McElrath: Innate to Adaptive Immunity
Innate immunity is the body’s first line of defense against pathogens and involves relatively non-specific antibody and T-cell responses. Innate immunity can be elicited through the use of adjuvants, which are formulations that can enhance and direct a vaccine’s immune response. Although widely used, most adjuvants have been discovered empirically.
The McElrath-led research consortium is taking a comprehensive approach to understanding how innate immunity can enhance vaccine-induced immunity. The researchers have developed a systematic in vitro and in vivo approach to unraveling the precise molecular pathways of innate immunity that adjuvants and vectors stimulate. Coordinated studies assess the consequence of these activities on the quality and long-term persistence of the HIV-specific adaptive immune response. These findings will rationally guide improved formulations of adjuvants with candidate HIV immunogens. We have identified priming regimens using HIV proteins with poly I:C or IC31 that induce strong multifunctional T-cell and antibody responses. We are conducting extensive preclinical testing of these vaccine candidates, and if deemed safe, our current plans are to advance these vaccines into phase I clinical trials.
- Construct or procure a diverse array of adjuvants and vectors, and combine with HIV antigens and genes for evaluation in partnerships with industry, biotech and academia.
- Standardize and implement an in vitro platform using human peripheral blood mononuclear cells (PBMC) to screen and fully evaluate the innate immune responses induced by vectors and adjuvants alone and in combination; then assess the impact of these innate responses on the phenotype, function and magnitude of HIV-specific T cell responses induced.
- Elucidate how adjuvants/innate responses shape the antibody and T-cell immune responses using in vivo murine models.
- Assess innate, adaptive T-cell and antibody immune responses upon vaccination of rhesus macaques with SIV immunogens.
- Evaluate innate immune responses that drive improved antigen-specific T-cell and antibody responses in human trials.
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 clinically relevant vaccine adjuvants and constructed a number of viral 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 ability of TLR agonists to mature dendritic cells when used for priming as compared to boosting. Poly IC appeared to induce the most substantial and distinct transcriptional remodeling in dendritic cells compared to the other tested adjuvants.
Using in vivo murine models (Objective 3), we showed that the order of prime/boost using CN54gp140 protein vaccine with a NYVAC vector impacts the immunogenicity of the vaccines. In addition, alum can be combined with TLR agonist adjuvants (IC31, Poly-IC/LC) to further enhance antibody and T-cell responses. We have also analyzed and compared the innate and adaptive responses to a variety of poxviral and adenoviral vectors, and found that while the amount and duration of antigen in vivo correlates with immunity, excessive innate activation by viral vaccine vectors may be detrimental.
We are using the rhesus macaque model to further test our vaccine concepts (Objective 4). We first compared TLR3, 4, 7/8 and 9 ligands and their combinations, and identified poly IC as the most potent adjuvant to enhance antibody and CD4+ T-cell responses and cross-present CD8+ T cells. We have just completed a pivotal NHP study to model RV144 using a potentially more immunogenic MVA vector with SIV Env protein adjuvanted with Poly-IC/LC to detect protection against SIV acquisition and post-infection virologic control. The vaccinated animals were not conferred protection against SIV infection although all vaccinated animals showed a peak viral load reduction, which correlated with CD4+ T-cell responses to Env. We have also tested nanoparticle formulations with TLR4 and TLR7/8 agonists as well as 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. Based on our preclinical data on TLR3 and TLR9 agonists, these adjuvants can be tested with HIV Env proteins in future clinical trials. 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.