Annual and Interim Progress Report Summaries
Principal Investigator: Julie McElrath
Project: Harnessing Innate Immunity to Enhance the Immunogenicity of T-Cell Inducing HIV Vaccines
Submitted March 1, 2011 (Interim Report)
To accelerate HIV vaccine development, our goal is to understand how innate immunity can enhance and improve vaccine-induced immunity. We have established and integrated four systems – an in vitro human system, in vivo mouse models, non-human primate models, and human clinical trials – to build a comprehensive matrix of the innate signatures of candidate adjuvant and vaccine formulations to determine which will provide optimal T- and B-cell memory responses. This platform is ideally suited to examine promising regimens emerging from the CAVD and from outside partners and to advance new HIV vaccine candidates and regimens into phase I clinical trials.
We have procured and constructed clinically relevant vaccine adjuvants and vectors (Objective 1), and have conducted extensive cross-platform preclinical evaluation of these materials using our four systems. In our in vitro human system (Objective 2), using CD8+ and CD4+ T-cell priming systems, we have identified distinct differences in the efficiency of poly I:C as an adjuvant to mature DC when used or priming as compared to boosting. Poly I:C also induces the most substantial and distinct transcriptional remodeling in dendritic cells compared to all of the other tested adjuvants.
Using in vivo murine models (Objective 3), we showed that the order of prime/boost using CN54gp140 protein vaccine with adjuvants and with a NYVAC vector impacts the immunogenicity of the vaccines. We are also analyzing and comparing the innate and adaptive responses to a variety of poxviral and adenoviral vectors.
We are using the rhesus macaque model to further test our vaccine concepts (Objective 4).
Based on the findings and results from the RV144 study, we are performing a NHP study to model RV144 using a potentially more immunogenic MVA vector with SIV Env protein adjuvanted with Poly-ICLC to detect protection against SIV acquisition and post-infection virologic control. We are also testing rapamycin, nanoparticle formulations and other clinically relevant adjuvants in separate NHP studies.
Microarray transcriptional analysis has detected distinct signatures of innate immune responses from these adjuvants.
Findings from our in vitro and in vivo systems have led us to design and develop novel HIV vaccine regimens with the potential to induce effective protective immunity. Meanwhile, we are continuing innate immune analyses of vaccines from current HVTN trials and will integrate those findings with our in vitro and in vivo study results, including transcriptional analysis by microarrays.