Distinct Immune Cell Responses to LNPs and mRNA-LNPs
Distinguishing immune responses by vaccine component
Lipid nanoparticles (LNPs) carrying messenger RNA (mRNA) and empty LNPs induced different responses in cell-culture experiments using immune cells from healthy people. In this comparison of BNT162b2 vaccine formulations, the LNP component mainly activated monocytes, while mRNA-LNPs, unlike empty LNPs, activated B cells and induced a type 2 conventional dendritic cell (cDC2) response.
Although mRNA-LNP vaccines are known to trigger immune responses, it has been unclear which immune cells respond and how LNPs and mRNA each contribute. The researchers compared responses to the two formulations using peripheral blood mononuclear cells (PBMCs) from healthy people. They used spectral flow cytometry to examine changes in co-stimulatory molecule expression across cell populations and multiplex cytokine analysis to measure cytokine production in the culture medium.
Distinct immune profiles induced by LNPs and mRNA-LNPs
The LNP component mainly activated monocytes, increasing the expression of antigen-presentation and co-stimulatory molecules. Co-stimulatory molecule expression was also induced in type 1 conventional dendritic cells (cDC1s) and plasmacytoid dendritic cells (pDCs), regardless of whether mRNA was present. However, the abstract did not report an increase in antigen-presentation molecules in these two dendritic cell populations.
Unlike empty LNPs, mRNA-LNPs activated B cells and induced a cDC2 response. This shows that the two formulations had different patterns of cell-specific activation. This comparison alone does not establish the effect of mRNA by itself or show that immune signals from the two components can be regulated independently.
Cytokine responses also differed. Under conditions containing mRNA, production of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-10 (IL-10) increased. By contrast, the major inflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6) were not induced under the culture conditions used. The researchers reported that overall cytokine production was relatively low and consisted mainly of GM-CSF and IL-10.
Implications for vaccine design and remaining questions
These findings provide a basis for assessing cell-specific activation alongside cytokine production when evaluating responses to vaccine components. Protein-expression changes observed in monocytes and B cells were interpreted as responses that support antigen presentation and communication between lymphocytes.
However, this was a cell-culture study using cells from healthy people, so it did not directly assess clinical efficacy or adverse effects in vaccine recipients. The observation that some inflammatory cytokines were not induced also cannot be interpreted to mean that inflammation or adverse effects do not occur in people. The supplied abstract provided no information on the number of donors, treatment concentrations, culture duration, magnitude of changes, or statistical results, making it difficult to assess the magnitude and reproducibility of the responses in detail. Whether these findings can guide the design of safer or individually optimized vaccines remains to be tested.
Source: Bibliographic information and abstract for the paper published in Vaccine.
BACKGROUND: While messenger RNA- RNA-lipid nanoparticle (mRNA-LNP) vaccines are known to be immunogenic, the specific innate immune cells activated and the distinct contributions of the LNP and mRNA to the immune response remain unclear. METHODS: Using spectral flow cytometry and a multiplex cytokine assay, we define the change in expression of co-stimulatory molecules in specific innate immune cell populations and cytokine production from healthy human peripheral blood mononuclear cells (PBMCs) in response to LNP and mRNA-LNP. RESULTS: Our data reveal distinct activation profiles induced by the BNT162b2 vaccine formulation LNP and mRNA-LNP. The LNP component primarily activated monocytes, upregulating antigen presentation and costimulatory molecules, and also induced costimulatory molecule expression on type 1 conventional dendritic cells (cDC1) and plasmacytoid DCs (pDCs) independently of the presence of mRNA. The mRNA-LNP activated B cells in contrast to empty LNP and induced cDC2 responses. The presence of mRNA enhanced GM-CSF and IL-10 production in culture but did not induce classic proinflammatory cytokines like TNF-α, IL-1β, or IL-6. CONCLUSION: This study defines the innate immune responses induced by the BNT162b2 vaccine formulation LNP and mRNA-LNP. Upregulation of proteins that support antigen presentation and communication with lymphocytes on monocytes and B cells were reflective of LNP and mRNA-LNP stimulation. Cytokine production was relatively modest with GM-CSF and IL-10 predominating. These findings provide insights into the mechanisms underlying immune responses to mRNA-LNP vaccine components.
In follow-up studies comparing vaccine formulations, activation markers in monocytes, B cells, and dendritic cells, together with GM-CSF and IL-10 production, could be considered as candidate measures for joint evaluation. For example, testing empty LNPs alongside formulations containing mRNA could help examine whether a response in a particular cell type also occurs with LNPs alone or differs when mRNA is present. This study provides cell-specific response patterns that may inform such comparisons. However, whether these markers predict vaccine protection or adverse effects has not been established. Further experiments and confirmation in people are needed before the observed differences can be used to improve formulations.