Mentored Scientist Award

Immunodominance and CD8+ T-cell avidity in mRNA vs. Ad vaccine efficacy and viral evasion

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HIV/SIV has evolved numerous strategies to evade the immune system, complicating efforts to develop effective prophylactic or therapeutic vaccines. Critical to this evasion is the virus's ability to undergo rapid antigenic variation and elicitation of lower-avidity vaccines by many of the most widely used vectors. These factors significantly influence the effectiveness of the immune response against HIV/SIV, affecting the recognition and elimination of infected cells by CD8+ T-cells. High-avidity CD8+ T-cells are essential for recognizing and mounting a robust response to low concentrations of critical antigens. This recognition is crucial for the early containment and control of HIV/SIV after infection.

Our preliminary data show that although therapeutic SIV/Gag vaccination using adenovectors of multiple serotypes can effectively generate CD8+ T-cell responses, in most cases, this antiviral activity is insufficient to limit the systemic spread of SIV. In addition, we have observed that loss of control is associated with an increase in viral sequence diversity; for example, we found that two valine-for-isoleucine substitutions occurred at positions 140 and 206 of gag (I140V and I206V) together with the common Gag CM9 escape mutation (T182A). These observations underscore the necessity of better understanding the functions of SIV-specific T cells and their interactions with evolving viral epitopes.

Given the limitations of current adenovector-based vaccines, we hypothesize that mRNA vaccines encapsulated in lipid nanoparticles (LNP) could offer a more potent alternative. These vaccines may be capable of generating T-cells with higher functional avidity and breadth, thereby overcoming the challenges posed by viral variation and evasion strategies. The goal of this project is to understand qualitative differences in T-cell responses to mRNA vs. adenovectored SIV vaccines that may explain greater efficacy of the former in my work on therapeutic vaccination.