August 19, 2022

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mRNA vaccine side effects:  LNP component may be the main factor

mRNA vaccine side effects:  LNP component may be the main factor



 

mRNA vaccine side effects:  LNP component may be the main factor.

 

The nucleoside-modified mRNA-LNP vaccine platform used by Pfizer-BioNTech and Moderna in the SARS-CoV-2 vaccine has been extensively studied in preclinical and clinical studies.

It may surpass the activation of Tfh cells and the generation of protective humoral immune responses. Other vaccines.

 

Regarding side effects, there have been reports of high incidence of side effects related to vaccination, including pericarditis, myocarditis, and nervous system inflammation.

Although the sponsors of clinical studies published data that these side effects have nothing to do with the vaccine itself, there are still many academic institutions that have conducted related research.

 

 


Reports on the side effects of mRNA vaccines in different countries

 

Mexico

 

A prospective study in Mexico, including data from 704,003 first-dose vaccinators, reported 6536 cases of post-vaccination side effects (adverse events following immunization, AEFI), of which 65.1% had at least one nervous system AEFI (99.6% non-serious) .

33 serious events were reported; 17 cases (51.5%) were neurological side effects (approximately 2.4/100,000 doses) (Reference 2).

 

South Korea

A questionnaire study of a university hospital, including 2498 medical staff who received the Pfizer-BioNTech COVID-19 vaccine. Seven days after each injection, a diary card was used for investigation.

The questionnaire response rate for the first dose of patients was 75.1% (1876/2498), and the questionnaire response rate for the second dose of patients was 73.8% (1840/2493).

Among local reactions, pain was the most common report (84.9% after the first medication, 90.4% after the second medication).

After the second injection, two people came to the emergency room due to severe local pain, but were not hospitalized or had skin necrosis.

Among the systemic reactions, fatigue was the most common (52.8% after the first dose, 77.0% after the second dose), followed by myalgia (49.0% and 76.1%), headache (28.7% and 59.2%), chills (16.7% and 54.0%) and arthralgia (11.4% and 39.2%).

One or more serious adverse events occurred in 0.2% of the first dose and 0.7% of the second dose.

Except for urticaria, more adverse events were reported after the second dose than the first dose (Reference 3).

 

Czech Republic

A Czech study on the side effects of the Pfizer-BioNTech COVID-19 vaccine for medical staff.

The results: injection site pain (89.8%), fatigue (62.2%), headache (45.6%), muscle pain (37.1%) and chills (33.9) %) is the most common side effect.

All general side effects are more common in the group of ≤43 years old, and their duration is mainly 1 day (45.1%) or 3 days (35.8%) after vaccination (Reference 4).

 

mRNA vaccine side effects:  LNP component may be the main factor

 

Italy

A survey of employees of medical institutions in central Italy receiving Pfizer-BioNTech vaccines. 340 people (61.5% were women; average age 49) participated in the study.

279 cases (82%) reported adverse events after the first dose of vaccination, and 281 cases (82.6%) reported adverse events after the second dose of vaccination.

Mild reactions were the main ones (80.9% and 80.3%), followed by moderate reactions (11.8% and 37.1%) and severe reactions (3.8% and 4.7%).

Adverse events are the same as those that have been described as very common (81.8% and 80.6%). Most adverse events are minor and are related to women and young people (Ref. 5).

 

 


Research on Adverse Reaction Mechanism

 

The mRNA components of Pfizer-BioNTech and Moderna vaccines are modified with nucleosides to reduce potential innate immune recognition .

LNP was chosen as a carrier to protect mRNA from degradation and help intracellular delivery and endosome escape.

LNPs are composed of a mixture of phospholipids, cholesterol, pegylated lipids, and cationic or ionizable lipids.

Phospholipids and cholesterol have the effect of stabilizing the structure, while PEGylation prolongs the half-life.

 

Cation/ionizable lipids can help the translation of mRNA from endosome to cytoplasm.

The development of ionizable lipids is to reduce the high inflammatory and cytotoxic effects of some permanently charged cationic lipids.

A preclinical study showed that nucleoside modified mRNA and Acuitas’ ionizable lipid LNPs complex has auxiliary activity.

However, the potential pro-inflammatory properties of these LNPs have not been evaluated.

 

A preclinical study conducted by the Department of Microbiology and Immunity of Thomas Jefferson University in the United States found that the use of LNPs for intradermal, intramuscular or intranasal delivery in mice triggers inflammation, which is characterized by leukocyte infiltration, activation of different inflammatory pathways, and various inflammatory factors. Secretion of chemokines.

 

Ionized lipids are highly correlated with inflammation (Reference 8), and the inflammatory cytokines IL-1β and IL-6 are involved.

 

mRNA vaccine side effects:  LNP component may be the main factor

 

Inflammatory side effects mechanism of the first and second doses

The side effects observed in the first dose of SARS-CoV-2 vaccine may be related to the inflammatory properties of LNPs.

LNPs activate different inflammatory pathways, which will lead to the production of inflammatory cytokines, such as IL-1 and IL-6, which can initiate and maintain local and systemic inflammation and side effects.

 

mRNA vaccine side effects:  LNP component may be the main factor

 

The dotted line in the figure above indicates that LNPs may also spread to any organ of the body, including the central nervous system (hypothalamus), where they may directly induce side effects.

Polyethylene glycol is widely used in food and pharmaceutical additives, and many of us produce polyethylene glycol antibodies. T

herefore, the PEGylated lipids of LNPs can induce the human body with pre-existing PEG-specific antibodies to produce complement activation-related pseudoallergies (CARPA).

 

Humans tend to have more serious side effects during the second injection, which may be caused by a variety of reasons.

First, the innate immune memory for LNPs may be formed after the first vaccination, which may lead to a stronger inflammatory response during the second vaccination.

Secondly, after the first vaccination, an adaptive immune response is formed against the viral protein encoded by the mRNA.

Therefore, cells expressing viral protein-derived peptides or the protein itself (red shape) can become targets for CD8+T or NK cell-mediated killing (ADCC), respectively.

Since LNPs can spread throughout the body and transfect any cell through mRNA, and mRNA can also be further distributed through extracellular vesicles, the target cell population that is lost may be huge and diverse.

 

 


Summary

The incidence of side effects of mRNA vaccines is 80-90%.

Although most of them are common low-grade side effects, moderate to severe side effects have reached about 10%.

Research from academic institutions shows that most of the side effects come from the components of LNP, such as PEG, ionized lipids, etc.

Innate immunity and adaptive immunity are involved.

 

 

 

References:

Nicola P Klein et al,Surveillance forAdverse Events After COVID-19 mRNA Vaccination,JAMA .2021 Oct 12;326(14):1390-1399.
MiguelGarcía-Grimshaw et al,Neurologic adverse events among 704,003 first-dose recipients of theBNT162b2 mRNA COVID-19 vaccine in Mexico: A nationwide descriptive study,Clin Immunol . 2021 Aug;229:108786.
Jae Hyoung Im etal,AdverseEvents with the Pfizer-BioNTech COVID-19 Vaccine among Korean HealthcareWorkers,Yonsei Med J . 2021 Dec;62(12):1162-1168.
Riad A, Pokorná A,Attia S, Klugarová J, Koščík M, Klugar M. Prevalence of COVID-19vaccine side effects among healthcare workers in the Czech Republic. J Clin Med2021;10:1428
GiancarloRipabelli et al,Active Surveillance of Adverse Events in Healthcare WorkersRecipients After Vaccination with COVID-19 BNT162b2 Vaccine (Pfizer-BioNTech,Comirnaty): A Cross-Sectional Study,J Community Health. 2021 Oct 9;1-15
Mohamad-GabrielAlameh et al, Messenger RNA-Based Vaccines Against Infectious Diseases, CurrTop Microbiol Immunol 2020 Apr 17. doi: 10.1007/82_2020_202.
Pardi, N., Hogan,M.J., Naradikian, M.S., Parkhouse, K., Cain, D.W., Jones, L., Moody, M.A.,Verkerke, H.P., Myles, A., Willis, E., et al. (2018a). Nucleoside-modified mRNAvaccines induce potent T follicular helper and germinal center B cell responses.J. Exp. Med. 215, 1571– 1588
Ndeupen, S., Qin, Z., Jacobsen, S., Bouteau, A., Estanbouli, H.,Igyártó, B.Z., The mRNA-LNP platform’s lipid nanoparticle component used inpreclinical vaccine studies is highly inflammatory, ISCIENCE (2021),

mRNA vaccine side effects:  LNP component may be the main factor

(source:internet, reference only)


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