The Ragon Institute has recently established that clinical vaccine trials will be a key strategic priority of the Institute. The aims of this strategic initiative include: (i) applying cutting edge immunology and technology to the evaluation of HIV-1 vaccine candidates in humans, (ii) improving our basic understanding of human HIV-1 vaccinology, and (iii) advancing promising HIV-1 vaccine candidates in clinical development towards efficacy trials.

The initial strategy of the Ragon Institute Clinical Vaccine Trials Initiative is to leverage existing capacity and resources, including performing detailed immunologic analyses of existing clinical trial specimens, conducting innovative phase 1 clinical trials with novel GMP-grade vaccine candidates, and developing site capacity for future clinical trials in high incidence settings.

The long term strategy is to evaluate a portfolio of novel HIV-1 vaccine candidates in humans, to establish collaborative partnerships with other clinical trial networks, and to accelerate clinical development of promising HIV-1 vaccine candidates towards phase 2b efficacy trials.

Well-defined clinical cohorts developed by the Ragon Institute provide a critical resource for expanding our understanding of the immune response to infections. The advent of systems biology approaches attempting to quantify and then interpret the vast complexity present in clinical samples is leading to new and sometimes unexpected insights into human immune responses.

However, two major issues, one practical and one conceptual, limit the rate of progress in using clinical samples to expand our understanding of human immunology.

First, in practice, clinical specimens such as sera, biopsies, or peripheral blood samples provide a finite and often limiting amount of cells/analyte, and the parallel nature of typical biological measurements (e.g., gene profiling, flow cytometricphenotyping, ELISA) constrains the amount of information that can be obtained from a given sample.

Second, in most current systems biology studies, the state of the host response in a given sample is typically read out by static “snapshots”: the phenotype and functional status of cells/tissues/sera are determined directly ex vivo, returning a fingerprint of the sample at one point in time, hopefully with close fidelity to its state prior to removal from the in vivo environment. Such measurements do not illuminate the dynamic interconnections that exist between cells and extracellular factors. Determining these interconnections is of great interest for predicting how the immune response will unfold as infection progresses or is resolved.

The goal of the Ragon Systems Biology Initiative is to address these two major limitations by bringing together approaches from diverse disciplines.

An important challenge confronting the development of an effective HIV-1 vaccine is the high mutability of the virus, making escape from immune pressure induced by vaccination relatively easy.

The recent discovery of broadly neutralizing antibodies, a T cell – based vaccine showing protection in some monkeys, and the RV144 study offer hope that this challenge can be overcome. Many believe that a potent vaccine against HIV-1 will be one that combines an antibody response with a potent cytotoxic T lymphocyte (CTL) response. But, broadly neutralizing antibodies have not been induced by vaccination, and the characteristics of a potent CTL response to HIV-1, and how to induce it by vaccination in people with diverse genotypes, remain unclear.

The goal of the Ragon Immunogen Design Initiative is to help overcome this challenge by designing and testing novel immunogens that may elicit broadly neutralizing antibodies and potent memory CTL responses in persons with diverse genotypes.

New adjuvants and delivery systems that can safely promote the immune response to vaccine antigens or vectors may play a critical role in the development of a highly effective HIV vaccine. The ability to better promote more durable immune responses, broaden humoral or T-cell responses, increase the polyfunctionality of T-cell responses, or increase the avidity of antibody responses compared to existing licensed adjuvants such as alum are all attractive goals for novel adjuvant design. For translation, these immunological requirements must be matched with manufacturability and a high level of safety.

The Vaccine Adjuvant/Delivery Initiative aims to develop new adjuvants that can meet these goals and provide new materials for clinical testing in the Ragon Clinical Vaccine Trials Initiative.

It is becoming increasingly apparent that the engagement of the innate immune system is required for an effective antiviral response. More recently, NK cells have been shown to (i) provide direct antiviral activity again HIV-1 and (ii) to mediate virus-specific memory in mouse models of viral infections.

Very little is however known about the precise mechanisms how NK cells recognize HIV-1-infected cells, the receptors involved in this process, and whether NK cell memory to HIV-1 exists in humans and can be modulated by vaccination.

The goal of the NK cell Immunity Initiative is to stimulate collaborative research on NK cells to address these questions and to identify novel approaches to NK cells for vaccine design.