Exploring New Pathways to HIV Vaccines
Report from AIDS Vaccine 2007 Meeting
About 900 researchers met in Seattle at the AIDS Vaccine 2007 meeting to address the recent advances in HIV vaccine research. This report summarizes some highlights and themes that emerged at the meeting.
Dr. Tachi Yamada, the director of the Gates Foundation’s Global Health Program, co-opted Donald Rumsfeld’s observation on terrorism, “There are things we know, we know. There are some things we do not know. But there are also things we don't know, we don't know,” for the field of HIV vaccine research to underscore the importance of exploring unconventional approaches in responding to the AIDS epidemic.
Dr. Anthony Fauci, the Director of NIAID, echoed the same message by emphasizing the need for new ideas to achieve the goal of a successful HIV vaccine as the old vaccine strategies have failed. He also pointed out that progress towards the goal is being made one crucial step forward at a time.
Some of the headways made are in the areas of:
New Assay to assess role of CTLs in controlling HIV Replication
Dr. Otto Yang of University of California, Los Angeles reviewed the advantages and disadvantages of two validated assays - ELISPOT and Intracellular cytokine staining (ICS) - used for assessing HIV vaccine immunogenicity in clinical trials. Both these surrogate assays measure only one facet of cytotoxic T cells (CTLs) function - their ability to secrete cytokines when they recognize viral antigens on infected cell surfaces. Therefore, these approaches do not provide direct clues about killing efficiency of CTLs as the high concentration of synthetic peptides used to detect immune responses bypass the normal processes of antigen processing and presentation, and cannot distinguish between high and low affinity interactions between the T cell receptor and MHC-peptide complex. For example, in cell cultures CTLs targeting Tat peptides are more efficient in killing than those recognizing Gag or reverse transcriptase epitopes. Although the ELISPOT and ICS assays may not necessarily predict the ability of the CTLs to inhibit viral replication, they are useful for vaccine evaluation as they are standardized and validated. If current vaccine trials fail to demonstrate clinical benefit despite “immunogenicity”, it may be premature to discount a CTL-based vaccine approach because the vaccine tested so far may have been "immunogenic" only for epitopes that are inefficient CTL targets. Dr. Yang described a new antiviral suppression assay developed in his laboratory that measures the ability of CTLs to inhibit viral production by HIV-infected cells. CD4 and CD8 T cells from blood were separately expanded, infected with HIV, and then co-cultured to evaluate antiviral activity of CD8 T cells by measuring p24 production. With increasing CD8 to CD4 T cells, virus production drops off dramatically (J. Immunol. Methods 327, 75, 2007). Such functional assays will be needed to identify the most promising vaccine candidates to move forward into clinical trials, particularly if their performances in the standard ELISPOT and ICS assays are similar. However, the assay at this time is labor intensive and requires standardization before general use.
Should Gag be favored as Target Protein for Vaccine?
Viv Peut, working in Dr. Stephen Kent's laboratory at the University of Melbourne, Australia, showed T cell responses against Gag rather than Env generated by a vaccine expressing HIV Env and SIV Gag better controlled viral load and preserved CD4 T cells in monkeys challenged with SHIVmn229 (J. Virol. 81, 13125, 2007). She also described a new approach to HIV therapy called “Overlapping Peptide Pulsed Autologous Cells or OPAL” to enhance T cell response against the virus. In this therapy, blood was withdrawn from a monkey, the cells were pulsed with peptides 15 amino acid long, and then the stimulated cells were infused back into the same animal on the same day. The peptides were either Gag alone or a mix of peptides representing all SIV proteins. Although the concentration of Gag peptide was the same in both peptide sets, Gag responses were severely diminished in the all SIV peptides group. The results suggest that either Env or Gag-specific responses dominate but rarely do both occur in the same animal. The authors imply that a Gag-based vaccine may prove more immunogenic than a Env-based vaccine.
Improved Vaccine Delivery Vehicles
The benefits of live-attenuated measles virus and BCG as vectors were discussed by Dr. Hussein Naim of Berna Biotech AG and Dr. Anna-Lise Williamson of University of Capetown, South Africa respectively.
Measles virus (MV) has an impressive record of safety, efficacy, cost-effectiveness and a single injection (104 particles) can give life long immunity. A recombinant measles virus (rMV) expressing gp140 was stable even after 15 passages in cell culture. In IFNa/b knockout, human CD46 expressing transgenic mice immunized with rMV-SIV Env and Gag, virus-like particles expressing SIV Env and Gag and Gag-specific T cell responses were detected. Prime/boost with rMVs in this same mouse model elicited anti Env antibodies and T-cell responses, indicating that pre-existing anti-MV immunity does not prevent efficient boosting of immune responses to the vaccine.
Several advantages to using BCG as a vector for HIV antigens include antivector immunity fails to affect BCG, effective when given orally, and low cost. The vector has been given safely to billions of people as a TB vaccine. Dr. Williamson proposed using a DNA prime plus a rBCG (Gag) boost in humans. Baboons primed with recombinant BCG-Gag C prime plus MVA Responded well to Gag. rBCG-Gag C primed both antibody and T cell responses. However, rBCG vaccine displayed genetic instability as p24 antigen was deleted in successive BCG generations. Dr. Williamson’s group is working on developing a third generation BCG product with stable Gag insert.
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