Provisional licensing for Comirnaty was based on Study C4951001 and BNT162-01. We reported that trial BNT162-01 excluded participants with a history of lipid nanoparticles. Further analysis of the CSRs shows “that Previous participation in other studies involving study intervention containing lipid nanoparticles,” was also an exclusion criterion for study C4951001, the phase 3 trial.

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Lipid-based nanoparticles are used in gene therapies and vaccines, and several are being tested in clinical trials.  While one can understand the exclusion of participants previously containing lipid nanoparticles in a dosing study, there is more to it.   

A review of the role of lipid components in LNPS for vaccines and gene therapy suggests they might have been excluded due to immune concerns.

mRNA-LNP immunogenicity is highly dependent on the structure of the ionisable lipid. Controlling the size of the LNP during preparation is crucial, as it significantly affects the nanoparticle's pharmacokinetics and biodistribution. Apart from apoE, other plasma components also aid in the uptake of LNPs in hepatocytes or other cell types.

What's noticeable is the lack of understanding of the mechanisms of immune stimulation, tolerability, and immunogenicity. Notably, evidence is lacking in humans. 

“The internalization mechanism of the mRNA-LNP COVID-19 vaccines following intramuscular (i.m.) injection remains poorly characterized.”

“new ionizable lipids and a better understanding of endosomal uptake and escape should enable the development of LNPs that more efficiently deliver nucleic acids to target cells.”

“there is still much to learn about LNP mechanisms of immune stimulation, tolerability, and immunogenicity and the correlations between these.”

“The field also needs to embrace basic research to increase our fundamental understanding on e.g., LNP uptake processes, endosomal escape mechanisms, the interplay between LNP structures/components and the immune system, and safe ligands that can enrich LNPs in certain organ/tissues. “

A second Review, published in Nature on the Immunogenicity of Lipid Nanoparticles and their Impact on the Efficacy of mRNA vaccines, suggests the repeated delivery of LNPs can increase adverse effects. 

The review reports “only three RNA/LNP-based drugs approved by the FDA.  Note, not vaccines but “drugs”.

The LNP immune functions exert contrasting effects that require a deeper understanding. 

“Since the RNA/LNP platform is still in its early stages, it is unknown how these vaccines impact an individual’s body. After inoculation, several side effects of the COVID-19 vaccine have been reported, and many studies have been conducted on the immune function of LNPs. It appears that the immune function of LNPs exerts contrasting effects.”

Evidence supports LNPs acting as adjuvants. 

“Summarizing the above studies, the notion that lipid nanoparticles act as an adjuvant through when inoculated with mRNA vaccine is supported by: (1) mRNA-LNPs can be detected by TLR, MDA5, and NLRP3; (2) mRNA-LNPs cause the secretion of IL-1β, IFN-γ, and IL-6 through the innate immunity pathway; and (3) mRNA-LNPs promote CD8 + T cell, Tfh, and germinal center (GC) B-cell responses.”

Immunity must be boosted for mRNA-LNP to act as a vaccine, yet immunity needs to be dampened to diminish the adverse effects of repeated delivery.

“To use mRNA-LNPs as a vaccine, immunity must be boosted, and to minimize adverse reactions produced by the repeated delivery of mRNA-LNPs, immunity must be diminished. Therefore, strategies to modulate the immune system are essential.”

Review evidence elicits concerns that LNPs will stimulate immune response due to repeated exposures. Concerns over the accumulation of LNPs and their increase in the rate of adverse events also explain the exclusion of such participants from the trial. 

This post was written by two old geezers trying to understand the mode of action of mmRNA-LNPs. Impersonators did not write this post, which is not commercial in confidence. It is not carcinogenic and will not self-destruct or autodelete. Repeated exposure to this post will not lead to a heightened immune response or adverse effects, but it may give rise to a stress reaction. We are not on the payroll of any pharmaceutical company, and given the content of our posts, we have been notified that HMG will award us the Order of the Concrete Sweater.