HIV/AIDS

Agenda

* Presentation times are subject to change

Abstracts

Viral genetic diversity and the control of HIV/AIDS: challenges and opportunities

Michael Worobey, University of Arizona

The rapid accumulation of mutationsinSIV and HIV strains presents great challenges to treatment and, especially, vaccination development efforts. At the same time, these mutations leave a useful record of when and where important lineages emerged and spread both within hosts and between hosts at local and worldwide levels. These patterns can reveal (1) the key evolutionary and ecological processes underlying ‘successful’viral lineages; (2) the timing of key events in viral emergence; and (3) evolutionary processes relevant to vaccine design and other control efforts. Analyses of archival human and wild primate samples using ‘relaxed’ molecular clock phylogenetic methods have uncovered much of the timeline of SIV and HIV evolution. Early HIV-1 sequences show that extensive diversity was already present in the Democratic Republic of the Congo by 1960, placing the ancestor of the M group near the beginning of the twentieth century. The subsequent emergence of the virus from Africa appears to have begun as early as the 1960s and was characterized by a surprisingly low frequency of epidemically successful dispersal events. On the other hand, analyses of SIV suggest it has a vastly longer history than the HIV lineages derived from it. These insights suggest that colonial-era urbanization may have set the stage for the HIV/AIDS pandemic and, crucially, that HIV-1 lives close to the edge of extinction: changes in human ecology may have allowed it to become established, but compensatory efforts could conceivably have similarly dramatic effects on reducing the viability of HIV-1 populations, at least in some settings.

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

Dan H. Barouch, PhD, Beth Israel Deaconess Medical Center

Rare serotype Ad vectors such as rAd26 and rAd35 are biologically substantially different than rAd5 vectors. We have evaluated rAd26 and rAd35 vectors expressing SIV antigens in immunogenicity and challenge studies in rhesus monkeys, and we have recently advanced a prototype rAd26 vector expressing HIV-1 Env into a phase 1 clinical trial. Importantly, this vector has proven safe and immunogenic in humans at doses of 109 vp, 1010 vp, and 1011 vp. We have also assessed the capacity of vector-specific CD4+ T lymphocytes to traffic to mucosal surfaces following rAd vaccination in rhesus monkeys, and we have observed that trafficking of vector-specific CD4+ T lymphocytes to colorectal mucosa does not occur more readily in monkeys with baseline vector immunity as compared with monkeys without baseline vector immunity. In addition, we have demonstrated that computationally optimized “mosaic” HIV-1 Gag/Pol/Env antigens substantially expand cellular immune breadth and depth as compared with consensus or natural sequence antigens in rhesus monkeys. Taken together, these data suggest that a rAd35/rAd26 prime-boost vector regimen expressing mosaic HIV-1 antigens should be evaluated in clinical studies.

Recent progress in Isolating HIV-1 Broad Neutralizing Antibodies

Sanjay Phogat, IAVI

The ability to elicit broadly cross-reactive neutralizing antibodies (bNAbs) is a major challenge in the development of an HIV-1 vaccine capable of neutralizing the array of viruses in circulation. Nevertheless, a number of HIV-1 infected donors have broadly neutralizing sera and a handful of broadly neutralizing monoclonal antibodies have been isolated from clade B infected donors arguing that a vaccine strategy based upon eliciting broadly protective antibodies is feasible. The bNAbs isolated to date tend to display less breadth and potency against non-clade B viruses and they recognize epitopes on the viruses that have not yet been exploited to induce broadly neutralizing responses. Over the past few years systematic screening and mapping studies have identified HIV-1 clade B and non-clade B infected donors with broad neutralizing serum activity. These studies include IAVI protocol G, in which a large-scale systematic evaluation of neutralizing breadth in the sera of about 1,800 HIV-1 donors was completed. Protocol G identified of the order of 10-15% donors with broad neutralization, a subset of donors (elite neutralizers) were identified with outstanding potency and breadth of serum neutralization and these donors are being prioritized for the generation of novel bNAbs. Approximately 30,000 B cells from a Protocol G donor were plated out, single cells activated and supernate screened directly for function in a microneutralization assay to identify a family of six somatically related bNAbs, termed “PG antibodies”. The prototype antibodies, PG9 and PG16, target a conserved epitope on the variable loops V1/V2 and V3 of gp120, primarily in a native Env trimer context. The Vaccine Research Center at the NIAID using NIH cohorts, and B-cell sorting strategy has identified two novel anti-CD4bs bnAbs. Finally, CAVD investigators using clinical cohorts infected with non-clade B HIV-1 and improved EBV immortalization approach have identified a bnAb to the CD4bs with potency and breadth similar to b12. These additional new bNAbs to different targets on HIV-1 Env will accelerate and support novel immunogen design, screening and selection strategies and will likely make them valuable tools for HIV-1 vaccine design.

Using Epitopes Recognized by Monoclonal Antibodies as Vaccine Templates

Susan Zolla-Pazner, NYU School of Medicine and Veterans Affairs Medical Center

Bioinformatics analysis of gp120 sequence data demonstrates structural conservation in the 2nd and 3rd variable loops (V2 and V3) of gp120. Immunochemical data provide evidence of antigenic conservation in V2 and V3, and immunochemical and functional studies of monoclonal antibodies that target quaternary neutralizing epitopes (QNEs) composed of regions of V2 and V3 also provide evidence of cross-reactivity reflective of structural and antigenic conservation in this compound epitope. Since antibodies to these regions can mediate virus neutralization, these regions of the HIV-1 Envelope should be included among the targets of an AIDS vaccine intended to induce neutralizing antibodies. In order to target structurally-conserved, sequence-variable regions of a protein, 3D visualization is required; this can be accomplished through physical methods (crystallography and NMR) and through molecular modeling. Indeed, these approaches have revealed a generic structure for the V3 loop, and have recently been applied to the design of V3-scaffold immunogens that contain variants of this generic V3 structure. Several such immunogens have been synthesized and tested for antigenicity and immunogenicity in rabbits and shown to induce cross-clade neutralizing antibodies. The data indicate that it is possible to induce neutralizing antibodies to conserved epitopes in variable regions, providing a practical pathway for further development rationally-designed HIV vaccines.

New insights into immunologic vulnerabilities of highly pathogenic SIV

Louis J. Picker, Oregon Health & Science University

The rapid onset of massive, systemic viral replication during primary HIV/SIV infection and the immune evasion capabilities of these viruses pose fundamental problems for vaccines that depend upon initial viral replication to stimulate effector T cell expansion and differentiation. We hypothesized that HIV/SIV vaccines designed to elicit and maintain differentiated “effector memory” T cell (TEM) responses at sites of viral entry and initial amplification might improve efficacy by impairing viral replication at its earliest, most vulnerable stage. We therefore developed SIV protein-encoding vectors based on rhesus cytomegalovirus (RhCMV), the prototypical inducer of life-long TEM responses, for use as a HIV/AIDS vaccine prototype. RhCMV vectors expressing SIV Gag, Rev/Nef/Tat, and Env persistently infected rhesus macaques, regardless of pre-existing RhCMV immunity, and primed and maintained robust SIV-specific CD4+ and CD8+ TEM responses in the absence of neutralizing antibodies, Vaccine regimens including these vectors have demonstrated complete protection of ~50% of vaccinated RM against progressive infection after intra-rectal challenge with highly pathogenic SIVmac239. These data suggest a new paradigm for AIDS vaccine development: that vaccines capable of generating and maintaining HIV-specific TEM might allow for complete control of HIV infections in the first few days following sexual exposure.

Insights from Recent Clinical HIV Vaccine Trials That Can Guide Future Vaccine Designs

Juliana M. McElrath, Fred Hutchinson Cancer Research Center

Recent results of two large-scale international HIV vaccine trials highlight the importance of understanding the basic mechanisms of inducing long-term immunologic memory that can protect against the diverse circulating strains of HIV at mucosal sites of exposure. Candidate HIV vaccine regimens have consistently targeted cellular and/or humoral immunity, but achieving greater potency and breadth of these responses have been difficult. This presentation will report recent findings in clinical trials, examining both innate signatures and adaptive responses, and contrast responses induced by various vaccine approaches that may be important in guiding new vaccine designs.

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

Harriet L. Robinson, GeoVax Inc

A Phase 1 clinical trial testing DNA priming and MVA boosting and MVA priming and boosting has shown excellent safety and unique patterns of immunogenicity in a study conducted by the HIV Vaccines Trials Network (HVTN 065). The GeoVax DNA and MVA-vectored HIV vaccines use single recombinant moieties to express non-infectious, immature, virus-like-particles bearing native forms of Env. This vaccine design was originally tested and developed using rhesus macaque-SHIV models. The clinical trial HVTN 065 first tested a dose escalation of two doses of DNA (0.3 mg. or 3 mg) followed by two doses of MVA (1x107 or 1x108 TCID 50)(DDMM) at 8 week intervals. Following the demonstration of immunogenicity, two additional regimens at the full dose were tested. These delivered a single dose of DNA followed by two doses of MVA (DMM) or three doses of MVA (MMM) at weeks 0, 8 and 24. No significant systemic adverse events were associated with the various regimens and the most severe local reactogenicity was limited to moderate grade reactions in <30% of the participants receiving full dose MVA inoculations. The full dose regimen using two DNA primes and two MVA boosts elicited the highest levels of CD4+ and CD8+ T cell responses (76% and 42% responders respectively) whereas the three doses of MVA elicited the highest Env-specific antibody responses. The DDMM regimen is currently in a Phase 2a study (HVTN 205); and, given the results of the Thai trial and recent preclinical findings (see below), Phase 2a testing of the MVA-only regimen is being planned. Preclinical studies in rhesus macaques using SIV239 prototypes of the HIV vaccines in full dose DDMM and MMM regimens were recently completed. For a measurement of vaccine efficacy, these studies used a repeat intrarectal heterologous challenge with E660 SIV (MID40) (a dose of 40 to 400 times higher than experienced in a typical human exposure). Both the DDMM and MMM regimens induced immune responses that protected 25% (2/8) of the challenged animals through 12 weekly challenges. Following 6 challenges, 60% of the MMM vaccinated animals were protected, whereas only 40% of the DDMM vaccinated animals were protected, suggesting that protection for the simpler MMM regimen was at least as good, if not better than the DDMM regimen. Interestingly, expression of granulocyte-monocyte colony stimulating factor (GM-CSF) in the DNA prime, increased protection against the 12 weekly challenges to a highly encouraging 70% (5/7). The GM-CSF-adjuvatned group had higher avidity anti-Env Ab, higher frequencies of neutralizing Ab for a tier 1 variant of E660 (E660.11) and higher frequencies of anti-HIV IgA in rectal secretions. The use of the GM-CSF adjuvant for the GeoVax DNA/MVA vaccine regimen is being advanced into clinical trials as part of the GeoVax pipeline.

Update of the Thai Phase III HIV vaccine trial: the way forward

Jerome Kim, Walter Reed Army Institute of Research

Background: In September 2009 the Thai Phase III collaboration reported the results of a prime-boost HIV vaccine study in 16,000 18-30 year old Thai men and women. The vaccine showed, for the first time, that a vaccine combination could provide modest protection (31.2%, 95% CI 1.1, 52.1) against infection over a 42 month period of follow-up. There was no effect on post infection viral load or CD4 T cell counts. Results: Additional analyses and laboratory studies have provided further insight. First, the vaccine efficacy may have been more apparent in persons at lower risk of HIV infection. In addition, vaccine efficacy may have been higher in the period immediately after vaccination and declined thereafter. These observations suggest that a strategy involving a booster injection at 12 months may prolong the durability of the response and potentially providing protection to persons at higher risk. Laboratory studies have suggested a waning of the humoral immune response. ADCC data appear very similar to prior Phase I/II studies. Finally, analysis of breakthrough infections appears to suggest that the Env predominance of responses seen in HIV negative vaccine recipients persists in vaccine recipients who become infected. Peptide mapping of these responses shows distinct peptide recognition by vaccine and placebo recipients with breakthrough infection and sequencing of the breakthrough viruses has commenced. The broadly constituted Scientific Working groups have now started to look for potential correlates of protection. Proposals for future trials in Thailand and elsewhere are now being reviewed. Conclusion: The ALVAC-HIV and AIDSVAX B/E prime-boost HIV vaccine regimen may reduce the risk of HIV infection in a community-based population in Thailand with largely heterosexual risk and did not affect post-infection viral load or CD4 count. While modest and likely without immediate public health benefit, the results offer insight for future research. A comprehensive approach for the elucidation of a correlate/surrogate of protection and plans for follow-on clinical studies will be presented.

HIV vaccine research today, the Global HIV Vaccine Enterprise, and the Enterprise Scientific Strategic Plan

Alan Bernstein, Global HIV Vaccine Enterprise

The development of safe and effective HIV vaccines will be absolutely essential to ending the AIDS epidemic. This is a time of both great progress and significant challenges in HIV vaccine research. Advances such as RV144 (the Thai trial) and the discovery of new neutralizing antibodies are important steps forward, but significant challenges and obstacles remain. The opportunities presented by recent advances in HIV vaccine research must be carefully chosen and efficiently exploited. Turning these opportunities into real scientific progress requires an exceptional level of collaboration across the field. The Global HIV Vaccine Enterprise is an unprecedented collaboration of HIV vaccine researchers, funders, policy makers and advocates, working to promote effective research, answer the most pressing questions and overcome the greatest obstacles to developing safe and effective HIV vaccines. This presentation provides a broad overview of the state of the field and the major challenges that confront us, including the need to maximize learnings from vaccine clinical trials, incorporate new research approaches into HIV vaccine development and expand the participation of young and early-career investigators and developing world research institutions. The presentation will also provide an brief overview of the updated Global HIV Vaccine Enterprise Scientific Strategic Plan, a global roadmap for HIV vaccine research developed with the participation of more than 100 researchers from across the world, to be released later this year.

Travel & Lodging

Our Location

The New York Academy of Sciences

7 World Trade Center
250 Greenwich Street, 40th floor
New York, NY 10007-2157
212.298.8600

Click here for directions.

Hotels Near 7 World Trade Center

Recommended partner hotel:

Club Quarters, World Trade Center

140 Washington Street
New York, NY 10006
Phone: (212) 577-1133

Located on the south side of the World Trade Center, opposite Memorial Plaza, Club Quarters, 140 Washington Street, is just a short walk to our location. The New York Academy of Sciences is a part of the Club Quarters network. Please feel free to make accommodations on-line to save significantly on hotel costs.

Password: NYAS

Other hotels located near 7 WTC: