor Cells Clinical Cancer Research 14, 1603-1608.

    27. J. H. W. Distler, L. C. Huber, A. J. Hueber, C. F. Reich III, S. Gay, O. Distler and D. S. Pisetsky, 2005, The release of microparticles by apoptotic cells and their effects on macrophages The Journal of Apoptosis, Volume 10, Number 4, Pages 731-741

    28. Lars C. Huber, Astrid Jüngel, Jörg H. W. Distler, Falk Moritz, Renate E. Gay, Beat A. Michel, David S. Pisetsky, Steffen Gay and Oliver Distler, 2006. The role of membrane lipids in the induction of macrophage apoptosis by microparticles The Journal of Apoptosis, Volume 12, Number 2, Pages 363-374

    29. Roberta Valenti, Veronica Huber, Manuela Iero, Paola Filipazzi, Giorgio Parmiani and Licia Rivoltini, 2007, Tumor-Released Microvessicles as Vehicles of Immune Suppression. Cancer Research 67, 2912-2915

    30. Roberta Valenti, Veronica Huber, Paola Filipazzi, Lorenzo Pilla, Gloria Sovena, Antonello Villa, Alessandro Corbelli, Stefano Fais, Giorgio Parmiani and Licia Rivoltini, 2006, Human Tumor-Released Microvesicles Promote the Differentiation of Myeloid Cells with Transforming Growth Factor-ß–Mediated Suppressive Activity on T Lymphocytes Cancer Research 66, 9290-9298

    31. Aled Clayton, J. Paul Mitchell, Jacquelyn Court, Malcolm D. Mason and Zsuzsanna Tabi, 2007, Human tumor-derived exosomes selectively impair lymphocyte responses to interleukin-2 Cancer Research 67, 7458-7466

    32. Veronica Huber, Stefano Fais, Manuela Iero, Luana Lugini, Paola Canese, Paola Squarcina, Annamaria Zaccheddu, Marisa Colone, Giuseppe Arancia, Massimo Gentile, Ettore Seregni, Roberta Valenti, Giuseppina Ballabio, Filiberto Belli, Ermanno Leo, Giorgio Parmiani and Licia Rivoltini, 2005, Human colorectal cancer cells induce T-cell death through release of proapoptotic microvesicles: role in immune escape. Gastroenterology, Volume 128, Issue 7, Pages 1796-1804.

    33. Shaohua Yu, Cunren Liu, Kaihong Su, Jianhua Wang, Yuelong Liu, Liming Zhang, Chuanyu Li, Yingzi Cong, Robert Kimberly, William E. Grizzle, Carla Falkson and Huang-Ge Zhang, 2007, Tumor exosomes inhibit differentiation of bone marrow dendritic cells. The Journal of Immunology, 178: 6867-6875

    34. M Iero, R Valenti, V Huber, P Filipazzi, G Parmiani, S Fais and L Rivoltin, 2008, Tumour-released exosomes and their implications in cancer immunity Cell Death and Differentiation 15, 80–88

    35. HAYNES, Barton, F. , SMITH, Nancy, G. , Publication Date:24.07.2008, METHOD OF MONITORING HIV INFECTION World Intellectual Property Organization patent application WO/2008/088747

    36. Tedqui, A, Mallat, Z, 2003, Apoptosis, a major determinant of atherothrombosis. Arch Mal Coeur Vaiss, 96(6):671-5

    37. Morel O, Toti F, Bakouboula B, Grunebaum L, Freyssinet JM., 2006, Procoagulant microparticles: ‘criminal partners’ in atherothrombosis and deleterious cellular exchanges Pathophysiology of Haemostasis and Thrombosis, 35(1-2):15-22

    38. S. P. Ardoin, J. C. Shanahan, D. S. Pisetsky, 2007 The role of microparticles in inflammation and thrombosis Scandinavian Journal of Immunology 66 (2-3) , 159–165

    39. Nikos Werner; Sven Wassmann; Patrick Ahlers; Sonja Kosiol; Georg Nickenig, 2006, Circulating CD31+/annexin V+ apoptotic microparticles correlate with coronary endothelial function in patients with coronary artery disease. Arteriosclerosis, Thrombosis, and Vascular Biology. 26:112

    40. Liudmila Zakharova, Maria Svetlova, Alla F. Fomina, 2006. T cell exosomes induce cholesterol accumulation in human monocytes via phosphatidylserine receptor Journal of Cellular Physiology, Volume 212, Issue 1, Pages 174-181.