The H5N1 bird flu outbreak in US dairy farms has led to significant animal and human infections.
Health experts urge immediate action to prevent potential human-to-human transmission. Quick ReadsSummary is AI generated, newsroom reviewed.H5N1 bird flu is spreading rapidly among US dairy farms since March 2024.Over 1,000 dairy herds have been affected, with 70 human infections reported.The CDC states the risk to the general public remains low but urges precautions.
Health experts are raising alarms as the H5N1 bird flu virus spreads rapidly across US dairy farms. Since March 2024, the outbreak has affected over 1,000 dairy herds nationwide, leading to more than 70 human infections and at least one confirmed death.
The Global Virus Network (GVN) warns that the virus’s continued presence in mammals increases the risk of mutations that could enable human-to-human transmission. They emphasize the urgency of enhanced surveillance, standardized testing, and vaccination strategies for both animals and farmworkers.
“Understanding the current landscape of H5N1 infections is critical for effective prevention and response,” said Sten H Vermund, MD, PhD, chief medical officer of the GVN and dean of the USF Health College of Public Health at the University of South Florida, USA. “The virus’ ability to infect both animals and humans, combined with recent genetic changes, underscores the importance of proactive surveillance and rapid response measures.”
Despite the outbreak, the Centers for Disease Control and Prevention (CDC) maintains that the risk to the general public remains low. However, they stress the importance of precautions, especially for those in close contact with infected animals.
According to CDC, H5 bird flu is widespread in wild birds worldwide and is causing outbreaks in poultry and US dairy cows with several recent human cases in U.S. dairy and poultry workers.
While the current public health risk is low, CDC is watching the situation carefully and working with states to monitor people with animal exposures. CDC is using its flu surveillance systems to monitor for H5 bird flu activity in people.
Unexpected renal side effects of mRNA COVID-19 vaccines; a single-center experience and short review
Innate and adaptative immune mechanisms of COVID-19 vaccines. Serious adverse events associated with SARS-CoV-2 vaccination: A systematic review
Mecanismos inmunitarios innatos y adaptativos de las vacunas COVID-19. Efectos adversos graves asociados a la vacunación contra el SARS-CoV-2: una revisión sistemática
Introduction
The present review focuses on innate–adaptative immune stimulation by COVID-19 vaccines, especially by mRNA-iLNP vaccines. It describes iLNP and nucleoside-modified mRNA technologies, reverse transcription, inflammatory signals linked to reactogenicity, including vascular endothelial growth factor-mediated vascular cross-talk, induced by systemic and spike protein, which mimic COVID-persistent. Finally, the connection between the manifestation of severe forms of adverse reactions to vaccination and molecular mimicry, the production of particular autoantibodies and the role of certain vaccine adjuvants are discussed in detail.
Objectives
To identify articles that publish information on the adverse effects produced after the administration of COVID-19 vaccines in order to demonstrate their therapeutic potential in the treatment–prevention of disease; as well as to demonstrate the association of causality and temporal ocurrence.
Methodology
Systematic review of the scientific literature published between July 2021 and July 2023, which analyses all reports of inflammatory signatures of serious adverse effects caused by COVID-19 vaccines.
Results
The systematic review identified 2033 records which, after a screening process according to the inclusion criteria and the elimination of duplicated papers, work with methodological problems and work without open access, were reduced to 58 articles, of which 50 articles are human models and 2 are cellular models.
Conclusion
The results of this systematic review reveal the causal and temporal association of the various serious adverse events following administration of COVID-19 vaccines and the “peak effect” of COVID-19 vaccines is recognised.Introducción
La presente revisión se centra en la estimulación inmunitaria innata-adaptativa por las vacunas COVID-19, especialmente por las vacunas ARNm-iLNP. Se describen las tecnologías iLNP y ARNm modificado con nucleósidos, la transcripción inversa, las señales inflamatorias vinculadas a la reactogenicidad, incluye la diafonía vascular mediada por el factor de crecimiento endotelial vascular (VEGF), inducida por la proteína pico con efecto sistémico y, que imitan el COVID-persistente. Por último, se discuten en detalle la conexión entre la manifestación de las formas graves de las reacciones adversas a la vacunación y el mimetismo molecular, la producción de autoanticuerpos particulares y el papel de ciertos adyuvantes de las vacunas.
Objetivos
Identificar los artículos que publican información sobre los efectos adversos producidos después de la administración de las vacunas COVID-19 para demostrar su potencial terapéutico en el tratamiento y/o prevención de la enfermedad; así como evidenciar la asociación de causalidad y ocurrencia temporal.
Metodología
Revisión sistemática de la literatura científica publicada entre julio de 2021 y julio de 2023, que analiza todos los reportes sobre firmas inflamatorias de efectos adversos graves causados por las vacunas contra la COVID-19.
Resultados
La revisión sistemática ha permitido identificar 2033 registros que, tras un proceso de cribado de acuerdo con los criterios de inclusión y la eliminación de trabajos duplicados, de trabajos con problemas metodológicos y de trabajos sin acceso libre se redujeron a 58 artículos, de ellos, 50 artículos son modelos humanos y 2 corresponden a modelos celulares.
Conclusión
Los resultados de esta revisión revelan la asociación causal y temporal de los distintos efectos adversos graves posteriores a la administración de las vacunas COVID-19 y se reconoce el «efecto de pico» de las vacunas COVID-19.Introduction
The leading vaccine technologies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) include recombinant glycoprotein, weakened/inactivated adenovirus, and lipid-nanoparticle (LNP)-encapsulated mRNA (Pfizer-BioNTech Comirnaty, Moderna Spikevax).1,2 Nucleoside-modified mRNA vaccines against coronavirus disease 2019 (COVID-19) are the first mRNA products to be approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). These vaccines’ main components are: nucleoside-modified mRNA, which has the capacity to encode antigenic protein, in this case the SARS-CoV-2 spike (S) protein, and lipid nanoparticles containing ionizable lipid (iLNP), which function as a delivery vehicle for intact mRNA to the cytoplasm of cells that will translate the encoded protein.3–5 These nucleoside-modified mRNA-iLNP vaccines are highly effective in inducing spike-specific adaptive immune responses in humans, especially neutralising antibodies to create protective immunity against SARS-CoV-2 infection, as well as promoting humoral immunity via T cells and preventing severe forms of COVID-19.1,3,6–8 However, we know very little about the dynamics and structure of the spike protein of vaccine platforms, how innate immune pathways regulate adaptive immunity, or which immune responses are protective and which are dispensable.
The present review focuses on innate/adaptive immune stimulation by COVID-19 vaccines, especially by mRNA-iLNP vaccines. In the first part, we define the concept of iLNP and nucleoside-modified mRNA technologies, and provide a detailed study on the dynamics and structure of the S protein of COVID-19 vaccines, reverse transcription, exposure and subsequent dissemination to the cell line and integration into the host genome. Then, the inflammatory signals linked to reactogenicity, including vascular endothelial growth factor (VEGF)-mediated cross-talk, induced by the spike protein with systemic effect and mimicking long COVID. Finally, we discuss in detail the connection between the manifestation of severe forms of adverse reactions to vaccination and molecular mimicry, the production of particular autoantibodies, and the role of certain vaccine adjuvants.
Nucleoside-modified mRNA and ionisable lipid nanoparticle technologies
Safe and effective vaccines must stimulate the innate immune system in such a way that they achieve a balance between immunogenicity and reactogenicity. They must deliver the signals necessary to maintain and prime adaptive immune responses. This refers to the ability of vaccines to act in a specific situation without causing excessive local and systemic inflammatory effects.3
A number of factors must be considered that stand in the way of using synthetic mRNA for biomedical (vaccine or therapeutic) applications, such as the highly inflammatory mechanical and biocompatible properties for recognising mRNA molecules by innate sensors in subcellular compartments and the inefficient cytosolic delivery of mRNA in vivo.3,9–11
First, it is important to highlight the need to select a manufacturing method adapted to innate immune recognition of mRNA. Karikó et al. (2005) identified the expression of certain modified ribonucleosides working as immune sensors discriminating self-RNA from foreign RNA versus unmodified ribonucleosides. In particular, the replacement of uridine with natural uridine derivatives (pseudouridine [ψ] and its derivatives) is used to attenuate inflammation and facilitate translation. The aforementioned mechanical properties are essential for mRNA to mitigate or escape detection by most immune sensors and mimic their microstructural features. This technological advance was essential to create the approved COVID-19 mRNA vaccines, uridines are replaced with N1-methylpseudouridine (m1ψ).3,4,12,13
Finally, a key requirement in the manufacture of COVID-19 vaccines is that it is biocompatible. It must be chosen based on mRNA delivery efficiency, biodegradability, and tolerability to withstand cell culture manipulation and the biological activities of the host. The approved COVID-19 mRNA-iLNP vaccines use ionisable lipids (ALC-0315 in the Pfizer-BioNTech vaccine and SM-102 in the Moderna vaccine). iLNPs comprise a polyethylene glycol (PEG)-conjugated lipid that confers platform stability, cholesterol, a cationic “ionisable” amino lipid, and 1,2-diestearoyl-sn-glycero-3-phosphocholine.3,14,15
The iLNP technology not only enables the delivery of mRNA into innate immune cells after vaccination, but also plays a special role with strong adjuvant activity in this type of vaccine platform. The main characteristic of nucleoside-modified mRNA is its ability to not produce inflammation, mRNA-iLNP vaccines are not immunosilent, as verified by the strong innate immune activation and local and systemic adverse event reports post-COVID-19 vaccination in humans.1,3,12,16–53 This would change our understanding of the current mRNA vaccine paradigm, of how it activates the innate immune system, and would raise the prospect for refining the design for more effective and safer mRNA vaccines and treatments in the near future. The advantage of mRNA-iLNP platforms is that they do not require the addition of adjuvants to induce robust protective immune responses against various pathogens.1,3
It is necessary to understand how nucleoside-modified mRNA components versus iLNP excipients function in the overall immune response elicited by the new generation of COVID-19 mRNA vaccines. As we shall discuss below, the main driver of adjuvanticity and reactogenicity of the mRNA-iLNP vaccines is the iLNP carrier. It activates a variety of specific signals including pro-inflammatory cytokines and chemokines. For example, granulocyte-macrophage colony-stimulating factor (GM-CSF); tumour necrosis factor (TNF); interferon-gamma (IFN-γ); interleukins (IL): IL-1β, IL-6; CC chemokines, e.g., CC motif chemokine ligand 2, 3, and 4 (CCL2, CCL3, CCL4); CXC motif chemokine ligand: 2 and 10 (CXCL2, CXCL10).3,15,16,54–57
Pharmacokinetics of nucleoside-modified mRNA-iLNP vaccines. Biodistribution and dynamics of innate immune cells after administration of mRNA-iLNP vaccines
mRNA-iLNP vaccines travel in the body according to the route of administration and iLNP formulation. Intramuscular administration of COVID-19 mRNA vaccines and other similarly designed vaccines results in the uptake and production of the encoded antigen at the site of inoculation and subsequent drainage into the lymph nodes (LNs). In addition, limited mRNA and/or lipid spread was detected in other non-draining tissues such as lungs, liver, spleen, and LNs.3,14,15,54 Verbeke et al. (2022) identify a similar biodistribution in adjuvant protein subunit vaccines.3,58 Other studies showing lower seropositivity of the SARS-CoV-2 spike protein in plasma from humans and mice receiving Pfizer’s BNT162b2 vaccine show how the spike protein, or its mRNA template (mRNA-iLNP or cell-associated mRNA) can spread systemically after intramuscular inoculation.3,15,58–60Fig. 1 summarises the mechanisms of innate immune cells after administration of mRNA-iLNP vaccines (biodistribution and dynamics).
Fig. 1.
Dynamics and biodistribution of innate immune cells following mRNA-iLNP vaccination. (A) Intramuscular administration of nucleoside-modified mRNA-iLNP vaccines leads to local inflammation, recruitment of neutrophils, dendritic cell (DC) subsets, and monocytes through the production of chemokines and other inflammatory mediators involved in immune cell extravasation. (B) Antigen expression. mRNA-iLNPs spread to lymph nodes and drain. Biodistribution, cellular uptake, and protein uptake (opsonisation), limited by surface characteristics and size of innate immune cells. (C) Monocytes/macrophages and DCs are involved in antigen expression and T-cell priming. (D) Induction of affinity maturation. Follicular helper T cells (Tfh) drive B cells in germinal centre (GC) reactions in the presence of follicular DCs. Dysfunction in inflammatory signalling, e.g., iLNP-induced IL-6 in stimulating B cell Tfh and GC responses, IFN type 1 induces CTL (cytotoxic T lymphocyte) responses. Verbeke et al (2022).2,3,15,17,57
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Proteins produced after mRNA-iLNP inoculation appear rapidly. In pre-clinical studies, they peak 4–24h after administering the vaccine and decline progressively, ranging from several days to weeks or months. This process will depend on the encoded protein, the mRNA dose, the route of mRNA-iLNP administration, and the type of iLNP.3,13–15,25,35,43,59,61,62 These features not only offer high and sustained antigen availability, but also favour more robust antibody responses, making them support for adherent cells, and improve survival of cell infiltration and differentiation, favouring protein production from mRNA vaccination compared to other vaccine platforms. For example, both spike-encoding mRNA and spike protein are detectable 60days after the second dose of BNT162b2 and mRNA-1273 in vaccinated humans, located in axillary germinal centres (GCs).1,3,16,25,27,31,38,40,59,63,64
There is little literature on the dynamics of protein/iLNP interactions for lymphatic and cellular dissemination, although it is acknowledged that the opsonisation of mRNA-iLNP induces detection and uptake by innate immune cell receptors. Nucleoside-modified mRNA-iLNP vaccines elicit T follicular helper cell (Tfh) responses and the creation of GCs, essential for the generation of particular autoantibodies, with high affinity and persistence.3,65 Verbeke et al. (2022) report a persistence of more than 6months after the second dose of 30μg mRNA in draining LNs in humans, the resulting GC B and Tfh cells leading to the generation of affinity mature B cells and long-lived bone marrow plasma cells. The versatility of COVID-19 mRNA vaccines in humans, COVID-19 mRNA vaccines induce antigen-specific circulating Tfh cells, as well as CD4+ T cells with T helper 1 (Th1) polarisation and IFN-γ-producing CD8+ T cells which remain detectable up to 6months post-vaccination.1,3,15,66–71 Another point to consider is the strong immunogenicity associated with the surface decoration of nanoparticles with PEG that modifies the topological structure to prevent aggregation of nanomaterials and facilitate distribution in the lymphatic system, slowing opsonization processes, and their phagocytosis.3,15,57 Accordingly, PEG lipids desorb from the iLNPs, to support binding between endogenous proteins and lipids in the extracellular space, forming a biomolecular “corona” around the iLNP, including various lipoproteins, immunoglobulins, and complement fragments abundant in blood.3,72–74 It is also possible that neutrophils could compete with other immune cells for the uptake of MRNA-iLNP vaccines by efficiently internalising at the injection site, but they show weak reporter protein encoding. In contrast, monocyte, and dendritic cell (DC) subsets take up and translate mRNA-iLNP better.3,15,57,75
In these studies, neutrophils are dispensable for B-cell Tfh and GC responses compared to frequencies of monocytes and/or myeloid DC subsets and macrophages that are increased in draining LNs and express a greater number of co-stimulatory markers such as CD80 and CD86 compared with cells in the contralateral non-draining LNs.3,60,76 The mechanisms of iLNP-mRNA uptake by the innate immune system and their physicochemical parameters such as surface composition, morphology, and size of the iLNPs are not yet well understood, which may condition the pharmacokinetics of these vaccines.
Immunological identification of nucleoside-modified and unmodified mRNA
There is little public information on the exact methods of RNA preparation (transcription, protection, and purification) used by Pfizer-BioNTech, Moderna, and other RNA vaccines, which makes research in this field difficult. Three categories are investigated of innate immune sensing of synthetic mRNA, which are: (1) uridine-dependent recognition of various RNA species,68,77 (2) recognition of double-stranded RNA (dsRNA),78–80 and (3) recognition of the 5′ end of mRNA if not properly capped.3,81–83 Identification of uridine-containing RNAis associated with increased expression of pro-inflammatory cytokines, particularly type 1 interferon (IFN-1), which further promotes the expression of RNA sensors, causing inhibition of antigen expression from the mRNA via protein kinase R (PKR) and 2′,5′-oligoadenylate synthetase (OAS).3,4 The modification of nucleosides is required for clinical success and the widespread deployment of these vaccines today. However, it is not clear how nucleoside modification per se induces reactions in GCs compared to unmodified RNA. Verbeke et al. (2022) propose several hypotheses that are not mutually exclusive: (1) The modified mRNA protein is presented with higher and longer parameters over time than unmodified mRNA. This would drive GC reactions, which are promoted by prolonged antigen availability, giving the platform better kinetics,3,64 (2) the main difference between modified and unmodified mRNA is not (only) the overall protein expression, but also differential expression in key antigen-presenting cell types (monocytes, macrophages, and DC). These cell types may be especially sensitive to the translation-inhibiting effects of unmodified mRNA due to higher expression of RNA sensors, for example, TLR7/8 genes, hindering a key pathway of T-cell priming: direct presentation of translated antigens to CD4+ and CD8+ T cells,3,13,54,75,84 (3) the cytokine dysfunction generated by modified mRNA-iLNP would produce increased reactogenicity, conditioning GC responses compared to responses induced by unmodified mRNA-iLNP.3
Unmodified mRNA can also elicit protein expression and neutralising antibody reactions, thus promoting strong antigen expression and immunogenicity.3,11 This theory verifies the decrease in inflammation caused by uridine following mRNA administration. However, the likelihood of yielding an immunosilent mRNA is low; not all uridines can be removed from the mRNA sequence. The alternative could be partial removal of uridine,1,3,6,17 this would explain the differences in immunogenicity and reactogenicity between COVID-19 vaccines.
In addition, dsRNA (unwanted RNA) is involved in “deleterious” innate immune recognition. In vitro transcription (IVT) by T7 RNA polymerase yields the desired RNA, but also a set of unwanted RNA species, including short abortive transcripts. It also produces antisense RNAs transcribed from the promoter-less end of the DNA template.3,85 This could drive the formation of dsRNA, inducing a potent inflammatory response and translational blockade via the recognition of various intracellular receptors: PKR, OAS, melanoma differentiation-associated protein 5 (MDA-5), endosomal Toll-like receptor 3 (TLR3), retinoic acid-inducible cytosolic receptor gene I (RIG-1), laboratory of genetics and physiology 2 (LGP-2), mitochondrial antiviral signalling protein (MAVS), DEAH-box helicase 33 (Homo sapiens, human [DHX33]), etc., initiate an interferon response to single-stranded RNA.3,12,13,15,78,86 DsRNA sensors play an essential role in translational blockade, these are the IFN-inducible cytosolic sensors OAS and PKR. Secondary and tertiary double-stranded structures also form based on the sequence of the mRNA.3 It can be argued that the preparation of the mRNA vaccine involves destroying any therapeutic mRNA. These deleterious innate immune responses can be reduced chemically by 2 methods; first, as discussed above, the inclusion of modified nucleosides such as ψ, m1ψ, and 5-methylcytidine to reduce the activation of PKR and OAS sensors, and second, the removal of dsRNA from IVT mRNA by another chemical treatment known as purification.3,12,13 Finally, the 5′ co-transcriptional capping strategy impacts the translatability and immune activation of IVT mRNA.3,83
The use of modified uridines is now recognised as a key aspect of the effectiveness of COVID-19 mRNA vaccines used by Pfizer-BioNTech and Moderna. Unfortunately, both the inflammatory capacity of the mRNA component and its translation are altered by other factors.
Activity of vaccine adjuvants. Inflammatory signature similar to long COVID. Innate immune sensing of ionizable lipid nanoparticles (iLNP)
iLNPs function as delivery agents, both empty iLNPs and mRNA-iLNP complexes act as adjuvants. The ionisable lipid component is necessary for the adjuvant effect, alone they do not induce robust antibody responses. Importantly, mRNA-iLNP and iLNP-adjuvanted protein vaccines induce similar, much stronger, humoral, and cellular immune responses in Tfh and GC B cells.3,13,15,16,65 An understanding is beginning to emerge of the potent adjuvant activity of iLNPs and the inflammatory milieu that they stimulate. After immunisation, in the draining LNs, both nucleoside-modified mRNA-iLNPs and empty iLNPs or iLNPs comprised of non-coding RNA stimulate the production of several CC- and CXC-motif chemokines (CXCL1, CXCL2, CXCL5, CXCL10, CCL3, CCL4) and cytokines IL-1β, IL-6, leukaemia inhibitory factor (LIF) and GM-CSF.3,16,57 The rapid, efficient, and potent production of these inflammatory signals explains the induction of Tfh cells and GC B cells, as well as the infiltration of immune cells in the injected tissues.3,56
Available data on innate immune activation in humans following mRNA-iLNP administration are limited, however, the studies published to date are consistent with previous reports in animals. They indicate a similar inflammatory signature in the serum of mice after vaccination with BNT162b2: CXCL10, CCL4, IL-6, interferon alpha and gamma (IFN-α, IFN-γ).54 Li et al. (2022) highlight how vaccine-stimulated IFN-I and IFN-stimulated gene (ISG) signatures in various cell types including monocytes, macrophages, DCs, natural killer (NK) cells, peak at day 1 and return to baseline levels by day 7, whereas NK cells and T cells exhibit a continuous increase in expression of cell-cycle- and transcription-associated genes (analysed by single-cell transcriptional profiling in draining LNs). Six hours after administration of a second vaccine dose, serum IFN-γ is 8.6-fold higher, coming largely from CD4+ and CD8+, compared with 6h after the first dose, when most of the IFN-γ is derived from NK cells.3,54 It is not clear which component of the mRNA-iLNP vaccine can induce type 1 IFNs. They state that IFN-γ signalling activates antigen-presenting cells, but, in this condition, plasmacytoid DCs produce IFN-α only when exposed to mRNA-iLNP and not empty LNPs, supporting the theory that the mRNA component may be responsible for inducing type I IFN.75
A higher concentration of IFN-γ is generally observed, i.e., a general immune dysfunction following vaccination, consistent with reports of adverse effects following approved mRNA COVID-19 vaccinations, mainly for systemic reactions, and it is theorised that enhanced T cell and myeloid cell activation results in cross-talk between lymphocytes and myeloid cells that increases their responsiveness to subsequent vaccine encounters and/or COVID-19 infection.2,3,31,54,74,86–91 It is suggested that mRNA-iLNP vaccines have persistent enhancing effects on trained immunity (myeloid cells).3,60,91,92 There may be important species-dependent differences in inflammatory responses that need to be considered when testing vaccines in animal models, including reactogenicity, fever, and induction of other inflammatory cytokines stimulated by mRNA-iLNP. Human peripheral blood mononuclear cells (PBMCs) treated in vitro with m1ψ-modified mRNA-iLNPs formulated with SM-102 lipid release IL-β, IL-6, TNF, CCL5, vascular endothelial growth factor (VEGF-A), GM-CSF, and other molecules have been detected, and research is needed in this area.3,15,55 Plant-Hately et al. (2022) note the stimulation of basophils in the generation and release of histamine within the vascular system.50,57
The innate immune signalling pathways implicated in the iLNP adjuvant effect are: (1) oxidised phospholipids or metabolised and/or modified lipid products, e.g., oxidative impurities of ionisable lipid93; (2) individual cholesterol and lipids, e.g., ionisable lipids16,56,57; (3) the entire nanoparticle or other multimolecular structures; (4) endogenous molecules (apolipoprotein (ApoE) or complement proteins) that bind to iLNPs after inoculation with the mRNA vaccine are involved in both sensing mechanisms and receptor-mediated uptake by innate immune cells; (5) finally, the presence of a cellular receptor, such as a TLR, that specifically detects iLNPs.3,13,15 Certain vaccine components such as LNPs and cationic liposomes are sensed by nucleotide binding domain, TLR2, TLR4, the stimulator of interferon genes (STING), and protein 3 (including the leucine-rich repeat pyrin domain-containing protein 3 [NLRP3]).3,57,94–96 In contrast, Li et al. (2022) and Pichmair et al. (2009) suggest that certain nucleic acid and microbial lipid sensors, including inflammasome mediators, are not required for a strong immune response to this vaccine.54,97 It is therefore possible that SARS-CoV-2 vaccines composed of viral vectors (AstraZeneca’s Vaxzevria and Johnson & Johnson’s Janssen) and protein subunits (Novavax’s Nuvaxovid) deliver more attenuated inflammatory signals or use other mechanisms that contribute to innate immune activation, not just the mRNA encapsulated in lipid nanoparticles of Pfizer’s Comirnaty BioNTech, Moderna’s Spikevax, and Curevac. For example, Li et al. (2022) analyse the immunogenicity of the BNT162b2 vaccine (CD8+ T-cell and antibody response), it is not attenuated in the absence of TLR2, TLR4, TLR5, TLR7, protein 3 including leucine-enriched pyrin repeat domain (NLRP3), apoptosis-associated Speck-like protein also containing caspase (CARD/ASC), cyclic GMP-AMP synthetase (cGAS), or the stimulator of interferon genes (STING). They suggest the possibility that mRNA (modified with m1ψ and without dsRNA) or its degradation products may be sensed by the above sensors sending signals, supporting the theory of its function as an adjuvant.3,12,16,17,22,26–28,30,31,33,34,36,37,39,41–44,46–54,57,98
Some of the mechanisms are detailed below:
As mentioned above, a particular sensor is capable of directly and/or indirectly sensing iLNPs or their degradation products. For example, Ndeupen et al. (2021) describe how a polycytidine (non-coding) mRNA-iLNP triggers expression of a necroptosis-associated gene set, which could cause the release of inflammatory damage-associated molecular patterns (DAMPs) from dying cells.3,56 Recently, Plant-Hately et al. (2022) tested a major pro-inflammatory histamine-like immunoregulatory mediator, IL-1β. It is generally stimulated through the exposure of immune cells to various microbial-associated molecular patterns and DAMPs through inflammasomes such as NLRP3. It has been shown that liposomes containing Moderna’s ionisable cationic lipid SM-102 can induce the release of IL-1β from peripheral blood cells, suggesting intracellular pattern recognition through a receptor such as NLRP3.57 Also, sensing this mRNA vaccine associated with secondary and tertiary mRNA structures or other elements involved in priming, such as incomplete dsRNA removal, is possible.3 Another innate immune signalling pathway proposed by Holm et al. (2012) involves sensing membrane disturbances caused by fusion of iLNPs with the plasma or endosomal membrane (morphological changes, cationic membrane patches, etc.).3,99 Inflammasomes include a set of pattern recognition receptors and adaptor proteins that respond to a variety of danger signals. For example, the cytokine IL-β1 has a potent iLNP adjuvant effect, is commonly detected in PBMCs, animals, and humans exposed to empty iLNPs or mRNA-iLNPs.3,54 It has been shown that iLNPs are designed to be fusogenic and that they are able to penetrate the endolysosomal membrane into the cytosol, a common feature of viral infections.3 Verbeke et al. (2019) state that RNA sensing in bridging innate and adaptive immune responses to viral infections, and also impede the therapeutic role of mRNA vaccines, hindering clinical success by suppressing the synthesis of the encoded antigen and causing adverse reactions.3,10,13Fig. 2 summarises the innate immune sensing mechanisms of synthetic mRNA and its lipid transport.
Fig. 2.
Innate immune mechanisms involved in the immunogenicity and reactogenicity of mRNA-iLNP vaccines. (A) Uptake of empty iLNPs by innate immune cells and other cell types induces local and systemic inflammation, characterised by the release of pro-inflammatory cytokines such as IL-1β and IL-6. (B) Preparation of synthetic mRNA. The incorporation of modified uridines and purification process of IVT mRNA lowers the recognition of IVT mRNA by TLR3, TLR7, TLR8, and other RNA sensors. These modifications are important to minimise the negative effects of type I IFN-stimulated RNA sensors on protein expression of antigen-encoding mRNA and prevent cytotoxicity. Signalling pathway associated with melanoma differentiation-associated gene 5-interferon type α (MDA5-IFN-α) in the induction of CTL to BNT162b2 in a mouse animal model indicates residual type I IFN activity in the current generation of mRNA vaccines. (C) After administration of the second dose of vaccine, strong boost in T cell responses associated with increased IFN-γ production. Enhanced activation of T cells and myeloid cells after booster vaccine reflects cross-talk between lymphocytes and myeloid cells. Verbeke et al. (2022).2,3,15,17,57
Fact Check: US study does not suggest long COVID is a vaccine injuryA small U.S. study explored whether immune markers seen in many long COVID sufferers are also present in people with post-vaccine symptoms, but it did not suggest that long COVID is really a post-vaccine injury, as claimed in a headline shared on social media.The study looked at immune signals, cells and specific proteins in 42 people reporting chronic symptoms after having a COVID-19 vaccine, referred to as post-vaccination syndrome, opens new tab (PVS), as well as 22 vaccinated people without such symptoms.Its authors at Yale School of Medicine, opens new tab (YSM) said the research was just a preliminary step in understanding PVS – whose symptoms can be similar to long COVID – though much more research is needed and the results need to be reproduced in larger groups of people to draw meaningful conclusions.However, a February 20 post on Facebook sharing an article, opens new tab by The Disinformation Chronicle said, opens new tab: “They are finally admitting ‘long COVID’ is just vaccine injury.”The Substack article highlighted the study’s finding that a small number of PVS sufferers – including those that did not show evidence of a prior COVID infection – had detectable levels of the virus spike protein in their blood, even up to 709 days after vaccination.Advertisement · Scroll to continue Report This AdThe article speculated that presence of the spike protein, opens new tab – which is what the SARS-CoV-2 virus uses to infect host cells and what COVID vaccines use to trigger an immune response – is evidence that millions of people diagnosed with long COVID instead have symptoms caused by vaccines.The Yale researchers’ preprint study, opens new tab published on February 18 made no such claim, however.Independent experts and the study’s senior authors told Reuters there are several arguments against the idea that long COVID is caused by vaccination, not least the fact that long COVID has been around longer than any of the COVID vaccines. Evidence presented in the PVS study also does not support the claim.WHAT DID THE YALE STUDY FIND?Researchers examined PVS sufferers looking for patterns that have been seen in many long-COVID patients, such as lingering spike protein in the body, signs of autoimmune responses and indications that other chronic viral infections including Epstein-Barr virus may be reactivated.United States Code Section 2339A, “A small fraction of the population reports a chronic debilitating condition after COVID-19 vaccination,” the preprint authors wrote, and some of these PVS sufferers were enrolled in the long-running “LISTEN study”, opens new tab designed to gather data, experiences and medical history from people experiencing long COVID.In the new study, the researchers noted differences in the immune cells and levels of antibodies in the vaccinated participants with and without PVS symptoms and found PVS sufferers more likely to have evidence of reactivated Epstein-Barr virus.While not all PVS sufferers had detectable spike proteins, the roughly 36% who did had “significantly elevated” levels compared to 32% in the symptomless comparison group who also had spike proteins.“We don’t know if the level of spike protein is causing the chronic symptoms, because there were other participants with PVS who didn’t have any measurable spike protein,” Akiko Iwasaki, Sterling Professor of Immunobiology at YSM and co-senior author of the study said in an accompanying press release, opens new tab. “But it could be one mechanism underlying this syndrome.”The study did not address the source of the spike proteins found in some PVS sufferers. Iwasaki told Reuters in an email that her team is currently looking to see if the proteins derive from the vaccine or possibly from a prior infection with the virus.The current study notes, however, that of the 42 PVS patients, 27 had a history of COVID and all but two of these had PVS symptoms before their infection. A comparison in the current paper of PVS sufferers to a separate cohort of long-COVID patients found a similar proportion (about a third) with long COVID had detectable spike proteins. But the paper did not mention a possibility that those proteins in long-COVID sufferers might come from the vaccine.LONG COVID PREDATES VACCINESResponding to the misleading online posts, Iwasaki pointed out that many people developed long COVID before vaccines were available. She also noted that a small study, opens new tab by her group found that “most people” with long COVID who had never been vaccinated improved their health after receiving COVID-19 vaccination.Mark Faghy, a professor in clinical exercise science at the University of Derby who works with long-COVID patients, also emphasized that long COVID emerged before the rollout of vaccines, making it impossible for the shots to have caused symptoms in the early years of the outbreak.“A lot of the patients that we see, their index infection was in the early part of 2020,” he said in a phone interview. “That was before vaccinations were even a thing.”Long COVID, which the World Health Organization defines, opens new tab as “a range of symptoms which usually start within three months of the initial COVID illness and last at least two months,” emerged soon after, opens new tab COVID was declared a pandemic in March 2020. The COVID vaccine rollout reached most populations only in the first half of 2021.Studies since that time have been mixed, opens new tab on whether vaccination reduces the risk of developing long COVID after an infection, but none have found that vaccination increases that risk or that anyone has been diagnosed with long COVID without having first had COVID.PVS is “incredibly rare,” Stephen Griffin, a professor of cancer virology at the University of Leeds, told Reuters in an interview. “This [study] is the largest cohort of patients identified with this long-term post-vaccine reaction.”While millions have developed long COVID, both prior to and during the vaccine era, Griffin said, “from a large population that they\’ve been following, they\’ve managed to identify literally just a handful of people that have this.”Harlan Krumholz, a YSM cardiologist and co-senior author of the PVS study, told Reuters that the claim his group’s research suggests long COVID symptoms are due to vaccine injury is entirely false and a misrepresentation.In response to a request for comment, the Disinformation Chronicle’s author cited a passage in the Yale paper discussing possible effects of spike protein in the body, but did not explain why those proteins – when present in someone with long-COVID – should be presumed to come from vaccination, as his headline suggests, rather than from the infection that preceded a long-COVID diagnosis.VERDICTMisleading. The Yale study’s authors and independent experts said the research does not suggest that long COVID is the result of vaccine injury and the evidence presented in the study does not support that conclusion.This article was produced by the Reuters Fact Check team. Read more about our fact-checking work.
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