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Abstract
Background Heterologous vaccine strategies, priming with one type of vaccine and boosting with another, have shown improvements in generating immune responses in clinical and preclinical studies for infectious diseases and cancer treatment in comparison to homologous immunization strategies. Here, we sought to determine whether prime-boost vaccine strategies with mRNA encapsulated in lipid nanoparticles (LNP) and a DNA (pDNA) vaccine, each encoding ovalbumin (OVA) as an antigen, could affect the expansion and function of CD8 T cells.
Methods Naïve B6 mice were immunized with 100ug of pTVGsOVA, a pDNA vaccine encoding the secreted version of ovalbumin, and/or sOVA-encoding mRNA encapsulated in ALC-0315 LNP. Mice were immunized with the following prime-boost regimens: Control, pDNA -> pDNA, mRNA-> mRNA, pDNA -> mRNA, mRNA -> pDNA, mRNA+pDNA -> mRNA+pDNA. Five days after the second immunization, mice were euthanized and assessed for differences in splenic T cell phenotype by flow cytometry. In separate studies, mice bearing E.G7-OVA-PDL1hi tumors were treated with the regimens listed above on days 1 and 8 post tumor implantation and were followed for tumor growth.
Results Naïve mice immunized with two doses of a mixed vaccine containing mRNA-LNP + pDNA exhibited a significantly greater magnitude (~25%) of antigen-specific CD8+ T cells in the spleen as assessed by tetramer staining in comparison to the other prime-boost vaccine strategies tested. Additionally, priming with DNA prior to mRNA-LNP significantly increased the percentage of proliferating antigen-specific cells in the spleen. However, in the therapeutic setting of tumor-bearing mice, there were no significant differences between prime-, boost- or mixed- vaccine strategies with mRNA-LNP and/or pDNA. This was likely due to a significant upregulation of the checkpoint receptors PD1, LAG3, VISTA, and TIGIT on CD8+ T cells, as targeted therapeutic treatment of tumor-bearing mice with these checkpoint inhibitors in combination with the mRNA-LNP + pDNA vaccine resulted in delayed tumor growth and prolonged survival.
Conclusions Two doses of a mixed vaccine containing sOVA-encoding mRNA-LNP + pDNA can significantly enhance the accumulation of antigen-specific T cells in the spleen, however, this was met with an upregulation of several checkpoint receptors. Ongoing studies are seeking to identify mechanisms of response to targeted combination therapy.
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