History of CHAVI-ID

The Duke Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) is a consortium established by the National Institute for Allergy and Infectious Diseases to undertake the immunologic research tackling major scientific obstacles in the development of an effective HIV-1 vaccine.

Based on the success of the CHAVI, two new Centers for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) have been established at Duke University and at the Scripps Institute to continue to meet the goal of developing an HIV vaccine.

The Duke Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) is a consortium that was established by the National Institute for Allergy and Infectious Diseases (NIAID) to undertake the immunologic research that will tackle the major scientific obstacles in the development of an effective HIV-1 vaccine.


CHAVI-ID Full Color Logo

In July 2005, the NIAID awarded the CHAVI grant to a consortium of investigators from Duke University, the University of North Carolina at Chapel Hill, 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 tested 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 studied the transmitted virus and the biological events that occur during transmission. The CHAVI helped to define protective innate and adaptive host defenses against HIV in humans and SIV in primates.

The overall goals of the CHAVI were as follows:

  1. Determine the viral and immunological events and host genetic factors associated with HIV transmission, infection and (partial) containment of virus replication
  2. Develop novel HIV-1 vectors, immunogens and adjuvants that suppress viral replication and elicit persistent mucosal and/or systemic immune responses
  3. 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
  4. Test novel HIV-1 vaccine candidates in phase I clinical trials

In 2003, international scientific leaders called for a Global HIV Vaccine Enterprise to address the need for a concentrated global effort to combat the AIDS epidemic, which by 2003, had infected more than 40 million people world-wide (Science). The proposal for the Enterprise recognized that research efforts at the time did not have the degree of collaboration nor the funding needed to successfully develop and test novel HIV vaccine candidates. By promoting global collaboration, the Enterprise served to complement existing research endeavors rather than replace them. The design of the Enterprise emphasized an iterative process among investigators based on information sharing, common resources, and the identification and prioritization of scientific challenges. Because of this collaborative design, the Enterprise is not an organization, but an alliance of global investigators modeled after the Human Genome Project.

The Enterprise developed a Scientific Strategic Plan in January 2005 (PLoS Med). The priorities of the Strategic Plan include Vaccine Discovery, Laboratory Standardization, Intellectual Property, Product Development & Manufacturing, Clinical Trials Capacity, and Regulatory Issues.

In June 2004, the Enterprise was endorsed by members of the G8 Summit in Sea Island, Georgia and US President Bush and the National Institutes of Health announced plans to establish a second HIV Vaccine Research and Development Center in the US. In September 2004, the NIAID released a Request for Applications to establish this center, the Center for HIV/AIDS Vaccine Immunology (CHAVI). In July 2005, the NIH awarded the CHAVI to Duke University. The CHAVI grant could be an award up to $300 million over 7 years.

In August 2006, the Bill and Melinda Gates Foundation announced the award of $287 million to support 16 HIV-1 vaccine development centers, collectively deemed the Collaboration for AIDS Vaccine Discovery (CAVD).

CHAVI 001 – Host Immune Responses to HIV-1 Acute HIV-1 Infection

Patients with Acute HIV-1 infection (AHI) within 2-3 weeks of transmission were recruited for study in the CHAVI RO-1 and in the Mucosal and Innate Immunity Discovery Teams' work in the CHAVI 001 protocol.

CHAVI 002 – Anti-HIV-1 Immune Responses in Exposed and Uninfected Subjects (EU’s) in London, UK and Entebbe, Uganda

The CHAVI 002 protocol was the study of characterized exposed and uninfected (EU) patients at St. Mary’s Hospital London and in Entebbe, Uganda to determine the presence of anti-HIV immune responses.

CHAVI 005 – Analysis of Host Response to HIV-1 in Autoimmune Disease Patients

The purpose of this study was to test a hypothesis for why broadly reactive neutralizing antibodies are predominantly absent during AHI. This protocol screened patients with autoimmune diseases, such as lupus or Anti-Phospholipid Antibody Syndrome, who were co-infected with HIV in order to study the quality of anti-HIV neutralizing antibodies. The hypothesis was that patients with B cell tolerance defects would be able to make more robust anti-HIV antibody responses.

CHAVI 007 – Partnership of CHAVI and HPTN 052 --A Randomized Trial to Evaluate the Effectiveness of Antiretroviral Therapy plus HIV Primary Care versus HIV Primary Care Alone to Prevent the Sexual Transmission of HIV-1 In Serodiscordant Couples

HPTN 052 is comprised of 9 global sites recruiting 1,750 discordant couples and studying them for 5 years. Through this collaboration, CHAVI worked to determine the genetic and immunologic basis for resistance to HIV in discordant couples when exposure and resistance had been established.

CHAVI 008- Molecular Characterization of HIV-1 Neutralizing Antibody Breadth and Potency in Natural Infection

The purpose of CHAVI 008 was to collect peripheral blood specimens from patients chronically infected with HIV-1 to study the frequency and molecular basis of broad and potent antibody-mediated virus neutralization and the viral mechanisms of antibody avoidance, as well as other aspects of the immunobiology or immunogenetics of HIV-1 infection pertaining to virus containment.

CHAVI 009- Immunologic and Virologic Correlates of Maternal to Child Transmission of HIV-1 via Breast Milk

The CHAVI 009 clinical protocol began as a pilot study of ~80-100 HIV-infected pregnant women in rural Blantyre, Malawi with plans to become a larger prospective study. The purpose of this study was to define the immunologic and virologic correlates of breast milk transmission of HIV-1 in order to elucidate the mechanisms of viral transmission. The goal of this study was to improve antiviral immunity which can prevent the transmission of HIV from mother to child during breastfeeding.

CHAVI 010 - Understanding the Breadth and Specificity of HIV-2 Elicited Neutralizing Antibodies and Cellular Responses against HIV-2 and HIV-1 Proteins

The purpose of CHAVI 010 was to collect blood specimens from HIV-2-positive patients and HIV-1- and HIV-2-negative patients in order to identify the breadth and specificity of HIV-2 elicited neutralizing antibodies (Nabs) against primary single genome amplified (SGA) HIV-2 Env proteins. Investigators identified the specificities of Nabs that conferred protection against HIV-2 and whether comparable antibody specificities may have been beneficial in an HIV-1 vaccine.

CHAVI 011 - Formative Research to Enhance Recruitment, Retention, Prevention Counseling, and Partner Notification Strategies for CHAVI 001

As an ancillary study of CHAVI 001, the purpose of the 011 was to facilitate implementation of CHAVI 001 studies by enhancing recruitment, retention, partner notification, and prevention counseling through the collection of formative research. The principal investigators of the 011 study were Dr. Catherine MacPhail at the Reproductive Health and HIV Research Unit at the University of the Witwatersrand in Johannesburg, South Africa and Dr. Irving Hoffman at the University of North Carolina Chapel Hill in Chapel Hill, North Carolina, USA.

CHAVI 012 - Mucosal and Innate Immune Responses, and Viral Reservoirs in Tissues and Cells During Acute HIV-1 Infection

The purpose of CHAVI 012 was to increase scientific knowledge through basic research on mechanisms of transmission, innate immunity, protective immune responses and host defense at the mucosal level to facilitate the development of vaccines to prevent and/or control mucosal HIV infection.3)

CHAVI 014 - Investigation of Gene Variants Associated with Resistance and Susceptibility to HIV-1 Infection in HIV-1 Exposed But Uninfected Individuals with Hemophilia A

The purpose of CHAVI 014 was to prospectively obtain peripheral blood specimens from existing cohorts of HIV-1 exposed, yet uninfected patients with hemophilia A to study the genetic factors that may influence susceptibility and resistance to HIV-1 infection. The hypothesis was based on the finding that a minority of individuals with hemophilia A are HIV-uninfected despite exposure to donor FVIII concentrate products between 1979-1984, which are assumed to have a high risk of HIV-1 contamination given the high proportion of HIV-1 infections in persons with hemophilia treated during this time period or from known HIV-1 contaminated batches. Up to 25% of these HIV-uninfected individuals are homozygous for the protective CCR5D32 allele compared to a 1% frequency of homozygosity in the general population, demonstrating the importance of human genetic variation in resistance to HIV-1 infection, but explaining only a small proportion of these cases. Additional gene variants may contribute to resistance to HIV infection following blood-borne exposure. This study aimed to identify additional human genetic variants that influence susceptibility or resistance to HIV infection and compared the results with those of previously obtained HIV-1-positive controls.

Adjuvant Development Discovery Team

The Adjuvant Development Discovery Team is led by Dr. Norm Letvin of Beth Israel Deaconess Medical Center.  Investigators in adjuvant development will work to develop novel adjuvants that optimize the immunogenicity of candidate HIV-1 vaccines produced by the CHAVI.

B Cell Immunology Discovery Team

The B Cell Immunology Discovery Team is led by Dr. Barton Haynes of Duke University.  Investigators in B cell immunology will work to define the ontogeny of epitope-specific anti-HIV-1 binding and neutralizing antibodies as well as antigen specific B cells during acute HIV infection (AHI) in order to determine why broadly neutralizing antibodies are rarely made in AHI.  With the antibodyome CHAVI - Gates collaboration, this team has used new technology to clone out specific monoclonal antibodies.

Host Genetics Discovery Team

The Host Genetics Discovery Team is led by Dr. David Goldstein of Duke University.  This team uses both CHAVI and other cohort collaborations in various genome wide association and /or full genome sequencing studies in order to determine genes that contribute to control or prevention of HIV-1. This team works collaboratively with the other discovery teams to take these findings and perform functional follow up studies.

Innate Immunity Discovery Team

The Innate Immunity Discovery Team is led by Dr. Andrew McMichael of Oxford University and Dr. Persephone Borrow of the Edward Jenner Institute.  Investigators in innate immunity will study the functional properties of peripheral blood natural killer (NK) and dendritic cells (DC) in order to find a way to decrease the setpoint viral load and increase or maintain the levels of central memory CD4+ T cells.  By focusing on the NK and DC cells during the acute stages of HIV infection, investigators can ascertain their T cell stimulatory capacity and their ability to suppress HIV replication.  This research aims to develop vaccines that can recruit an accelerated innate immune response to HIV-1.

Mucosal Immunity Discovery Team

The Mucosal Immunity Discovery Team is led by Dr. Robin Shattock of St. George’s Hospital in London.  Investigators in mucosal immunity will work to define the immune responses and host defenses at mucosal surfaces during HIV-1 transmission in order to develop vaccines that prevent mucosal transmission of HIV.

Non-Human Primate Discovery Team

The Non-Human Primate Discovery Team is led by Dr. Norm Letvin of Beth Israel Deaconess Medical Center.  This team is working to define the correlates of immune protection.

Structural Biology Discovery Team

The Structural Biology Discovery Team is led by Dr. Joseph Sodroski of the Dana-Farber Cancer Institute and with Dr. Steven Harrison of the Children’s Hospital Boston.  Investigators in structural biology will focus on the structural properties of the HIV-1 trimer in order to develop a comprehensive picture of the conformational changes the virus undergoes during Acute HIV infection (AHI).  This team works in conjunction with the B cell and Viral Biology discovery teams.  This research will assist investigators in the design of stable envelope forms of HIV-1 that can potentially induce broadly reactive neutralizing antibodies.

T Cell Immunology Discovery Team

The T Cell Immunology Discovery Team is led by Dr. Andrew McMichael of Oxford University.  Investigators in T cell immunology are performing a comprehensive analysis of the ontogeny of CD4 and CD8 T cell responses specific to HIV-1 in acutely infected HIV-1 patients.  The role of T regulatory cells is also being explored.  In addition, this team is  performing clarifying studies to determine whether or not exposed and uninfected (EU) patients have anti-HIV-1 immune responses that are correlates of protection.

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.  This team is ultimately responsible for ascertaining whether something should be considered for vaccine development.

Viral Biology Discovery Team

The Viral Biology Team is led by Beatrice Hahn while the Computational Biology Team is led by Bette Korber. Together they lead the work in this discovery team to generate panels of transmitted viruses in acute infection and to create and maintain a transmitted HIV-1 sequence database for vaccine design and viral biology studies. This team works very closely with the T cell Immunology Discovery Team and provides resources to all of the teams.

Previous SLG

Barton Haynes, MD, PhD - Duke University 
Barton Haynes, MD, PhD is a Frederic M. Hanes Professor of Medicine and Immunology at Duke University Medical Center. He is the Director of the Duke Human Vaccine Institute and the Duke Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID). 

Dr. Haynes is an expert in T and B-cell immunology, retrovirology, and HIV vaccine development. Dr. Haynes received his M.D. from Baylor College in 1973 and has served as Chief of the Division of Rheumatology, Allergy, and Clinical Immunology from 1987-1995 and as Chair of the Department of Medicine from 1995-2002 at Duke University Medical Center. He is a Fellow of the Infectious Disease Society of America, a member of the Association of American Physicians, a member of the National Academy of Sciences Institute of Medicine, and a member of the American Academy of Arts and Sciences. In HIV research, Haynes led the CHAVI team that defined the initial immune responses to transmitted/founder viruses in acute HIV infection, discovered the polyreactivity of broad neutralizing antibodies (BnAbs), and defined the role of host immune tolerance controls in limiting BnAb production. Additionally, Haynes led the team that mapped the co-evolution of transmitted/founder viruses and BnAbs, developed small molecules that mimic BnAb Env regions, and produced HIV envelope vaccine candidates for human clinical trials.

Garnett Kelsoe, D.Sc. - Duke University 
Garnett Kelsoe, D.Sc. is the James B. Duke Professor of Immunology and member of the Duke Human Vaccine Institute. Kelsoe and his collaborators have long been interested in the biology of B lymphocytes and have worked to demonstrate stochastic variable (V) gene segment use in the primary B-cell repertoire; the migrations of antigen-activated T and B lymphocytes during humoral responses; the germinal center as the primary site of V(D)J hypermutation and affinity-driven selection; the role of complement in the germinal center response and affinity maturation of serum antibodies; the nature, role, and distribution of cryptic, V(D)J recombination signals in the mammalian genome; and the basic mechanisms of central B-cell tolerance. In addition, Kelsoe and his collaborators at the Duke Human Vaccine Institute have worked to understand the role of B-cell tolerance in determining the tempo and quality of serum antibody responses to HIV-1 and influenza.

Bette Korber, PhD - Los Alamos National Laboratory 
Bette Korber, PhD is a Laboratory Fellow at Los Alamos National Laboratory and an external professor at the Santa Fe Institute. She obtained a Ph.D. in Immunology from Caltech in 1988, and was a Leukemia Society postdoctoral fellow in retrovirology at Harvard before joining the Theoretical Biology group at Los Alamos in 1990. At that point, she turned from the lab bench to theory and analyses. She has led an HIV sequence and immunology database project at Los Alamos for the past 15 years.

In part, using the collected data in the HIV database as a foundation for her work, and in part working with experimentalist collaborators from around globe, she has co-authored more than 200 scientific papers. Most of these studies focus on HIV, but occasionally involve work on other pathogens. Her primary areas of research include HIV vaccine design and HIV evolution in the context of the host immune response. Scientifically, she most enjoys working in interdisciplinary collaborations to understand and interpret complex experimental data. She received the E.O. Lawrence Award, the highest scientific honor from the Department of Energy, and was Elizabeth Glaser Scientist.

Andrew McMichael, MD - Oxford University
Andrew J. McMichael, MD qualified in Medicine in 1968 and obtained a PhD in Immunology in 1974. He has worked primarily on human T cell immune responses to viruses. He first showed that virus specific CD8 T cells were HLA restricted and his group demonstrated that virus derived peptides were presented to T cells by HLA class I molecules. Since 1987 he has studied the T cell response to HIV, with a particular interest in virus escape from T cell recognition. For the last five years he has focussed on HIV vaccines. His group have designed and tested two candidate HIV vaccines in phase I clinical trials. His group has also been involved in developing novel methods for measuring T cell responses including HLA tetramers, and cultured elispot assays.

He is currently Director of the Weatherall Institute of Molecular Medicine in Oxford University, Honorary Director of the Medical Research Council Human Immunology Unit, Chair of the Infections and Immunity Board of the MRC and a member of MRC Council. He was recently elected a member of EMBO and is a Fellow of the Royal Society.

George Shaw, MD, PhD - University of Pennsylvania
George M. Shaw, MD, PhD is Professor of Medicine and Microbiology at the University of Pennsylvania. Dr. Shaw’s research interests include viral dynamics and mechanisms of HIV-1 persistence in vivo, including virus escape from adaptive humoral and cellular immune effector arms. Dr. Shaw’s research interests also include the study of molecular mechanisms of HIV-1 neutralization, development of recombinant-based HIV infectivity assays to detect epitope-specific neutralizing antibodies, and development of new strategies to elicit potent, broadly neutralizing antibodies by vaccination.

Joseph Sodroski, MD - Dana-Farber Cancer Institute
Joseph Sodroski, MD received his M.D. from Jefferson Medical College in 1980 and did his postdoctoral training at Dana-Farber Cancer Institute in the laboratory of Dr. William Haseltine. He is currently Professor of Pathology at Dana-Farber Cancer Institute, Harvard Medical School and Professor of Immunology and Infectious Diseases at the Harvard School of Public Health.

Dr. Joseph Sodroski’s research has focused on the molecular mechanisms of replication and pathogenesis of human retroviruses, including human immunodeficiency virus (HIV-1), the cause of acquired immunodeficiency syndrome (AIDS). Dr. Sodroski first demonstrated that human retroviruses encode proteins that regulate viral gene expression. Dr. Sodroski then explored the basis of HIV-1’s killing of the host cell and demonstrated the involvement of the viral envelope proteins in this process. Using an animal model of HIV-1 infection that he developed, Dr. Sodroski linked this killing effect to the loss of CD4-expressing T lymphocytes, a major cause of AIDS immunosuppression. Dr. Sodroski has characterized the entry of HIV-1 into the host cell, identifying the second receptors of the virus. In collaboration with Drs. Hendrickson and Kwong, Dr. Sodroski solved the first x-ray crystal structure of the HIV-1 exterior envelope protein, a major target for drugs and vaccine-induced antibodies. Dr. Sodroski first modified HIV-1 to create defective lentivirus vectors for use in basic and clinical gene therapy. Using these vectors, Dr. Sodroski identified a factor, TRIM5alpha, that blocks HIV-1 soon after the virus enters the cells of monkeys.

Dr. Sodroski served as Director of the Center for AIDS Research at Dana-Farber Cancer Institute/Beth Israel Deaconess Medical Center/Children’s Hospital from 1994-2004, and is currently Associate Director of the Harvard Medical School Center for AIDS Research.

Adjuvant - a pharmacological agent that is added to a vaccine to enhance the immune response of the vaccine recipient.

Affinity maturation - the process by which B cells produce antibodies with increased affinity for antigen during an immune response.

Antibody - a protein molecule that is made and secreted by B cells in response to stimulation from antigens, such as viruses. Each antibody specifically binds to one antigen, which they target for neutralization or flag for destruction by white blood cells. The induction of neutralizing antibodies against HIV-1 is a key goal of an HIV-1 vaccine. See also broadly neutralizing antibodies, intermediate antibody, and recombinant monoclonal antibody.

Antibody-Virus Co-Evolution Project - a collaborative project of the Duke CHAVI-ID and the NIH Vaccine Research Center to isolate the evolution pathways of all known specificities of HIV-1 broadly neutralizing antibodies (BnAbs) and the evolution pathways of the founder HIV-1 virus that induced BnAbs in individuals with HIV-1 infection.

  • Liao et al. Co-evolution of a broadly neutralizing HIV-1 antibody and founder virus. Nature. 2013 Apr 25; 496(7446):469-76.

Antigen - a foreign substance, such as a virus, that enters the body and induces an immune response. Similar to a lock and key, antigens specifically bind to their respective antibodies via the epitopes that are exposed on the surface of the antigen.

B cell precursors - B lineage cells that are produced in the bone marrow before maturing into B cells.

B Cell Lineage Vaccine Design - a vaccine strategy of the Duke CHAVI-ID that is based on targeting the unmutated common ancestor (UCA) and intermediate antibody (IA) of broadly neutralizing antibody lineages using Envs or Env subunits that are designed to optimally bind to UCAs and IAs. 

  • Haynes BF, Kelsoe G, Harrison SC, Kepler TB. B-cell-lineage immunogen design in vaccine development with HIV-1 as a case study. Nat Biotechnol. 2012 May 7; 30(5): 423-33.

Binding affinity - the strength of the interaction between a single antigen binding site on an antibody and a single epitope on an antigen.

Broadly neutralizing antibodies (BnAbs) - antibodies that are capable of neutralizing a wide range of HIV-1 strains; however, they are rarely made during infection and are difficult to detect. The main focus of the Duke CHAVI-ID is to design immunogens that can be used in a vaccine to induce BnAbs for protection against a wide range of HIV-1 strains.

CH505 - the Env that was obtained from patient CH505 who developed neutralization breadth during follow-up from acute HIV-1 infection. This person was the first CHAVI 17 participant who was studied for antibody and viral co-evolution. See the Antibody-Virus Co-Evolution Project.

CHAVI 17 - 17 participants with acute HIV-1 infection in the CHAVI 001 study who developed neutralization breadth during follow-up.

Clonal lineage - a lineage of evolved mutated antibodies that are derived from a common unmutated ancestor antibody.

Deep Sequencing - a DNA sequencing method that is used to detect rare variants in viruses, bacteria, or cells by sequencing thousands of genomes from a single specimen. The Duke CHAVI-ID is using this technology to detect rare variants in B cell lineages that produce broadly neutralizing antibodies (BnAbs). The following instruments are currently being used for deep sequencing: 454 GS Junior (Roche), MiSeq (Illumina), and Ion Torrent PGM (Life Technologies).

Envelope (Env) - a viral protein that forms the viral envelope or surface of HIV-1.

Epitope - distinct molecular features on the surface of antigens that are recognized by the immune system. Also known as antigenic determinants. Antibodies target epitopes for antigen binding and neutralization.

Glycopeptide - peptides that contain glycans or carbohydrates. Glycopeptides have been synthetically produced to mimic regions of HIV-1 for binding with broadly neutralizing antibodies (BnAbs).

Gp41 (glycoprotein 41) - a transmembrane glycoprotein and a subunit of the HIV-1 envelope that assists in HIV-1 fusion to host cells.

Gp120 (glycoprotein 120) - a glycoprotein on the HIV-1 envelope that binds to CD4 cell receptors for virus entry into the cells.

HIV-1 diversity - the wide variety of HIV-1 subtypes. A successful HIV-1 vaccine must protect against all HIV-1 subtypes.

HIV-1 virus evolution - HIV-1 mutations that occur during infection. Please see the Antibody-Virus Co-Evolution Project.

HVTN082 - a phase II clinical trial that is being conducted by the HIV Vaccine Trials Network (HVTN) to test the safety and immunogenicity of a vaccine that was produced by the NIH Vaccine Research Center (same as HVTN204) in 4 pairs of twins (fraternal or identical). The effect of genetics on the antibody repertoires that are induced in response to the vaccine will be studied.

HVTN099 - a mosaic clinical trial that was designed by the Center for HIV/AIDS Vaccine Immunology (CHAVI) in collaboration with the Division of AIDS (DAIDS), the Bill and Melinda Gates Foundation, and the HIV Vaccine Trials Network (HVTN). Enrollment will start in the fall 2013.

  • Santra S et al. Mosaic vaccines elicit CD8+ T lymphocyte responses that confer enhanced immune coverage of diverse HIV strains in monkeys. Nat Med. 2010 Mar; 16(3):324-8.
  • Barouch DH et al. Mosaic HIV-1 vaccines expand the breadth and depth of cellular immune responses in rhesus monkeys. Nat Med. 2010 Mar; 16(3):319-23.

HVTN204 - a phase II clinical trial that is being conducted by the HIV Vaccine Trials Network (HVTN) to test the safety and immunogenicity of the VRC DNA-rAd5 vaccine (DNA vaccine VRC-HIVDNA016-00-VP and adenoviral vector vaccine VRC-HIVADV014-00-VP).

Immunogen - an antigen in a substance, such as a vaccine, that may be recognized by the immune system and targeted for destruction. HIV-1 vaccine immunogens are designed to bind with broadly neutralizing antibodies (BnAbs) to ensure that a robust antibody response is available to protect against HIV-1 infection.

Intermediate antibody - antibodies in a clonal lineage that are evolved and intermediate, in between an unmutated common ancestor precursor and a mature mutated antibody.

Intermediate Env immunogens - recombinantly produced monomeric gp120 or gp120 subunit immunogens.

Membrane-anchored Env trimer - a cleavage-negative, membrane-bound HIV-1 Env trimer that is solubilized in detergents (as described in Mao et al., below) for reconstitution into liposomes for immunization studies.

  • Mao Y, et al. Subunit organization of the membrane-bound HIV-1 envelope glycoprotein trimer. Nat Struct Mol Biol. 2012 Sep; 19(9):893-9.

Membrane proximal external region (MPER) - a region of the gp41 protein in the HIV-1 envelope. Rare neutralizing antibodies have been found to bind to the epitopes in this region. A key vaccine strategy of the Duke CHAVI-ID involves the production of an artificial virus particle with neutralizing epitopes for gp41 MPER.

Minimal Env immunogens - synthetic or recombinant immunogens that are designed to specifically and predominantly express a subdominant broadly neutralizing antibody (BnAb) epitope and to not, or minimally, express dominant non-neutralizing Env epitopes.

Recombinant monoclonal antibody (mAb) - an antibody that is produced from the rescued heavy and light chains of a single B cell using recombinant DNA techniques.

RNA Sequencing - is a sequencing technique that uses RNA as the template rather than DNA. The results show only the genes that are transcribed rather than the whole genome sequenced in DNA. This method is also called Whole Transcriptome Shotgun Sequencing.

RV144 - a phase III HIV vaccine efficacy trial that was conducted in Thailand, which consisted of a prime-boost combination of the ALVAC® HIV Vaccine and AIDSVAX® B/E. The Center for HIV/AIDS Vaccine Immunology (CHAVI) team led the case control study of RV144 and the subsequent studies of potentially protective antibodies.

  • Haynes BF et al. Immune-correlates analysis of an HIV-1 vaccine efficacy trial. N Engl J Med. 2012 Apr 5; 366(14):1275-86.
  • Montefiori DC et al. Magnitude and breadth of the neutralizing antibody response in the RV144 and Vax003 HIV-1 vaccine efficacy trials. J Infect Dis. 2012 Aug 1; 206(3):431-41.
  • Bonsignori M et al. Antibody-dependent cellular cytotoxicity-mediating antibodies from an HIV-1 vaccine efficacy trial target multiple epitopes and preferentially use the VH1 gene family. J Virol. 2012 Nov; 86(21):11521-32.
  • Liao HX et al. Vaccine induction of antibodies against a structurally heterogeneous site of immune pressure within HIV-1 envelope protein variable regions 1 and 2. Immunity. 2013 Jan 24; 38(1):176-86.
  • Alam SM et al. Antigenicity and immunogenicity of RV144 vaccine AIDSVAX clade E envelope immunogen is enhanced by a gp120 N-terminal deletion. J Virol. 2013 Feb; 87(3):1554-68.

Simian immunodeficiency virus (SIV) - a retrovirus similar to HIV that infects African non-human primates and causes simian AIDS (SAIDS) in certain types of primates.

Simian/Human Immunodeficiency Virus (SHIV) - a genetically engineered virus with an HIV envelope and an SIV core.

Single Genome Amplification (SGA) - A PCR technique in which the template is a single genome to prevent in vitro recombination. This technique ensures the amplified DNA genomes accurately represent the diversity in vivo and are not PCR artifacts.

Structure-based B Cell Mosaic Vaccine Design - a vaccine strategy that was developed by Dr. Bette Korber at Los Alamos National Laboratory to utilize an in silico design of Envs that is based on the recombination of the regions of Env trimer neutralizing epitopes.

T Cell Mosaic Vaccine Design - a vaccine strategy that was developed by Dr. Bette Korber at Los Alamos National Laboratory to utilize an in silico design of CD8 and CD4-stimulating vaccines that is based on the recombination of T cell epitopes to minimize HIV-1 diversity.

Transmitted/founder virus - a single transmitted virus that results in HIV-1 infection.

Unmutated common ancestor antibody - an antibody that is derived either experimentally or computationally, which represents the unmutated B cell receptor of the naïve B cell from which mutated antibodies are derived.

Viral vector - a virus that has been modified to be safe for use in humans that can carry, or express, HIV genes. Viral vectors, such as pox virus vectors, are being tested as vaccine candidates. 

T cell Mosaic Vaccine

Overcoming HIV diversity is a prime goal of an HIV vaccine. The Center for HIV/AIDS Vaccine Immunology (CHAVI) and now the Duke Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID) have developed a mosaic vaccine that is designed in silico and optimizes the coverage of T cell immune responses to globally diverse HIV strains. The T cell mosaic vaccine was developed by Dr. Bette Korber at Los Alamos National Laboratory within the Duke CHAVI-ID and is being tested for the first time in a human clinical trial. This trial is being conducted by the HIV Vaccine Trials Network, and Dr. Lindsey Baden of Harvard University is the Clinical Trial Principal Investigator. The clinical sites for the trial include Harvard University, the University of Rochester, the University of Alabama, and Basel Switzerland. The vaccine was produced from joint funding from the Division of AIDS, the National Institute of Allergy and Infectious Diseases (NIAID), the National Institutes of Health (NIH), and the Bill and Melinda Gates Foundation.

Sequential Vaccine of Evolved Envelope Mutants

Inducing broad neutralizing antibodies (BnAbs) is a prime goal of HIV vaccine development. However, the work of the Duke CHAVI-ID team has demonstrated that host tolerance control factors either directly or indirectly limit BnAb induction and make BnAb clonal lineages disfavored or subdominant in immune responses. To overcome this limitation, the Duke CHAVI-ID team has studied multiple individuals with BnAbs from the time of transmission to BnAb induction and has begun to develop immunization regimens that are based on the envelope proteins that induce BnAbs in vivo. The first such vaccine, the CH505 vaccine, has now been funded by the Division of AIDS, the NIAID, and the NIH. This vaccine is currently being produced according to good manufacturing practices (GMP) by KBI Pharmacia, Inc. of Durham, North Carolina. Clinical trials are currently being designed by the HIV Vaccine Trials Network and are targeted to begin in early 2015. The Duke CHAVI-ID has received support from the Division of AIDS, the NIAID, and the NIH for the GMP production of Envs for this trial.

HIV Env Gp41-Liposomal Vaccine for Neutralizing Antibody Induction

This vaccine will utilize an immunogen that is designed to mimic a viral particle. Neutralizing determinants for the gp41 membrane proximal external region are exposed on the surface of the artificial particle. This immunogen has the property of binding to HIV env gp41 broad neutralizing antibodies but not binding to gp41 non-neutralizing antibodies. In partnership with the Infectious Disease Research Institute in Seattle, Washington, Duke has recently received a grant from the Bill and Melinda Gates Foundation for the GMP production of this immunogen for human clinical trials.