eBriefing

HIV/AIDS: Vaccines and Alternate Strategies for Treatment and Prevention

HIV/AIDS
Reported by
Don Monroe

Posted July 26, 2010

Overview

On May 19, 2010, the Vaccine Science Discussion Group joined with the Global HIV Vaccine Enterprise to host a day-long symposium called "HIV/AIDS: Vaccines and Alternate Strategies for Treatment and Prevention." Although behavioral changes and strategies such as condom use, circumcision, microbicides, and prophylactic antiviral therapy have key roles to play in prevention, most of the discussion centered on vaccines, in part because the meeting came just a day after HIV Vaccine Awareness Day and in part because of the known effectiveness of vaccines in stopping many other infectious pathogens.

In spite of extensive scientific understanding of how the HIV-1 virus infects people, the prospects for an effective preventive vaccine remain unclear, because the immune correlates of protection are not known. Nevertheless a recent trial that showed a modest positive result in preventing acquisition has fuelled considerable enthusiasm amongst researchers and the broader community.

Use the tabs above to find a meeting report and multimedia from this event.

Presentations are available from:

Yegor Voronin (Global HIV Vaccine Enterprise)
Michael Worobey (University of Arizona)
Dan H. Barouch (Beth Israel Deaconess Medical Center)
Sanjay Phogat (International AIDS Vaccine Initiative)
Susan Zolla-Pazner (NYU School of Medicine and Veterans Affairs Medical Center)
Chris Miller (University of California, Davis)
Harriet L. Robinson (GeoVax Inc.)
Alan Bernstein (Global HIV Vaccine Enterprise)
Jerome Kim (Walter Reed Army Institute of Research)


Presented by

  • Global HIV Vaccine Enterprise
  • The New York Academy of Sciences

Academy Friends

Grant Support

This program is supported by an educational grant from Merck & Co., Inc.

Photo credit: CDC/ Dr. A. Harrison; Dr. P. Feorino

Overview of the Challenges


Yegor Voronin (Global HIV Vaccine Enterprise)
  • 00:01
    1. Introduction; Global HIV Vaccine Enterprise; Obstacles
  • 03:35
    2. Scientific challenges; Introduction conclude

Update of the Thai Phase III HIV Vaccine Trial: The Way Forward


Jerome Kim (Walter Reed Army Institute of Research)
  • 00:01
    1. Introduction; Risk and the treatment effect
  • 11:07
    2. Evidence of an early effect; Model for early effect and low risk effect
  • 16:04
    3. Immunogenicity update
  • 22:06
    4. Persistance of ENV responses after intercurrent infection
  • 27:05
    5. RV148 and RV144; Progress of SGA sieve analysis
  • 29:42
    6. The search for the correlate; Humoral/innate and cellular working groups
  • 34:35
    7. Summary of clinical development discussions
  • 39:37
    8. The big picture questions; Conclusion and acknowledgement

HIV Vaccine Research Today, the Global HIV Vaccine Enterprise, and the Enterprise Scientific Strategic Plan


Alan Bernstein (Global HIV Vaccine Enterprise)
  • 00:01
    1. Introduction
  • 04:40
    2. Enterprise plan history and outline
  • 12:20
    3. Optimizing clinical trials
  • 16:00
    4. Harnessing the full potential of model systems; Cross-cutting considerations
  • 21:30
    5. Conclusio

Viral Genetic Diversity and the Control of HIV/AIDS: Challenges and Opportunities


Michael Worobey (University of Arizona)
  • 00:01
    1. Introduction; History of SIV and HIV
  • 08:57
    2. The spread of HIV begins
  • 15:07
    3. The emergence of HIV/AIDS from the African epicenter
  • 20:00
    4. The present; The war within the host; Vaccines
  • 26:19
    5. Summary; Prevention; Conclusio

Recent Progress in Isolating HIV-1 Broad Neutralizing Antibodies


Sanjay Phogat (International AIDS Vaccine Initiative)
  • 00:01
    1. Introduction; The neutralizing antibody problem
  • 05:47
    2. Antibody discovery approach
  • 09:34
    3. Screening of slgG+ memory B-cells; PG9 and PG16; QNE specific antibodies
  • 12:11
    4. The VRC and CAVD strategies
  • 17:28
    5. Antibody identification since 2009; Targets still to be identified
  • 19:51
    6. Acknowledgements and conclusio

Using Epitopes Recognized by Monoclonal Antibodies as Vaccine Templates


Susan Zolla-Pazner (NYU School of Medicine and Veterans Affairs Medical Center)
  • 00:01
    1. Introduction; Definition of QNEs
  • 03:23
    2. QNE history; V1V2 epitopes; Similarities of QNE mAbs
  • 11:48
    3. Implications of broadly reactive QNE antibodies; Conservation within V1 and V2
  • 19:45
    4. Conservation within V3; V3-CTB immunogens
  • 28:44
    5. Conclusions and acknowledgement

Novel Vectors and Antigens for a Next Generation HIV-1 Vaccine


Dan H. Barouch (Beth Israel Deaconess Medical Center)
  • 00:01
    1. Introduction; Desirable features of next generation candidate
  • 04:56
    2. Clinical development strategy; Studies and results
  • 17:00
    3. Antigen development; The mosaic cocktail; Study and results
  • 28:47
    4. Generating the right epitopes; Proposed next-generation candidate
  • 31:08
    5. Summary, conclusion, and acknowledgement

Clinical and Preclinical Studies for DNA and Recombinant MVA Vaccines Expressing HIV-1 Virus-Like-Particles


Harriet L. Robinson (GeoVax Inc.)
  • 00:01
    1. Introduction; VLP expression
  • 03:28
    2. Preclinical high dose challenges; HVTN 065 Phase 1
  • 11:27
    3. SIV239 immunogens
  • 15:58
    4. GM-CSF and protection against acquisition
  • 21:37
    5. Analyses for correlates for protection; GeoVax Clade B, MMM-VLP, and DNA/MVA
  • 26:54
    6. Acknowledgements and conclusio

A Protective Live-Attenuated AIDS Vaccine Suppresses Innate Immunity and Inflammation in Immunized Rhesus Macaques


Chris Miller (University of California, Davis)
  • 00:01
    1. Introduction; Explanation of live attenuated system
  • 13:54
    2. Lymphocyte depletion experiment
  • 23:46
    3. Immune activation after SIV challenge
  • 28:44
    4. Currently licensed vaccines; Effectiveness
  • 32:17
    5. Acknowledgements and conclusio

Panel Discussion: Where Are We Going and What's Next?


Moderator: Sarah Schlesinger (The Rockefeller University)
  • 00:01
    1. Introduction; Non-vaccine prevention strategies
  • 06:00
    2. Advocacy among risk groups; Taking science into trials
  • 15:20
    3. Enhancement of infection; Correlates of protection; Political fallout
  • 29:57
    4. The impact of privatization on research; The virus latency pool
  • 35:15
    5. Concluding remark

Web Sites

Center for HIV/AIDS Vaccine Immunology
The Center for HIV/AIDS Vaccine Immunology (CHAVI) is a consortium of universities and academic medical centers established by the National Institute of Allergy and Infectious Diseases (NIAID) under Barton Haynes, MD, of Duke University. The Center's goal is to solve major problems in HIV vaccine development and design.

The Collaboration for AIDS Vaccine Discovery (CAVD)
The Collaboration for AIDS Vaccine Discovery (CAVD) is an international network of scientists and experts dedicated to designing a variety of novel HIV vaccine candidates and advancing the most promising candidates to clinical trials.

GeoVax Labs Inc.
GeoVax Labs Inc., is a company dedicated to the development of an HIV vaccine.

Global Advocacy for HIV Prevention (formerly AIDS Vaccine Advocacy Coalition)
Founded in 1995, AVAC is an international non-profit organization that uses education, policy analysis, advocacy, and community mobilization to accelerate the ethical development and eventual global delivery of AIDS vaccines and other new HIV prevention options as part of a comprehensive response to the pandemic.

Global HIV Vaccine Enterprise
The Global HIV Vaccine Enterprise is a unique global alliance of independent organizations working together to accelerate the development of safe and effective HIV vaccines.

HIV Vaccine Trials Network (HVTN)
The HIV Vaccine Trials Network (HVTN) is an international collaboration of scientists and educators searching for an effective and safe HIV vaccine. The HVTN's mission is to facilitate the process of testing preventive vaccines against HIV/AIDS. Our organization conducts all phases of clinical trials, from evaluating experimental vaccines for safety and the ability to stimulate immune responses, to testing vaccine efficacy.

IAVI: International AIDS Vaccine Initiative
IAVI's mission is to ensure the development of safe, effective, accessible, preventive HIV vaccines for use throughout the world.

South African AIDS Vaccine Initiative (SAAVI)
The South African AIDS Vaccine Initiative (SAAVI) was formed in 1999 as a lead programme of the Medical Research Council (MRC) of South Africa. SAAVI was established to co-ordinate the research, development and testing of AIDS vaccines in South Africa.

The Step Study
Home site for the Step HIV vaccine study.

Theraclone Sciences
Theraclone Sciences is a company involved in antibody screening efforts.

U.S. Military HIV Research Program
In 1985, the U.S. military recognized the emerging HIV-1 epidemic as a new threat to U.S. and allied forces worldwide. A military directive emerged to develop effective preventive measures to include prevention education, vaccine development and implementation of novel anti-viral therapies and clinical management tools for the Department of Defense (DoD). The United States Congress mandated the formation of a U.S. Army-led HIV/AIDS research unit in 1986.

Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases
The mission of the Vaccine Research Center (VRC) is to conduct research that facilitates the development of effective vaccines for human disease. The primary focus of research is the development of vaccines for AIDS.

Monogram Biosciences
The mission of Monogram Biosciences is to improve healthcare by advancing individualized medicine through the discovery and commercialization of innovative products to guide and improve the treatment of HIV, cancer, and other serious diseases.


Journal Articles

Dan H. Barouch

Barouch DH. 2008. Challenges in the development of an HIV-1 vaccine. Nature 455: 613-619. Full Text

Barouch DH, O'Brien KL, Simmons NL, et al. 2010. Mosaic HIV-1 vaccines expand the breadth and depth of cellular immune responses in rhesus monkeys. Nat. Med. 16:319-323.

Fischer W, Perkins S, Theiler J, et al. 2007. Polyvalent vaccines for optimal coverage of potential T-cell epitopes in global HIV-1 variants. Nat. Med. 13: 100-106.

Liu J, O'Brien KL, Lynch DM, et al. 2009. Immune control of an SIV challenge by a T-cell-based vaccine in rhesus monkeys. Nature 457: 87-91. Full Text

O'Brien KL, Liu J, King SL, et al. 2009. Adenovirus-specific immunity after immunization with an Ad5 HIV-1 vaccine candidate in humans. Nat. Med. 15: 873-875. Full Text

Santra S, Liao HX, Zhang R, et al. 2010. Mosaic vaccines elicit CD8+ T lymphocyte responses that confer enhanced immune coverage of diverse HIV strains in monkeys. Nat. Med. 16: 324-328.

Jerome Kim

Nitayaphan S, Pitisuttithum P, Karnasuta C, et al. 2004. Safety and immunogenicity of an HIV subtype B and E prime-boost vaccine combination in HIV-negative Thai adults. J. Infect. Dis. 190: 702-706. (PDF, 92 KB) Full Text

Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, et al. 2009. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N. Engl. J. Med. 361: 2209-2220. Full Text

Thongcharoen P, Suriyanon V, Paris RM, et al. 2007. A phase I/II comparative vaccine trial of the safety and immunogenicity of CRF01 AE (subtype E) candidate vaccines: ALVAC-HIV (vCP1521) prime with oligomeric gp160 (92TH023/LAI-DID) or bivalent gp120 (CM235/SF2) boost. J. Acquir. Immune Defic. Syndr. 46: 48-55.

Julie McElrath

Buchbinder SP, Mehrotra DV, Duerr A, et al. (Step Study Protocol Team) 2008. Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial. Lancet 372: 1881-1893. Full Text

Fellay J, Ge D, Shianna KV, et al. (NIAID Center for HIV/AIDS Vaccine Immunology (CHAVI)) 2009. Common genetic variation and the control of HIV-1 in humans. PLoS Genet. 5: e1000791. Full Text

Flynn NM, lynn NM, Forthal DN, et al. (rgp120 HIV Vaccine Study Group) 2005. Placebo-controlled phase 3 trial of a recombinant glycoprotein 120 vaccine to prevent HIV-1 infection. J. Infect. Dis. 191: 654-665. (PDF, 229 KB) Full Text

Gilbert PB, Peterson ML, Follmann D, et al. 2005. Correlation between immunologic responses to a recombinant glycoprotein 120 vaccine and incidence of HIV-1 infection in a phase 3 HIV-1 preventive vaccine trial. J. Infect. Dis. 191: 666-677. (PDF, 479 KB) Full Text

McElrath MJ, De Rosa SC, Moodie Z, et al. (Step Study Protocol Team) 2008. HIV-1 vaccine-induced immunity in the test-of-concept Step Study: a case-cohort analysis. Lancet 372: 1894-1905. Full Text

Pitisuttithum P, Gilbert P, Gurwith M, et al. (Bangkok Vaccine Evaluation Group) 2006. Randomized, double-blind, placebo-controlled efficacy trial of a bivalent recombinant glycoprotein 120 HIV-1 vaccine among injection drug users in Bangkok, Thailand. J. Infect. Dis. 194: 1661-1671. (PDF, 1.41 MB) Full Text

Russell ND, Graham BS, Keefer MC, et al. (National Institute of Allergy and Infectious Diseases HIV Vaccine Trials Network) 2007. Phase 2 study of an HIV-1 canarypox vaccine (vCP1452) alone and in combination with rgp120: negative results fail to trigger a phase 3 correlates trial. J. Acquir. Immune Defic. Syndr. 44: 203-212. Full Text

Chris Miller

Genescà M, Skinner PJ, Bost KM, et al. 2008. Protective attenuated lentivirus immunization induces SIV-specific T cells in the genital tract of rhesus monkeys. Mucosal Immunol. 1: 219-228.

Genescà M, Skinner PJ, Hong JJ, et al. 2008. With minimal systemic T-cell expansion, CD8+ T Cells mediate protection of rhesus macaques immunized with attenuated simian-human immunodeficiency virus SHIV89.6 from vaginal challenge with simian immunodeficiency virus. J. Virol. 82: 11181-11196. Full Text

Genescà M, Miller CJ. 2010. Use of nonhuman primate models to develop mucosal AIDS vaccines. Curr. HIV/AIDS Rep. 7: 19-27. Full Text

Stone M, Ma ZM, Genescà M, et al. 2009. Limited dissemination of pathogenic SIV after vaginal challenge of rhesus monkeys immunized with a live, attenuated lentivirus. Virology 392: 260-270.

Sanjay Phogat

Corti D, Langedijk JP, Hinz A, et al. 2010. Analysis of memory B cell responses and isolation of novel monoclonal antibodies with neutralizing breadth from HIV-1-infected individuals. PLoS One 5: e8805. Full Text

Li Y, Migueles SA, Welcher B, et al. 2007. Broad HIV-1 neutralization mediated by CD4-binding site antibodies. Nat. Med. 13: 1032-1034.

Scheid JF, Mouquet H, Feldhahn N, et al. 2009. Broad diversity of neutralizing antibodies isolated from memory B cells in HIV-infected individuals. Nature 458: 636-640.

Simek MD, Rida W, Priddy FH, et al. 2009. Human immunodeficiency virus type 1 elite neutralizers: individuals with broad and potent neutralizing activity identified by using a high-throughput neutralization assay together with an analytical selection algorithm. J. Virol. 83: 7337-7348. Full Text

Walker LM, Phogat SK, Chan-Hui PY, et al. 2009. Broad and potent neutralizing antibodies from an African donor reveal a new HIV-1 vaccine target. Science 326: 285-289.

Louis Picker

Hansen SG, Powers CJ, Richards R, et al. 2010. Evasion of CD8+ T cells is critical for superinfection by cytomegalovirus. Science 328: 102-106.

Hansen SG, Vieville C, Whizin N, et al. 2009. Effector memory T cell responses are associated with protection of rhesus monkeys from mucosal simian immunodeficiency virus challenge. Nat. Med. 15: 293-299. Full Text

Harriet L. Robinson

Amara RR, Villinger F, Altman JD, et al. 2001. Control of a mucosal challenge and prevention of AIDS by a multiprotein DNA/MVA vaccine. Science 292: 69-74.

Amara RR, Smith JM, Staprans SI, et al. 2002. Critical role for Env as well as Gag-Pol in control of a simian-human immunodeficiency virus 89.6P challenge by a DNA prime/recombinant modified vaccinia virus Ankara vaccine. J. Virol. 76: 6138-6146. Full Text

Amara RR, Villinger F, Staprans SI, et al. 2002. Different patterns of immune responses but similar control of a simian-human immunodeficiency virus 89.6P mucosal challenge by modified vaccinia virus Ankara (MVA) and DNA/MVA vaccines. J. Virol. 76: 7625-7631. Full Text

Buge SL, Ma HL, Amara RR, et al. 2003. Gp120-alum boosting of a Gag-Pol-Env DNA/MVA AIDS vaccine: poorer control of a pathogenic viral challenge. AIDS Res. Hum. Retroviruses 19: 891-900.

Ellenberger D, Otten RA, Li B, et al. 2006. HIV-1 DNA/MVA vaccination reduces the per exposure probability of infection during repeated mucosal SHIV challenges. Virology 352: 216-225.

Smith JM, Amara RR, Campbell D, et al. 2004. DNA/MVA vaccine for HIV type 1: effects of codon-optimization and the expression of aggregates or virus-like particles on the immunogenicity of the DNA prime. AIDS Res. Hum. Retroviruses 20: 1335-1347.

Wyatt LS, Earl PL, Vogt J, et al. 2008. Correlation of immunogenicities and in vitro expression levels of recombinant modified vaccinia virus Ankara HIV vaccines. Vaccine 26: 486-493. Full Text

Michael Worobey

Wertheim JO, Worobey M. 2009. Dating the age of the SIV lineages that gave rise to HIV-1 and HIV-2. PLoS Comput. Biol. 5: e1000377. Full Text

Worobey M, Gemmel M, Teuwen DE, et al. 2008. Direct evidence of extensive diversity of HIV-1 in Kinshasa by 1960. Nature 455: 661-664.

Gilbert MT, Rambaut A, Wlasiuk G, et al. 2007. The emergence of HIV/AIDS in the Americas and beyond. Proc. Natl. Acad. Sci. 104: 18566-18570. Full Text

Susan Zolla-Pazner

Almond D, Kimura T, Kong X, et al. 2010. Structural conservation predominates over sequence variability in the crown of HIV type 1's V3 loop. AIDS Res. Hum. Retroviruses 26: 717-723.

Gorny MK, Stamatatos L, Volsky B, et al. 2005. Identification of a new quaternary neutralizing epitope on human immunodeficiency virus type 1 virus particles. J. Virol. 79: 5232-5237. Full Text

Hioe CE, Wrin T, Seaman MS, et al. 2010. Anti-V3 monoclonal antibodies display broad neutralizing activities against multiple HIV-1 subtypes. PLoS One 5: e10254. Full Text

Jiang X, Burke V, Totrov M, et al. 2010. Conserved structural elements in the V3 crown of HIV-1 gp120. Nat. Struct. Mol. Bio. [Epub ahead of print]

Robinson JE, Franco K, Elliott DH, et al. 2010. Quaternary epitope specificities of anti-HIV-1 neutralizing antibodies generated in rhesus macaques infected by the simian/human immunodeficiency virus SHIVSF162P4. J. Virol. 84: 3443-3453.

Zolla-Pazner S, Cardozo T. 2010. Structure-function relationships of HIV-1 envelope sequence-variable regions refocus vaccine design. Nat. Rev. Immunol. 10: 527-535.

Zolla-Pazner S, Cohen S, Pinter A, et al. 2009. Cross-clade neutralizing antibodies against HIV-1 induced in rabbits by focusing the immune response on a neutralizing epitope. Virology 392: 82-93. Full Text

Organizers

Sarah Schlesinger, MD

The Rockefeller University
e-mail | web site | publications

Sarah J. Schlesinger is a research associate professor in the laboratory of cellular immunology and physiology at The Rockefeller University and a research scientist at The Aaron Diamond AIDS Research Center, a world-renowned biomedical research institute. Schlesinger has been actively engaged in HIV/AIDS and HIV vaccine research for 10 years, and has published over 50 papers on the subject. Schlesinger led the Dendritic Cell program at the Division of Retrovirology at the Walter Reed Army Institute of Research (1990–2002). She is now an active member of the research team at Aaron Diamond that is devoting considerable efforts to develop a vaccine to halt the spread of the AIDS epidemic.

Yegor Voronin, PhD

Global HIV Vaccine Enterprise
web site | publications

Yegor Voronin is a science officer at the Global HIV Vaccine Enterprise (Enterprise). In this role, he is responsible for the implementation of the vision of the Enterprise through identification, development, and management of Scientific Strategic Plan-related initiatives and activities. Prior to joining the Enterprise, Voronin did his postdoctoral training with Michael Emerman and Julie Overbaugh at the Fred Hutchinson Cancer Research Center (FHCRC). For over ten years he has studied HIV and other retroviruses on a variety of different levels, from their potential use as gene therapy vectors at the West Virginia University, to molecular mechanisms of reverse transcription at the National Cancer Institute, to viral population genetics and evolution at the FHCRC. Voronin holds a master's degree in molecular biology from Novosibirsk State University in Russia and PhD in biochemistry from West Virginia University.

Jennifer Henry, PhD

The New York Academy of Sciences
e-mail

Jennifer Henry received her PhD in plant molecular biology from the University of Melbourne, Australia, with Paul Taylor at the University of Melbourne and Phil Larkin at CSIRO Plant Industry in Canberra, specializing in the genetic engineering of transgenic crops. She was then appointed as Associate Editor, then Editor, of Functional Plant Biology at CSIRO Publishing. She moved to New York for her appointment as a Publishing Manager in the Academic Journals division at Nature Publishing Group, where she was responsible for the publication of biomedical journals in nephrology, clinical pharmacology, hypertension, dermatology, and oncology.

Jennifer joined the Academy in 2009 as Director of Life Sciences and organizes 35–40 seminars each year. She is responsible for developing scientific content in coordination with the various life sciences Discussion Group steering committees, under the auspices of the Academy's Frontiers of Science program. She also generates alliances with outside organizations interested in the programmatic content.


Speakers

Dan H. Barouch, MD, PhD

Beth Israel Deaconess Medical Center
e-mail | web site | publications

Dan Barouch received his PhD in immunology from Oxford University and his MD from Harvard Medical School. He is currently associate professor of medicine at Beth Israel Deaconess Medical Center and Harvard Medical School. His laboratory focuses on studying the immunology and virology of HIV-1 infection and developing novel vaccine strategies. He has demonstrated that cellular immune responses can partially control viral replication, but that the virus can readily escape from immune control. In particular, he has shown that adjuvanted DNA vaccines and viral vector-based vaccines expressing HIV-1 and SIV antigens can elicit potent cellular immune responses that partially control pathogenic virus challenges in rhesus monkeys. His laboratory has also developed a series of rare serotype and chimeric adenovirus vector-based vaccines that overcome the critical problem of pre-existing immunity to the common adenovirus serotype 5 (Ad5) vector in the developing world.

Barouch received two NIH U19 Integrated Preclinical/Clinical AIDS Vaccine Development (IPCAVD) program grants to construct these vaccine vectors, to explore their immunogenicity and protective efficacy in rhesus monkeys, and to advance optimal vaccine candidates into clinical trials. He identified Ad26 as an optimal rare serotype vector and Ad5HVR48 as a hexon-chimeric vector for clinical development, and phase 1 clinical trials with these novel HIV-1 vaccine vectors are currently in progress. His laboratory is a key part of the Bill & Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (CAVD), the NIH Center for HIV/AIDS Vaccine Immunology (CHAVI), and the Ragon Institute of MGH, MIT, and Harvard. Barouch is also highly committed to teaching students, clinical fellows, research fellows, and junior faculty and to providing clinical care to patients with infectious diseases.

Alan Bernstein, PhD

Global HIV Vaccine Enterprise
web site

Alan Bernstein is the inaugural executive director of the Global HIV Vaccine Enterprise. As executive director, Bernstein oversees the Enterprise Secretariat in implementing activities to support the goals and mission of the Enterprise, most significant of which is the development of a 2010 Scientific Strategic Plan. Prior to leading the Enterprise, Bernstein served as the founding president of the Canadian Institutes of Health Research (CIHR) where he helped build the organization into one of the world's leading research agencies, supporting more than 11,000 health researchers with an annual budget of US $1 billion. An internationally renowned researcher, Bernstein has authored more than 200 peer-reviewed scientific publications. His contributions to embryonic development, stem cells, hematopoiesis and cancer have been recognized by various institutions including the Royal Society of Canada, the National Cancer Institute of Canada and Institut de Recherche Clinique de Montreal.

Jerome Kim, MD

Walter Reed Army Institute of Research
e-mail | publications

Jerome H. Kim is currently deputy director (Science) and chief of the Department of Molecular Virology and Pathogenesis, Division of Retrovirology, Walter Reed Army Institute of Research (WRAIR) (U.S. Military HIV Research Program), a multidimensional, international research program encompassing vaccine research and development, HIV prevention research, and clinical research. He also serves as the HIV vaccines product manager, U.S. Army Medical Materiel Development Activity, Fort Detrick, MD.

Kim's research interests include HIV molecular epidemiology, host genetics, and HIV vaccine development. He serves as a reviewer for scientific journals and has served on consultations for the World Health Organization and the Global HIV/AIDS Vaccine Enterprise. Kim is a clinical associate professor of Medicine at the John A. Burns School of Medicine, University of Hawaii. He is a fellow of the American College of Physicians and a Fellow the Infectious Diseases Society of America. Military honors include Army Commendation Medal and Air Force/Army Meritorious Service Medal with 3 oak-leaf clusters, and the Order of Military Medical Merit.

Kim graduated Phi Beta Kappa with highest honors in Biology and high honors in History from the University of Hawaii, Manoa in 1980, where he won the Library Prize for Pacific Islands Area Research and the Arthur Lyman Dean Prize in the Humanities. He graduated from the Yale University School of Medicine in 1984. Kim completed his training in Internal Medicine (1987) and fellowship in Infectious Diseases (1990) at Duke University Medical Center and was elected into Alpha Omega Alpha while at Duke.

Julie McElrath, MD, PhD

Fred Hutchinson Cancer Research Center
e-mail | web site | publications

Julie McElrath is a member of Fred Hutchinson Cancer Research Center; professor, Department of Medicine, University of Washington; co-director of the Vaccine and Infectious Disease Institute and directs the Immunology and Vaccine Development Program. McElrath has clinical attending responsibilities on the Fred Hutchinson Cancer Research Center Infectious Diseases consult service for the Seattle Cancer Care Alliance and University of Washington Hospital. She is also the principal investigator and director of the HVTN Laboratory Program and Seattle Vaccine Trials Unit.

Her current research pursues a vaccine that will protect against HIV-1 infection and a deeper understanding of the components of immunity that contribute to control of HIV-1 disease. McElrath has built and maintains a successful international HIV vaccine laboratory program and conducted translational immunological research in humans in a multicenter setting. She has contributed to the fundamental understanding of how HIV-1 enters the mucosa to establish infection, and mechanisms of potential reduced susceptibility to infection in seronegative persons repeatedly exposed to HIV-1. In conjunction with a highly productive research program, she has assumed a leadership role or been a major contributor in a number of integrated programs at the national and international level to advance a coordinated effort to tackle the HIV epidemic through prevention efforts. She has mentored numerous junior faculty, young investigators, and graduate students in their career paths.

McElrath received her bachelor's degree from Furman University, Greenville, SC; her PhD and MD degrees from the Medical University of South Carolina, Charleston; her clinical training in infectious diseases at Columbia Presbyterian Medical Center, New York; and her post-doctoral training in molecular immunology at the Rockefeller University in New York.

Christopher J. Miller, DVM, PhD

University of California, Davis
e-mail | web site | publications

Christopher J. Miller is a professor of pathology, microbiology, and immunology in the UC Davis School of Veterinary Medicine and an adjunct professor of medicine in the School of Medicine. Miller is a veterinarian and virologist, a core faculty member of the Center for Comparative Medicine and a staff scientist at the California National Primate Research Center. His laboratory utilizes non-human primate models of AIDS and influenza A virus infection to define the pathogenesis of these viral infections, study the nature of protective antiviral immunity, and test vaccines and immunotherapeutic strategies to prevent AIDS and influenza.

Louis J. Picker, MD

Oregon Health & Science University
e-mail | web site | publications

Louis J. Picker is currently the associate director of the Vaccine and Gene Therapy Institute, head of the Pathobiology and Immunology Division of the Oregon National Primate Research Center, and professor of pathology at the Oregon Health & Science University. Picker was recruited from the Department of Pathology at the University of Texas Southwestern Medical Center at Dallas where he served as a principal investigator, medical director of the Flow Cytometry and Clinical Immunology Laboratory, and co-director of the Division of Hematopathology and Immunology.

Picker received his medical degree at the University of California, San Francisco in 1982, did an internship, residency, and chief residency in Anatomic and Clinical Pathology at the Beth Israel Hospital in Boston, Massachusetts from 1982-1986, and received advanced training in Immunopathology and Experimental Pathology at Stanford University Medical Center in Palo Alto, California from 1986–1989. Picker is well-known for his work elucidating memory T cell physiology in humans and non-human primates, including mechanisms of T cell homing, mechanisms of protection against persistent pathogens, AIDS vaccine development, and the immunopathogenesis of AIDS-causing lentiviruses, authoring over 140 journal articles in these areas. He has served on numerous advisory panels and study sections at the NIH and various private foundations, and is currently a member of the National Institute of Allergy and Infectious Diseases Council (DAIDS subcommittee) and the AIDS Vaccine Research Subcommittee. He is also executive consultant at VGTI-Florida, a newly established research institute at Florida's treasure coast.

Sanjay Phogat, PhD

International AIDS Vaccine Initiative
e-mail | web site | publications

Sanjay K. Phogat is a principal scientist at the International AIDS Vaccine Initiative's AIDS Vaccine Design and Development laboratory located in Brooklyn, N.Y. He is also a principal investigator of the IAVI Neutralizing Antibody Consortium (NAC). His research focus is on HIV-1 broad neutralizing antibodies, including HIV-1 envelope glycoprotein-based immunogen design and their presentation on a particulate platform. In addition, Phogat is involved with the IAVI medicinal chemistry research program in India, a partnership with the Indian government's Department of Biotechnology and supports several projects that are within the organization's Innovation Fund portfolio. In fact, Phogat was integrally involved in the recent discovery of two new potent and broadly neutralizing antibodies against HIV, PG9 and PG16, a finding that grew out of the Innovation Fund and IAVI's network of research centers in the developing world.

Prior to joining IAVI Phogat worked at the Vaccine research center. Phogat received numerous awards during his career: to name a few, the prestigious gold medal given by the late Excellency President of India K. R. Narayanan, Technology transfer awards by the National Cancer Institute and the Fellows award for research excellence by NIH. Phogat is also a founding member of NIH visiting Fellows committee, a board member of Global Alliance of Indian Biomedical Professional and former secretary of Fellows Committee (FELCOM).

Harriet L. Robinson, PhD

GeoVax Inc.
e-mail | web site | publications

Harriet L. Robinson, chief scientific officer at GeoVax Inc., a biotech company specializing in the development of HIV/AIDS vaccines, has a multi-protein clade B DNA/MVA vaccine in phase 2a clinical trials through the US HIV vaccine Trials Network (HVTN). The vaccine was developed in Robinson's former laboratory at the Emory Vaccine Center in collaboration with Bernard Moss's laboratory at the US NIH and researchers at the US Centers for Disease Control and Prevention. Robinson co-founded GeoVax to facilitate taking the vaccine from the research laboratory to clinical use.

Robinson, former Asa Griggs Candler Professor of Microbiology and Immunology at Emory University and chief of the Division of Microbiology and Immunology at the Yerkes National Primate Research Center, is internationally recognized for her work on HIV/AIDS vaccines, her pioneering studies on the use of recombinant DNA for vaccination and her seminal studies on insertional mutagenesis and oncogene transduction in retroviral induced cancers. She received her PhD from the Massachusetts Institute of Technology and her post doctoral training at the Virus Laboratory, University of California Berkeley. Robinson is active on several editorial boards and has consulted for the U.S. NIH, the U.S. Food and Drug Administration, the World Health Organization, and the Gates Foundation.

Michael Worobey, DPhil

University of Arizona
e-mail | web site | publications

Michael Worobey is an evolutionary biologist who grew up in British Columbia and received a BS in the Department of Biological Sciences, Simon Fraser University in 1997. He then moved to the University of Oxford, receiving a DPhil from the Department of Zoology (2001) and doing postdoctoral work as a research fellow of St. John's College. Since 2003 he has been a faculty member in the Department of Ecology and Evolutionary Biology at the University of Arizona, where he is an associate professor. He uses an evolutionary approach to investigate the origins, emergence, and control of pathogens, in particular rapidly evolving retroviruses and RNA viruses such as HIV and influenza virus.

Susan Zolla-Pazner, PhD

NYU School of Medicine and Veterans Affairs Medical Center
e-mail | web site | publications

Susan Zolla-Pazner is a biologist who has devoted her professional life to areas of Immunology where basic research intersects with the needs of modern medicine. By 1981, Zolla-Pazner had an established reputation for studying the immune systems of individuals with cancer. At that time, she was asked to consult on several patients who had an unusual type of tumor. These patients were the first patients to be seen with a new form of Kaposi's sarcoma, a tumor related to the disease which, only later, became known as AIDS. In the three decades since, Zolla-Pazner has authored more that 260 scientific papers on AIDS and related illnesses. She collaborates actively with researchers around the world and has support through the National Institutes of Health, the Department of Veterans Affairs, and the Bill and Melinda Gates Foundation for her studies to develop an AIDS vaccine and to train students and health care professionals from India, Cameroon, and China in the prevention, diagnosis and treatment of AIDS and tuberculosis.


Don Monroe

Don Monroe is a science writer based in Murray Hill, New Jersey. After getting a PhD in physics from MIT, he spent more than fifteen years doing research in physics and electronics technology at Bell Labs. He writes on physics, technology, and biology.

Sponsors

  • Global HIV Vaccine Enterprise
  • The New York Academy of Sciences

Academy Friends


Grant Support

This program is supported by an educational grant from Merck & Co., Inc.

Speakers:
Jerome Kim, Walter Reed Army Institute of Research
Julie McElrath, Fred Hutchinson Cancer Research Center
Alan Bernstein, Global HIV Vaccine Enterprise

Highlights

  • A successful vaccine may need to elicit both a cellular response by T-cells and a humoral, antibody response.
  • There have been few large-scale clinical efficacy trials of potential HIV vaccines and only one statistically significant positive result, but the modest protection from acquisition it showed has energized the field.
  • Analysis of vaccine-induced immune responses can augment the scientific value of trials.

Introduction

On May 19, 2010, the Vaccine Science Discussion Group joined with the Global HIV Vaccine Enterprise to host a day-long symposium called "HIV/AIDS: Vaccines and Alternate Strategies for Treatment and Prevention." Although behavioral changes and strategies such as condom use, circumcision, microbicides, and prophylactic antiviral therapy have key roles to play in prevention, most of the discussion centered on vaccines, in part because the meeting came just a day after HIV Vaccine Awareness Day and in part because of the known effectiveness of vaccines in stopping many other infectious pathogens.

In spite of extensive scientific understanding of how the HIV-1 virus infects people, the prospects for an effective preventive vaccine remain unclear, because the immune correlates of protection are not known. Researchers have long known of candidate targets for an immune response, such as the viral glycoprotein called Env, which forms spikes on the virus that bind with the CD4 receptor to gain entry into helper T-cells. Other viral genes, including gag, pol, tat, and nef, encode other internal proteins that may also make good targets. Nonetheless, early efforts using gp120 protein were disappointing, stimulating B-cells to produce antibodies to the virus but not blocking infection. A major challenge is the extreme variability of many HIV-1 virus components, notably Env. Many researchers expect that a successful vaccine will need to elicit both a cellular response by T-cells and a humoral, antibody response.

Rather than using proteins or peptide fragments directly to elicit a response, recent efforts aim to produce them locally from exogenous DNA in the cells. The vaccine can supply this DNA in the form of a plasmid that cells take up, or as part of a safe, genetically engineered virus. This strategy works particularly well when an initial "prime" inoculation is followed some time later by a "boost." Much current HIV vaccine research centers on "heterologous" prime-boost regimens, in which subsequent inoculations use different vectors.

The RV144 "Thai trial"

To date, three different HIV vaccine concepts have been carried to large-scale trials of their effectiveness. Only one showed a modest positive result in preventing acquisition. This trial, the RV144 "Thai trial," used a heterologous prime/boost regimen, which combined a canarypox-vector prime with a gp120 subunit boost. This regimen appeared to reduce the risk of infection by about one third (31.2%) in placebo-controlled study involving 16,000 Thai volunteers. While only providing modest protection, the results have provided some scientific clues for vaccine scientists and fuelled considerable enthusiasm that a more effective vaccine is possible.

The "Thai Trial," RV144, showed that a heterologous prime/boost regimen reduced HIV acquisition by about one third. This is the first positive human HIV/AIDS vaccine result. While the primary statistical analysis was statistically significant, two others were not due to loss of endpoints. However, they support the trend towards protection as shown above.

"We're very excited by the result," said Jerome Kim of the U.S. Military HIV Research Program (MHRP), centered at the Walter Reed Army Institute of Research, "and by the follow-on to the result." Indeed, the study of factors that co-exist with protection, the "immune correlates," may ultimately be more important than the modest protection the vaccine provides.

Correlates research is underway at MHRP and with nearly 20 other collaborating organizations from around the world, and samples from the study participants have been systematically distributed. Due to budgetary limitations, collection of PBMC was limited, so MHRP and NIAID developed a review process to ensure the most efficient and effective use of the samples. Kim said, "While we hope to identify the correlates, it should be noted that immune correlates of protection do not yet exist for some vaccines that have been licensed for years.”

Intriguingly, although the study was not designed to explore this issue, "this vaccine appeared to work best in people at the lowest risk of HIV infection" as judged by their reported behavior, Kim noted. The data also hint that the protective effect was highest at 6-12 months and was not durable, decreasing to 31.2% after 3.5 years. MHRP is planning two follow-on small clinical studies with an additional boost to see if they can extend the immune responses. These studies allow them to better characterize the immune response profile of ALVAC/AIDSVAX using state-of-the-art immune assessment platforms.

Although the vaccine appeared to prevent infection in some recipients, in those who nonetheless acquired the virus it did not reduce viral replication or prevent the decline of CD4+ T cells.

The Step trial

Such post-hoc analysis can be very informative, said Julie McElrath of the Fred Hutchinson Cancer Research Center. She reviewed results from the earlier Step trial, which in 2007 found no significant vaccine-induced protection.

The initial strategy was to elicit the CD8+ T-cell immune response, McElrath said, and early studies showed that "viral vectors that encoded HIV genes were the real winners." The researchers abandoned a canarypox vector like that used in the Thai trial after it showed a rather small effect. "Fortunately, others didn't," McElrath noted.

Instead, the Step trial used the more promising-looking adenovirus vector, Ad5, expressing the HIV-1 genes gag, pol, and nef. "The study did not lower HIV infection rates or post-infection plasma viremia," McElrath concluded, although 90% of vaccinees had detectable HIV-specific responses dominated by CD8+ T cells.

One problem is that many people have already been exposed to Ad5 and developed neutralizing antibodies before vaccination. "Those individuals who had a baseline Ad5 seropositivity in general had a blunted response to the HIV vaccine inserts," McElrath noted.

"We need to stop thinking about trials as built solely on acquisition or protection."

The CD8+ T cell response had antiviral activity, McElrath said, but the response may not have been adequate to suppress replication. More importantly, "it is unlikely that we were able to achieve sufficient breadth to be able to recognize incoming viral strains," she said. The vaccine did appear to impede viruses whose proteins had the amino-acid sequences in the vaccine, because "viruses infecting vaccinees were more likely to have epitope sequences that differed from those in the vaccine," McElrath said. Unfortunately, many subjects were infected by viruses with these differing sequences.

The experience with these trials shows that scientific goals should be emphasized earlier in study design, said Alan Bernstein, of the Global HIV Vaccine Enterprise. "We need to stop thinking about trials as solely built on acquisition or protection, and think of trials also as a way of perturbing the human immune system and therefore both an opportunity to try to understand what's going on and the best route to product licensure."

The integration of scientific inquiry with product development, as well as faster turnaround, is one priority of the enterprise's new strategic plan. The second priority, Bernstein said, is to "harness the full potential of preclinical models and the ongoing revolution in biomedical science." He stressed that the plan provides guidance on achieving synergies, but not specific tasks, for researchers and organizations. The full plan will be made public in coming months.

Speakers:
Michael Worobey, University of Arizona
Sanjay Phogat, International AIDS Vaccine Initiative
Susan Zolla-Pazner, New York University School of Medicine
Dan Barouch, Beth Israel Deaconess Medical Center

Highlights

  • Biogeographical analysis suggests that SIV is at least 100,000 years old.
  • The extraordinary natural variability of HIV proteins makes targeted immunity difficult, but some patients have antibodies that neutralize a very broad range of viruses.

Looking into the past

Michael Worobey of the University of Arizona provided a historical perspective on the diversity of HIV. He and his collaborators have been collecting "samples that take us back in time." From this perspective, the pandemic strain is intermingled in the evolutionary tree with various related strains found in non-human primates called simian immunodeficiency viruses (SIV). "HIV-1/M looks like a chimpanzee virus," he said. Some analyses had suggested it arose only within the past 200 years or so.

But the SIV found in mandrill-like drills on Bioko island in the Republic of Equatorial Guinea shares features with mainland SIV variants, even though the island was isolated by sea-level rise 12,000 years ago. "This biogeographical calibration I think is much more solid," Worobey said. Based on this reanalysis, "it's clear that SIV is old, very conservatively 100,000 years old.

The virus has probably been making forays into humans for a long time, Worobey suggested, so its recent success probably reflects higher population density in Africa. But samples from central Africa in 1959 and 1960 show that "you had a huge diversity and a suggestion of many decades of evolutionary change leading up to even that early time point." He traces the origin of the pandemic HIV-1/M to around the beginning of the twentieth century.

The escape of the virus from Africa is more recent, probably within a few years of 1969, Worobey said. "The common ancestor of subtype B [or clade B] as a whole looks like it existed in Haiti, where the virus diversified for several years before it stepped elsewhere into the U.S., Canada, and other countries."

"Across the scales that we look at we keep seeing evidence of extreme genetic bottlenecks," Worobey said. The observed separation of subtypes probably reflects the founder effects, he said. "You see the same pattern when the virus transmits from one host to the next: a real collapse in the genetic diversity."

The good news is that these bottlenecks show that the virus only rarely moves between groups or between people. "HIV-1 lives close to the edge of extinction," Worobey said. Reducing transmission, whether by vaccine or other means, could have a major impact on the epidemic.

The search for broad neutralizing antibodies

To accomplish this with vaccines, said Sanjay Phogat of the International AIDS Vaccine Initiative (IAVI), "we need neutralizing antibodies that can really cover the entire variability." In the past few years researchers have made significant progress in screening infected people for "broad neutralizing antibodies." Identifying the conserved molecular regions, or epitopes, that these antibodies target, may let researchers design antigens that elicit these antibodies in unexposed people.

"We need neutralizing antibodies that can cover the entire variability of the HIV virus."

The key to the recent progress is screening for antibodies that neutralize viral activity, rather than simply binding to viruses, Phogat said. Recent advanced techniques, requiring just a few antibody-producing B cells from a patient's serum, enable screening of many viral variants simultaneously for neutralizing ability.

Phogat reviewed the improved antibody screening approaches used by several labs. The NIH Vaccine Research Center (VRC) looks for binding to a target that was designed to expose specific regions of the envelope glycoproteins. "They got a very broad neutralizing antibody, VRC-01, that is dedicated to the CD4 binding site on the virus," Phogat noted. In parallel, the Collaboration for AIDS Vaccine Discovery (CAVD) used binding followed by a neutralization screen to find broad neutralizing antibodies, notably one designated HJ16.

Phogat and his colleagues at IAVI and The Scripps Research Institute took pains to collect, and to characterize well, samples from around the world. One patient from their "Protocol G" yielded two excellent antibodies, denoted PG9 and PG16. "These are very potent and broad neutralizing antibodies." Phogat said.

To move from these broad antibodies to vaccines that elicit them, researchers need to identify and mimic the epitopes the antibodies bind. Many of the broad neutralizing antibodies bind to previously known sites, such as the CD4 binding site that facilitates viral entry into the cell, or to one of the "variable loops" in the envelope glycoprotein.

The PG9 and PG16 antibodies, however, bind to epitopes in two different variable loops. As discussed by Susan Zolla-Pazner of the New York University School of Medicine, these antibodies primarily recognize "quaternary neutralizing epitopes," or QNEs, which form only when multiple subunits of the envelope protein arrange into the quaternary structure that makes them biologically active. For PG9, PG16, and 13 other QNE-specific human and macaque antibodies, this structure is a trimer of gp120 glycoproteins that forms the surface spikes of the virus.

Newly identified antibodies neutralize a wide range of variants of the glycoproteins gp120 and gp41. These glycoproteins, coded by the env gene, trimerize to form the spikes that interact with CD4 receptor and CCR5 coreceptors on T cells to enter the cells.

The broad neutralizing capability, Zolla-Pazner emphasized, "means that there must be conserved structures in the second and third 'variable' regions," known as V2 and V3. She and her colleagues studied the amino-acid sequences of V2 and V3 from diverse variants, and found little variation at many positions in each of these regions. This conservation appears to be related to the biological functions of these portions of the envelope, such as infectivity and glycosylation.

Zolla-Pazner also showed crystallographic structures for many V3 antibodies in complexes with V3 peptides, and found that the structure was conserved and sequence variability was confined to particular portions of the V3 loop. "This begins to tell you how to design an immunogen that will induce broadly neutralizing antibodies, what areas you want to target and what areas you want to avoid." She and her colleagues have spliced the critical region into cholera toxin B, and shown that in rabbits it induces neutralizing antibodies to diverse variants of the envelope glycoprotein.

Mosaic antigens

Dan Barouch of the Beth Israel Deaconess Medical Center described a different approach to inducing broad immunologic coverage. With Bette Korber of Los Alamos National Labs, he explored "mosaic antigens," which are "polyvalent in-silico recombined antigen sequences that aim to optimize coverage of global virus diversity," Barouch said.

The researchers decided that including just two of the computationally generated mosaic antigens provided a good balance between increasing coverage and practical constraints. Testing this bivalent vaccine in monkeys confirmed much of the theoretical promise. In terms of the breadth of the cellular immune response against a panel of HIV peptides from various clades, the mosaic vaccine was superior to both naturally occurring and consensus sequences. In addition, the mosaic vaccine elicited a greater depth of response, meaning that there was increased more viral variants.

The increased breadth "may improve coverage of global virus diversity, leading to the possibility of a globally relevant T-cell based vaccine," Barouch said, while the greater depth may make a vaccine more effective. "We feel that the 2-valent mosaic antigens are attractive for clinical evaluation."

Speakers:
Dan H. Barouch, Beth Israel Deaconess Medical Center
Harriet L. Robinson, GeoVax Inc.
Chris Miller, University of California, Davis
Louis J. Picker, Oregon Health & Science University

Highlights

  • Modified vaccinia Ankara virus shows promising results in monkey and early human trials.
  • Computationally generated "mosaic antigens" can elicit very broad response to natural virus populations.
  • Other virus vectors may have other advantages, notably the cytomegalovirus that creates long-term "effector memory" that could rapidly respond to new infections.

Adenovirus and vaccinia vectors

Dan Barouch described early studies of alternative adenovirus vectors, such as Ad26 and Ad35, to which individuals should have less pre-existing immunity than the Merck Ad5 serotype used in the Step trial. In addition to low seropositivity, these viruses are "biologically very different than Ad5," Barouch noted.

In a phase 1 dose-escalation clinical trial, the Ad26 vector proved safe and well tolerated. Surprisingly, even at the lowest dose used in the study, 109 viral particles, subjects developed a fairly consistent immune responses to EnvA antigen that was expressed by the vaccine.

These immune responses included both antibody responses and Env-specific T-cell responses. Interim analysis of this ongoing study "suggests that the Ad26 vaccine was safe and immunogenic at all three doses tested," Barouch said. Moreover, "there is a fairly large dose range" between the dose required for immunogenicity and the dose where there is modest reactogenicity, he added. Ad26 and Ad35 vectors are planned for further clinical evaluation this year.

Harriet Robinson of Geovax and her colleagues at the NIAID have been exploring a different viral vector, the modified vaccinia Ankara virus (MVA). Cells infected with this vaccine express non-infectious HIV-like particles. The products of env are displayed on the surface of the virus-like particles in a transmembrane, trimeric form, just as they are in the HIV-1 virus.

This modified MVA, expressing gag, pol, and env was used in a phase 1 human trial, in repeated doses on its own, and after one or more priming inoculations with a gag/pol/env DNA vaccine. The DNA prime improved the magnitude and breadth of the T-cell response. But in terms of antibody responses, "we found that our MVA-only regimen raised the highest antibody," Robinson noted.

In addition, the homologous MVA regimens had lower levels of CD4+ T-cell responses, relative to the CD8+ T-cell response. "That's important because you do not want your vaccine raising targets for infection," she stressed, and the antiviral CD4+ T cells are preferentially infected by HIV-1.

The researchers also studied the efficacy of these vaccine regimens in macaques against repeated rectal challenges with SIV. Both the heterologous DNA/MVA and homologous MVA/MVA vaccinated animals "are significantly protected relative to the controls," Robinson said, but there was little effect on viral replication once infection occurred. "Overall, it's very much like the Thai trial: we're preventing infection, we're not preventing post-infection viremia."

The researchers are currently pursuing phase 2 trials, to which they are adding a homologous MVA arm. Because the monkey experiments involved very high levels of challenge virus, 40 to 400 times higher than typical human exposure, Robinson expressed hope that the human protection will be better than the significant but incomplete protection afforded to the macaques.

Experiments with non-human primates let researchers test the efficacy of vaccines against intentional viral challenges, and also to explore the immune correlates of protection and the spread of infection in specific tissues. Chris Miller of the University of California, Davis, has looked for unique aspects of protection from live, attenuated vaccines. Although the risk of viral mutations that actually cause disease makes them an unlikely candidate for human use, he said, "in the non-human primate world, live-attenuated vaccines have been the only vaccine modality that have provided reliable protection from vaginal SIV challenge."

Miller's team vaccinated monkeys with a chimeric virus that is a combination of the envelope of HIV, with the rest of the genes from SIV. After vaginal viral challenge months later, he said, "about 60% of monkeys can control viral replication and don't have any CD4 loss," he said. "We have some evidence of complete protection" in these monkeys.

"Vaccines may be a two-edged sword."

To explore the correlates of protection, Miller said, "we wanted to look at immune responses in tissues, because our previous studies trying to look at correlates of protection in blood were not very satisfactory." At various stages after viral challenge, the researchers necropsied unvaccinated monkeys, and both protected and unprotected vaccinated monkeys. When the vaccine works, Miller noted, it seems to stop the virus before it spreads beyond the reproductive tract.

To check whether this protection is afforded by CD8+ T cells, the researchers used a monoclonal antibody to deplete these cells, as well as natural killer cells, in five protected animals. As expected, the depletion opened the monkeys to infection.

But in what Miller called a "sobering observation," the animals that were immunized and then depleted of CD8+ T cells had higher viral loads in their blood than did the unimmunized animals." He attributed this increased susceptibility to an increase in the CD4+ T cells that are targets for the virus, once the CD8+ cells are gone. "Vaccines are a two-edged sword in the case of a virus that actually infects CD4+ target cells," Miller said.

The effector memory T-cell response

Most HIV-vaccine research has expanded from focusing on a pure antibody response to include a CD8+ cellular response as well. But Louis Picker of Oregon Health and Science University cautions that the "central memory" T cell population may expand too slowly to stop acquisition of the virus. "The kinetics of the virus is much faster," he said, and peak replication may occur before memory cells can proliferate and migrate to the site of infection.

"We believe that the major obstacle for a T cell vaccine is not actually the sequence variability of the virus," Picker said, "it's this kinetic mismatch." To address this challenge, Picker proposes exploiting the effector memory T-cell response, which relies on resting, differentiated cells that, although limited in number, remain present in the affected tissues. "They are poised for immediate effector function," he said.

The rapid but limited effector-memory T-cell response could play an important role in slowing the intermediate stages of HIV infection and replication as part of a comprehensive vaccine paradigm.

"To generate those responses, we turned to cytomegalovirus (CMV) because it was known from previous work to be the quintessential inducer of high-frequency, effector-memory-dominant T-cell responses." Over the past eight years, Picker and his team have tracked the response of monkeys to a CMV vector that expresses SIV genes gag, rev, nef, tat, env, and pol.

The CMV infection results in a persistent effector-memory T-cell response to as few as 100 viral particles. These responses are "widely distributed in effector sites and extraordinarily durable," Picker notes, lasting seven years so far.

The response of monkeys to this vaccine was bimodal. "Roughly half of the animals appear to be completely protected" from HIV infection. In addition, Picker said, "this virological control must be very stringent," because the researchers saw no antibody response in the protected animals after challenge, even as they suppressed the infection.

The results "extend the T-cell HIV/AIDS vaccine paradigm, and suggest that effector T cells should be integrated into a vaccine approach," Picker said. "If we're going to be successful, we're going to have a vaccine that incorporates all of these elements."

Will live, attenuated vaccines ever be acceptably safe for use in humans?

Will a successful vaccine need to elicit an effector-memory T cell response, in addition to antibody and central-memory T cell responses?

How important is it that the vaccine-induced response minimize the increase of CD4+ T-cells that are targets for the HIV virus?

Can the immune responses to vaccination be adequately understood using blood samples alone?

How can the scientific information from clinical trials be more efficiently planned for and extracted?

What vectors, antigens, and regimen will provide the best protection from HIV?

Can the HIV epidemic be essentially stopped by a modest reduction in transmission?

What are the best ways of identifying the conserved sequence or structural features of a virus?