Background: Can antigen-producing cells also shape vaccine responses?

Immune responses to mRNA vaccines may depend on which cells produce the antigen protein. In a study published in Nature Biotechnology, mRNA expression in hepatocytes suppressed antigen-specific T-cell responses. In mice bearing lymphoma cells that expressed a tumor-associated antigen, a vaccine that suppressed expression in hepatocytes increased immune responses and reduced tumor burden.

Proteins encoded by an mRNA vaccine can be produced in several types of cells that receive the mRNA. However, how expression in each cell type contributes to the immune response remains incompletely understood. The researchers asked how the type of cell expressing the protein affects vaccine responses. To investigate this, they selectively suppressed expression in professional antigen-presenting cells, hepatocytes, and muscle cells.

Key findings: Direct expression in antigen-presenting cells was not essential

The researchers incorporated synthetic microRNA target sites (miRTs) into mRNA delivered by lipid nanoparticles (LNPs). This design allowed them to selectively suppress mRNA expression in professional antigen-presenting cells (pAPCs), hepatocytes, or muscle cells and compare immune responses. The intervention targeted mRNA expression in specific cell types.

In the experiments, mRNA expression within pAPCs themselves was not essential for the initial activation of antigen-specific T cells. Expression in muscle cells induced similar or stronger immune responses, and this pattern was also observed in experiments related to SARS-CoV-2, the virus that causes COVID-19. The researchers suggested that antigen cross-presentation or cross-dressing might play a greater role than direct mRNA expression within pAPCs. This is an interpretation of the results; it does not mean that the antigen-presenting function of pAPCs itself is unnecessary.

The findings differed in hepatocytes. mRNA expression in these cells suppressed antigen-specific T-cell responses, with PD1/PDL1 reported to contribute in part. The abstract provides no basis for equating this result with an explanation that vaccine components are wasted in the liver or that less material is delivered to immune cells.

The researchers also evaluated the design in mice bearing lymphoma cells that expressed a tumor-associated antigen (TAA). A TAA-encoding mRNA vaccine with miRT-mediated suppression of expression in hepatocytes increased immune responses and reduced tumor burden. However, the provided abstract does not report effect sizes, sample size, dose and route of administration, or observation period, making quantitative comparisons difficult.

Implications and outlook: Expression site as a vaccine design variable

The study provides evidence that antigen expression in cells other than antigen-presenting cells can also shape immune responses to mRNA vaccines. Cell-specific regulation of expression using miRTs showed potential as a design strategy for increasing or decreasing immunogenicity, the ability to elicit an immune response. The outcome depends on which cell type is targeted for suppression.

Clinical implications should be interpreted within the limits of these preclinical findings. Reduced tumor burden in mice with lymphoma does not establish efficacy against cancer in humans. Increased antibody levels, protection with a reduced dose, and reduced hepatotoxicity also cannot be confirmed from the provided abstract. Further studies should examine whether the effects are reproducible with other antigens and disease models while also assessing safety.

Source: Research abstract indexed in Europe PMC.