Page 7 - Dr Stephanie Seneff - Reviewing Some Possible Unintended Consequences of the mRNA Vaccines Against COVID - 19

cells. So, the mRNA needs to be encased in a nanoparticle that will keep it hidden from the immune
system. The second issue is getting the cells to take up the nanoparticles. This can be solved in part
by incorporating phospholipids into the nanoparticle to take advantage of natural pathways of lipid
particle endocytosis. The third problem is to activate the machinery that is involved in translating
RNA into protein. In the case of SARS-CoV-2, the protein that is produced is the spike protein.
Following spike protein synthesis, antigen-presenting cells need to present the spike protein to T
cells, which will ultimately produce protective memory antibodies (Moderna, 2020). This step is not
particularly straightforward, because the nanoparticles are mostly taken up by muscle cells, which,
being immobile, are not necessarily equipped to launch an immune response. As we will see, the
likely scenario is that the spike protein is synthesized by muscle cells and then handed over to
macrophages acting as antigen-presenting cells, which then launch the standard B-cell-based
antibody-generating cascade response.

The mRNA that is enclosed in the vaccines undergoes several modification steps following its
synthesis from a DNA template. Some of these steps involve preparing it to look exactly like a
human mRNA sequence appropriately modified to support ribosomal translation into protein.
Other modifications have the goal of protecting it from breakdown, so that sufficient protein can be
produced to elicit an antibody response. Unmodified mRNA induces an immune response that leads
to high serum levels of interferon-α (IF- α), which is considered an undesirable response. However,
researchers have found that replacing all of the uridines in the mRNA with N-methyl-pseudouridine
enhances stability of the molecule while reducing its immunogenicity (Karikó et al. 2008; Corbett et
al., 2020). This step is part of the preparation of the mRNA in the vaccines, but, in addition, a 7-
methylguanosine “cap” is added to the 5’ end of the molecule and a poly-adenine (poly-A) tail,
consisting of 100 or more adenine nucleotides, is added to the 3’ end. The cap and tail are essential
in maintaining the stability of the mRNA within the cytosol and promoting translation into protein
(Schlake et al., 2012; Gallie, 1991).
Normally, the spike protein flips very easily from a pre-fusion configuration to a post-fusion
configuration. The spike protein that is in these vaccines has been tweaked to encourage it to favor a
stable configuration in its prefusion state, as this state provokes a stronger immune response
(Jackson et al., 2020). This was done via a “genetic mutation,” by replacing a critical two-residue
segment with two proline residues at positions 986 and 987, at the top of the central helix of the S2
subunit (Wrapp et al., 2020). Proline is a highly inflexible amino acid, so it interferes with the
transition to the fusion state. This modification provides antibodies much better access to the critical
site that supports fusion and subsequent cellular uptake. But might this also mean that the
genetically modified version of the spike protein produced by the human host cell following
instructions from the vaccine mRNA lingers in the plasma membrane bound to ACE2 receptors
because of impaired fusion capabilities? What might be the consequence of this? We don’t know.

Researchers in China published a report in Nature in August 2020 in which they presented data on
several experimental mRNA vaccines where the mRNA coded for various fragments and proteins in
the SARS-CoV-2 virus. They tested three distinct vaccine formulations for their ability to induce an
appropriate immune response in mice. The three structural proteins, S (spike), M and E are minimal
requirements to assemble a “virus-like particle” (VLP). Their hypothesis was that providing M and E
as well as the S spike protein in the mRNA code would permit the assembly of VLPs that might

International Journal of Vaccine Theory, Practice, and Research 2(1), May 10, 2021 Page | 395