Figure 4.

Potential mechanism of side effects

The side effects observed with the SARS-CoV-2 vaccine's first dose are likely associated with the LNPs' inflammatory properties. LNPs activate different inflammatory pathways that will lead to the production of inflammatory cytokines, such as IL-1β and IL-6, that can initiate and sustain local and systemic inflammations and side effects. The dashed line indicates the possibility that the LNPs might also diffuse from the periphery and reach any organs in the body, including CNS (hypothalamus) where they could directly induce side effects. PEG is widely used as a food and medicine additive, and many of us develop antibodies to PEG. Therefore, the LNPs' PEGylated lipids can induce CARPA in humans with preexisting PEG-specific antibodies. Humans often experience more severe side effects with the second dose. Here we posit that might be due to multiple reasons. Firstly, innate immune memory against the LNPs might form after the first vaccination and that could lead to even more robust inflammatory responses upon the second vaccination. Secondly, after the first vaccination, adaptive immune responses are formed targeting the viral protein coded by the mRNA. As such, cells (shown as red shape) expressing the viral protein-derived peptides or protein itself can become the target of CD8⁺ T- or NK-cell-mediated killing (ADCC), respectively. Because the LNPs could diffuse throughout the body and transfect any cell in their path with the mRNA, and the mRNA could also be further distributed through extracellular vesicles (Maugeri et al., 2019), the target population could potentially be vast and diverse.