Immune Components Involved in Antigen Production with IM mRNA Vaccines
When administered intramuscularly, mRNA vaccines are primarily translated into antigens by antigen-presenting cells (APCs), particularly dendritic cells, which then process and present these antigens to initiate immune responses. 1
Mechanism of mRNA Vaccine Processing
Initial Uptake and Translation
- mRNA vaccines are administered via intramuscular injection, where lipid nanoparticles (LNPs) coating the mRNA allow uptake into antigen presenting cells (APCs) 1
- Once inside the cell, the mRNA is translated by cellular ribosomes into peptides (antigens) 1
- This translation process occurs in the cytoplasm of the cell, not in the nucleus, making it highly efficient and avoiding genomic integration 2, 3
Antigen Processing Pathway
- After translation, the peptides are processed by the proteasome and can follow two presentation pathways 1:
- Presented on MHC class I molecules directly
- Post-translationally modified into secreted proteins, which can then be taken up by APCs and presented by MHC class II molecules
Cellular Components Involved
- Dendritic cells are the primary and most potent antigen-presenting cells targeted for mRNA vaccine delivery 4, 5
- The mRNA is recognized by toll-like receptors (TLRs) and retinoic acid-inducible gene (RIG)-I, triggering a type I interferon response 1
- This recognition contributes to the adjuvant effect of the mRNA itself, enhancing immune responses 6
Immune Response Initiation
T Cell Activation
- Dendritic cells traffic to lymph nodes where they prime both CD4+ and CD8+ T cells 1
- CD4+ T cells differentiate into:
- T follicular helper (Tfh) cells, which form germinal centers
- Th1 cells, which produce cytokines like IFN-γ 1
- CD8+ T cells become circulating cytotoxic T cells capable of eliminating infected cells 1, 5
B Cell Response
- In the germinal centers, Tfh cells interact with B cells 1
- This interaction results in:
- Memory B cells (MBC) formation
- Long-lived plasma cells (LLPCs) that secrete antigen-specific antibodies 1
Technical Advantages of the mRNA Platform
- The LNP carrier acts as a powerful adjuvant for the mRNA vaccine platform, enhancing immune responses 6
- mRNA vaccines trigger both humoral and cellular immunity, making them highly effective 3
- The transient nature of mRNA expression (typically lasting days to weeks) provides a favorable safety profile 2, 7
Clinical Considerations
- The lipid nanoparticle formulation significantly impacts the efficiency of cellular uptake and subsequent antigen production 6, 7
- Targeting strategies to direct mRNA specifically to dendritic cells can improve vaccine potency 4
- Expression of the antigen typically lasts for a few days to weeks, depending on the specific mRNA formulation 2
Potential Pitfalls and Caveats
- Certain medications, particularly rituximab and abatacept, can significantly reduce vaccine immunogenicity by interfering with B cell and T cell responses 1
- Other medications like methotrexate may impact cytokine expression and B cell responses, potentially affecting vaccine efficacy 1
- The stability and delivery of the mRNA can affect the efficiency of antigen production and subsequent immune responses 5, 7