Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1
Matthew Halma
 -- 2571 2023-07-25 11:28:23 |
2 Reference format revised.
Lindsay Dong
 Meta information modification 2571 2023-07-26 03:34:39 |

Video Upload Options

We provide professional Video Production Services to translate complex research into visually appealing presentations. Would you like to try it?
No, upload directly Yes

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Halma, M.T.J.; Plothe, C.; Marik, P.; Lawrie, T.A. Management of Spike Protein-Related Pathology. Encyclopedia. Available online: https://encyclopedia.pub/entry/47233 (accessed on 16 November 2024).
Halma MTJ, Plothe C, Marik P, Lawrie TA. Management of Spike Protein-Related Pathology. Encyclopedia. Available at: https://encyclopedia.pub/entry/47233. Accessed November 16, 2024.
Halma, Matthew T. J., Christof Plothe, Paul Marik, Theresa A. Lawrie. "Management of Spike Protein-Related Pathology" Encyclopedia, https://encyclopedia.pub/entry/47233 (accessed November 16, 2024).
Halma, M.T.J., Plothe, C., Marik, P., & Lawrie, T.A. (2023, July 25). Management of Spike Protein-Related Pathology. In Encyclopedia. https://encyclopedia.pub/entry/47233
Halma, Matthew T. J., et al. "Management of Spike Protein-Related Pathology." Encyclopedia. Web. 25 July, 2023.
Management of Spike Protein-Related Pathology
Edit
This entry is adapted from the peer-reviewed paper 10.3390/microorganisms11051308

In the wake of the COVID-19 crisis, a need has arisen to prevent and treat two related conditions, COVID-19 vaccine injury and long COVID-19, both of which can trace at least part of their aetiology to the spike protein, which can cause harm through several mechanisms. One significant mechanism of harm is vascular, and it is mediated by the spike protein, a common element of the COVID-19 illness, and it is related to receiving a COVID-19 vaccine. Given the significant number of people experiencing these two related conditions, it is imperative to develop treatment protocols, as well as to consider the diversity of people experiencing long COVID-19 and vaccine injury. 

long COVID COVID-19 vaccine injury spike protein thrombosis

1. Introduction

According to available data, by 30 September 2022, 68% of the world’s population had received at least one dose of the COVID-19 vaccine, and 12.74 billion doses had been administered [1]. The vaccines most commonly administered were Comirnaty (Pfizer/BioNTech), Covishield (Astrazeneca), CoronaVac (Sinovac), Spikevax (Moderna), and Jcovden (Johnson & Johnson) [2]. Of these, approximately 30% of the doses produced by 22 January 2022 were in the form of a novel vaccine with a synthetic N1-methyl-pseudoiridinylated mRNA encapsulated in a lipid nanoparticle (LNP) [3].
LNPs are a new technology that was not used in vaccine delivery until the emergency use authorization (EUA) of the Pfizer/BioNTech BNT162b2 and Moderna mRNA-1273 COVID-19 vaccines [4]. This was also unprecedented in the approval process, being the fastest for any vaccine [5], leaving many concerns with regard to long-term safety [6], which was difficult to evaluate due to the unblinding of the initial clinical trials [7].
Whilst the delivery technology of LNPs have previously been used to deliver small molecules, it has only recently been used to deliver RNA. LNPs are advantageous for targeting brain tissue, as they can cross the blood–brain barrier (BBB) [8][9]. The first drug used and LNP to deliver RNA was a small interfering RNA (siRNA)-based drug, known as Onpattro (Alnylam Pharmaceuticals), first approved in 2018 for the treatment of polyneuropathies [10].
Given both the novelty of the technology and the paucity of data on which approval was based (which was also subject to data integrity issues [11]), long-term effects cannot be definitively ruled out, especially because many of the foundational claims on which approval was based have been contested by recent experiments [12][13][14]. For example, in contrast to claims that the injection stayed at the injection site [15], and that spike protein would only be expressed for a short period of time (based on the lability of non-pseudouridylated RNA [16]), the contents and products of the COVID-19 vaccines have been found in the blood stream of most vaccinees studied within hours to days [12].
The first claim was based on Intramuscular administration [15], and the second claim was based on the lability of RNA [17], with a typical RNA half-life of minutes [18]; however, biodistribution studies have found significant expression of spikes in other tissues and organs [12], and researchers have found both vaccine mRNA and spike protein (which is encoded by the vaccine sequence) two months post-administration [14], and even up to four months post-vaccination [13]. One preprint study of people with SARS-CoV-2 negative post-vaccination Long COVID-19-like symptoms showed spike protein persistence, on average, 105 days post vaccination [19]. Long COVID-19 patients (post SARS-CoV-2 infection) show spike protein persistence up to 15 months [20]. Another study showed spike protein persistence in the gut of long COVID-19 patients, but not in the bloodstream.
Spike proteins can be packaged in exosomes [13], possibly resulting in inflammation and immune activation [21][22] in organs and tissues distant from the injection site [13]. Extracellular vesicles are capable of crossing the blood–brain barrier [23], and LNPs, as well as exosomes, will exchange more readily in small diameter vessels with low flow rates (i.e., capillaries and small vessels) [24]. Importantly, the spike protein seems to additionally impact blood–brain barrier permeability [25][26]. These results challenge the initial mechanistic foundation on which the presumption of safety is contingent.
Compared with other vaccines, COVID-19 vaccines have a much higher adverse event rate [27]. Histopathological findings and autopsies of those dying post-vaccination support the causative role of the vaccine in deaths [28], most commonly from vascular-related events. Pharmacovigilance programs in several countries have observed a safety signal for myocarditis in the COVID-19 vaccinated population [29][30][31]. A US survey found that 19% of myocarditis cases had not recovered at 90 days after onset [32]. In addition, screening of BNT162b2 vaccine recipients among boys aged 13–18 in a Thai study revealed that 2.3% of the boys had at least one elevated cardiac biomarker or positive lab assessment, and 29% had at least one cardiac manifestation, such as tachycardia, palpitation, or myopericarditis [33]. Given this information, and given the ubiquitous use of COVID-19 vaccines, it is possible that widespread subclinical damage exists in the COVID-19 vaccinated population. Structurally, the spike protein, particularly the receptor-binding domain (RBD) of the S1 subunit, has attracted much attention, as it is the most prominent aspect of the viral capsid [34] (It consists of spike (S) and nucleocapsid (N)) glycoproteins. Cell entry is mediated by the binding of Spike RBD to the Angiotensin Converting Enzyme II (ACE2) [35]. Therefore, by preventing this binding through allosteric inhibition, it is possible to prevent the entry of SARS-CoV-2 virions into the cell and subsequent infection [36].

2. Pathophysiology

2.1. Mechanisms of Harm

As mentioned previously, while it was expected that the LNP-encapsulated synthetic mRNAs would remain at the injection site and rapidly degrade, there is substantial evidence that they enter the bloodstream [37], deposit in other tissues [38], and even in the breast milk of lactating mothers [39]. The S1 subunit of the spike protein can damage the endothelial lining of blood vessels [40][41][42]. Vaccine particles in the bloodstream can cause a significant inflammatory response in blood vessels [43].
Several hypotheses for the mechanisms of long COVID-19 exist, including immune dysregulation, auto-immunity, endothelial dysfunction, activation of coagulation, and latent viral persistence [44][45]. Cardiovascular complications, particularly microthrombus formation, feature both in the etiologies of long COVID-19 [46][47] as well as COVID-19 vaccine injury [48].
The SARS-CoV-2 (infection or vaccine produced) spike protein can bind to the ACE2 receptor on platelets, leading to their activation [49], and it can cause fibrinogen-resistant blood clots [50]. Spike protein fragments can also be amyloidogenic on their own [51]. Several reports demonstrate elevated troponin levels in cardiac symptoms following the COVID-19 vaccine [52].

2.2. Clinical Observations

Although no official definition exists for ‘post-COVID-19-Vaccine Syndrome,’ a temporal correlation between receiving a COVID-19 vaccine and the beginning or worsening of a patient’s clinical manifestations is sufficient to make the diagnosis of a COVID-19 vaccine-induced injury when the symptoms are unexplained by other concurrent causes. It should, however, be recognized that there is a significant overlap between the symptoms and features of the long COVID-19 syndrome [53] and the post-COVID-19-Vaccine Syndrome [54]. However, a number of clinical features appear to be distinctive of the post-COVID-19 vaccine syndrome; most notably, severe neurological symptoms (particularly small fiber neuropathy) appears to be more common following vaccination [55][56][57]. To complicate matters further, patients with long COVID-19 are often vaccinated [58], making the issue of definition more difficult.
Unfortunately, only post mortem examination to date can prove causal relationship when tissues damaged demonstrate the presence of spike protein and absence of nucleocapsid protein (SARS-CoV-2 only) [59].
The true magnitude of post-COVID-19-Vaccine Syndrome is unknown, as data are limited to short duration clinical trials. From a survey of vaccinated individuals, approximately 1% required medical attention immediately following vaccination [60]. A nationwide cohort study of U.S. veterans reported adverse reactions in 8.5% of recipients of the Pfizer vaccine and 7.9% of those receiving the Moderna vaccine [61].

3. Therapeutic Interventions

There are several non-specific means of counteracting the effects of long-COVID-19 and post-COVID-19 vaccine injury. These include nutritional support for general immune regulation and for overall health [62], as well as more specific, spike protein-specific therapeutics.
Non-specific therapeutic moieties include nutritional optimization, as diet-related pathologies, including obesity [63] and type 2 diabetes [64], were associated with worse outcomes from COVID-19 infection. Additionally, high blood glucose facilitates several steps of the viral lifecycle and infection progression [65], motivating the reduction in sugar and refined carbohydrate intake, which are associated with increases in blood sugar. Furthermore, adoption of a whole-food, plant-based diet is associated with decreased oxidative stress and inflammation [66] and better cardiovascular conditions. These positive impacts are attributed to their nutrient profiles, consisting of antioxidants, vitamins, minerals, and phytochemical-containing phenolic compounds, which can exert antioxidant, anti-inflammatory, and other beneficial effects [67][68].
The microbiota plays a fundamental role in the induction, training, and function of the host’s immune system and thus shape the responses to its challenges [69]. Gut microbiome composition was significantly altered in patients with COVID-19 compared with non-COVID-19 individuals, irrespective of whether patients had received medication [70]. The researchers said patients with severe illness exhibit high blood plasma levels of inflammatory cytokines and inflammatory markers. Additionally, given altered gut microbiota composition in SARS-CoV-2 infected subjects, there is substantial involvement of the GI tract during infection. These results suggest that gut microbiota composition is associated with the magnitude of immune response to COVID-19 and subsequent tissue damage and thus could play a role in regulating disease severity. The scientists also found that, because a small subset of patients showed gut microbiota dysbiosis, or imbalance, even 30 days after recovery, this could be a potential explanation for why some symptoms persist in long COVID-19 [71].
Given the intricate influence of gut microbiota (GM) on host immune effectors and subsequent inflammatory profile, GM composition and function might contribute to explaining the individual resilience/fragility with respect to COVID-19 and/or the response to therapeutics (vaccines), which deserve further research [72]. Microbial diversity can be improved by consuming many prebiotics and probiotics, such as sauerkraut and kimchi.
The design and discovery of spike protein inhibitors have followed a typical drug repurposing process. Given the structural similarity of the SARS-CoV-2 spike protein to other coronaviruses [73][74], compounds that work for these could potentially be repurposed for SARS-CoV-2 spike inhibition.
Typically, once a prospective compound for repurposing has been identified, it is tested using a ligand-binding assay (LBA) [75]. These assays can provide information on binding affinity and kinetics, as well as binding stoichiometries and even cooperative effects [75].
The next level of verification may be an in vitro assay for viral inhibition in cell culture, where cells are infected with a virus, and viral levels or titre (concentration) are measured by counting viral plaques [76] or measuring viral nucleic acid (NA) levels [77]. Control cells are compared with treated cells. Though the approach has limitations, in not considering the whole-body dynamics of a virus [78], it can serve as a useful starting point.
In vivo studies are a further level of verification, which show the impact of the intervention in an animal model. Beyond in vivo studies, there are clinical studies, which are typically of two design types: observational and randomized control trials (RCTs) [79].

3.1. Establishing a Healthy Microbiome

The state of the microbiome is an essential criterion for the progression of acute COVID-19 infection, long COVID-19, and post vaccine syndrome [80][81][82][83][84]. Patients with post-vaccine syndrome classically have a severe dysbiosis with loss of Bifidobacterium [85][86][87]. A whole-food, plant-based diet may improve outcomes in COVID-19 [88][89][90], and people following plant-based diets, on average, experienced less severe COVID-19 symptoms [91]. Dietary sources of probiotics include fermented dairy [92], chia seeds [93], glucomannan [94][95], and supplements [96].

3.2. Preventing Spike Protein Damage

Inhibiting Spike Protein Cleavage

The furin cleavage site on SARS-CoV-2 has been suggested as a reason for its increased infectivity relative to SARS-CoV [97], which had a higher fatality rate, which was much less infectious [98]. Cleavage of the full-length spike protein into S1 and S2 subunits is essential for SARS-CoV-2 entry into human lung cells [99][100][101][102]. The full-length spike is present in both SARS-CoV-2 infection, as well as vaccination, and it is the only protein common to SARS-CoV-2 infection and vaccination (it is the only protein present in vaccination) [103].
Vaccine-produced spike has an important difference as compared to the SARS-CoV-2 spike—the inclusion of two proline mutations to stabilize the pre-fusion state of the spike protein. These are related to Pfizer’s BNT162b2 [104], Moderna’s mRNA-1273 [105], Johnson & Johnson’s Ad26.COV2.S [106], and NovaVax’s NVAX-CoV2373 [107]. This was first discovered in the context of MERS [108]. Other vaccines apparently encode the full-length, wild-type spike protein, including AstraZeneca’s ChAdOx1 [109] and SinoVac’s CoronaVac [110].
These dual proline mutations featured in the mRNA vaccines stabilize the pre-fusion state, though some cleavage still occurs [108][111][112], and, interestingly, the mutations produce an unknown cleavage product of 40 kDa, where typical cleavage products for the wild-type spike protein are 80 kDa [112]. As such, targeting the cleavage of spike protein is likely to make a difference in long COVID, as well as vaccine injury from the vaccines encoding the full-length wild-type spike protein (AstraZeneca, SinoVac and others), though this may have less of an impact in vaccines encoding the pre-fusion-stabilized spike protein (Pfizer, Moderna, Johnson & Johnson, NovaVax and others).

3.3. Inhibiting Spike Protein Binding

One of the most direct therapeutic mechanisms is to seek compounds which disrupt the ACE2/Spike interface, either through binding ACE2 or spike in isolation, or disrupting the interface itself. This problem is a steric and conformational problem, for which computational prediction using structural models is highly amenable. A great many computational studies of the spike protein and ACE2 binding compounds have been performed, and some of these hits have further been developed through LBAs, in vitro studies, in vivo studies in animal models, and, lastly, clinical trials with human subjects. Few of the compounds reach the final stage, though several with this mechanism of action have been investigated. Most promising were ivermectin and quercetin, as computational prediction showed these bind to the spike. If the spike is bound in the receptor binding domain (RBD), the interaction with ACE2 receptors, by which spike protein exerts its inflammatory effect, is also inhibited.

3.4. Clearing Spike Protein

Importantly, to progress beyond this, it is necessary to clear out the spike protein. This can be accomplished through upregulation of the protein degradative pathways in the body through upregulation of autophagy. Autophagy can be upregulated by fasting [113] and calorie restriction [114], especially if protein is reduced [115]. Autophagy in many instances does not require the complete cessation of food intake (protocols are available at https://COVID19criticalcare.com/treatment-protocols/, accessed on 15 April 2023). Sharply decreasing protein intake can upregulate autophagy pathways [116], and this can be accomplished while still eating, which makes this more approachable as a protocol. Regular fasting was also associated with better outcomes from acute COVID-19 [117].

3.5. Healing the Damage

After the damage process has been attenuated, it is necessary to heal the damage that has occurred. The healing stage requires normalizing the immune response, reducing lingering inflammation (such as by targeting interleukin 6 [118]), and addressing any acute damage in affected tissues, particularly cardiovascular damage [46][47][48]. Damage reduction may also mean reducing the level of blood clotting if clotting is present and repairing any organ damage, if relevant. The stage of healing requires normalizing the immune response, reducing lingering inflammation (such as by targeting interleukin 6 [118]), and addressing any acute damage in whatever affected tissues, which, for the purposes, includes blood. Micro-clots are a possible etiological factor in long COVID-19 [119][120][121], as well as COVID-19 vaccine injury [122]. Damage reduction may also mean reducing the level of blood clotting if clotting is present, and repairing any organ damage, if relevant. Sufferers of long COVID-19 have been found to have a higher inflammatory response to the initial COVID-19 infection than those who recover completely from COVID-19 [123], so anti-inflammatory and immunomodulatory medications have been identified as potential long COVID-19 therapeutics.
Anti-coagulant medication, such as aspirin, can be useful in alleviating the cardiovascular complications of COVID-19 [124][125], as they have a long history of use in improving blood flow and reducing coagulopathies [126][127][128].

References

  1. Ritchie, H.; Mathieu, E.; Rodés-Guirao, L.; Appel, C.; Giattino, C.; Ortiz-Ospina, E.; Hasell, J.; Macdonald, B.; Beltekian, D.; Roser, M. Coronavirus Pandemic (COVID-19). Our World in Data 2020. Available online: https://ourworldindata.org/coronavirus (accessed on 1 October 2022).
  2. Staff, G. COVID-19 Vaccine Production to January 31st 2022. Available online: https://globalcommissionforpostpandemicpolicy.org/covid-19-vaccine-production-to-january-31st-2022/ (accessed on 1 October 2022).
  3. Halma, M.T.J.; Rose, J.; Lawrie, T. The Novelty of mRNA Viral Vaccines and Potential Harms: A Scoping Review. J 2023, 6, 220–235.
  4. ARCHIVE: Conditions of Authorisation for COVID-19 Vaccine Pfizer/BioNTech (Regulation 174). Available online: https://www.gov.uk/government/publications/regulatory-approval-of-pfizer-biontech-vaccine-for-covid-19/conditions-of-authorisation-for-pfizerbiontech-covid-19-vaccine (accessed on 1 October 2022).
  5. Ball, P. The Lightning-Fast Quest for COVID Vaccines—and What It Means for Other Diseases. Nature 2020, 589, 16–18.
  6. Anand, P.; Stahel, V.P. Review the Safety of COVID-19 MRNA Vaccines: A Review. Patient Saf. Surg. 2021, 15, 20.
  7. Doshi, P. COVID-19 Vaccines: In the Rush for Regulatory Approval, Do We Need More Data? BMJ 2021, 373, n1244.
  8. Bondì, M.L.; Di Gesù, R.; Craparo, E.F. Chapter Twelve—Lipid Nanoparticles for Drug Targeting to the Brain. In Methods in Enzymology; Düzgüneş, N., Ed.; Academic Press: Cambridge, MA, USA, 2012; Volume 508, pp. 229–251.
  9. Pottoo, F.H.; Sharma, S.; Javed, M.N.; Barkat, M.A.; Harshita; Alam, M.S.; Naim, M.J.; Alam, O.; Ansari, M.A.; Barreto, G.E.; et al. Lipid-Based Nanoformulations in the Treatment of Neurological Disorders. Drug. Metab. Rev. 2020, 52, 185–204.
  10. Akinc, A.; Maier, M.A.; Manoharan, M.; Fitzgerald, K.; Jayaraman, M.; Barros, S.; Ansell, S.; Du, X.; Hope, M.J.; Madden, T.D.; et al. The Onpattro Story and the Clinical Translation of Nanomedicines Containing Nucleic Acid-Based Drugs. Nat. Nanotechnol. 2019, 14, 1084–1087.
  11. Thacker, P.D. COVID-19: Researcher Blows the Whistle on Data Integrity Issues in Pfizer’s Vaccine Trial. BMJ 2021, 375, n2635.
  12. Ogata, A.F.; Cheng, C.-A.; Desjardins, M.; Senussi, Y.; Sherman, A.C.; Powell, M.; Novack, L.; Von, S.; Li, X.; Baden, L.R.; et al. Circulating Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Vaccine Antigen Detected in the Plasma of MRNA-1273 Vaccine Recipients. Clin. Infect. Dis. 2022, 74, 715–718.
  13. Bansal, S.; Perincheri, S.; Fleming, T.; Poulson, C.; Tiffany, B.; Bremner, R.M.; Mohanakumar, T. Cutting Edge: Circulating Exosomes with COVID Spike Protein Are Induced by BNT162b2 (Pfizer–BioNTech) Vaccination Prior to Development of Antibodies: A Novel Mechanism for Immune Activation by MRNA Vaccines. J. Immunol. 2021, 207, 2405–2410.
  14. Röltgen, K.; Nielsen, S.C.A.; Silva, O.; Younes, S.F.; Zaslavsky, M.; Costales, C.; Yang, F.; Wirz, O.F.; Solis, D.; Hoh, R.A.; et al. Immune Imprinting, Breadth of Variant Recognition, and Germinal Center Response in Human SARS-CoV-2 Infection and Vaccination. Cell 2022, 185, 1025–1040.e14.
  15. Spike Protein Behavior. Available online: https://www.science.org/content/blog-post/spike-protein-behavior (accessed on 1 October 2022).
  16. Schlake, T.; Thess, A.; Fotin-Mleczek, M.; Kallen, K.-J. Developing MRNA-Vaccine Technologies. RNA Biol. 2012, 9, 1319–1330.
  17. Shyu, A.-B.; Wilkinson, M.F.; van Hoof, A. Messenger RNA Regulation: To Translate or to Degrade. EMBO J. 2008, 27, 471–481.
  18. Baudrimont, A.; Voegeli, S.; Viloria, E.C.; Stritt, F.; Lenon, M.; Wada, T.; Jaquet, V.; Becskei, A. Multiplexed Gene Control Reveals Rapid MRNA Turnover. Sci. Adv. 2017, 3, e1700006.
  19. Patterson, B.; Francisco, E.; Yogendra, R.; Long, E.; Pise, A.; Beaty, C.; Osgood, E.; Bream, J.; Kreimer, M.; Heide, R.V.; et al. SARS-CoV-2 S1 Protein Persistence in SARS-CoV-2 Negative Post-Vaccination Individuals with Long COVID/PASC-Like Symptoms. Res. Sq. 2022, Preprint.
  20. Patterson, B.K.; Francisco, E.B.; Yogendra, R.; Long, E.; Pise, A.; Rodrigues, H.; Hall, E.; Herrera, M.; Parikh, P.; Guevara-Coto, J.; et al. Persistence of SARS CoV-2 S1 Protein in CD16+ Monocytes in Post-Acute Sequelae of COVID-19 (PASC) up to 15 Months Post-Infection. Front. Immunol. 2022, 12, 5526.
  21. Khan, S.; Shafiei, M.S.; Longoria, C.; Schoggins, J.W.; Savani, R.C.; Zaki, H. SARS-CoV-2 Spike Protein Induces Inflammation via TLR2-Dependent Activation of the NF-ΚB Pathway. Elife 2021, 10, e68563.
  22. Robles, J.P.; Zamora, M.; Adan-Castro, E.; Siqueiros-Marquez, L.; Martinez de la Escalera, G.; Clapp, C. The Spike Protein of SARS-CoV-2 Induces Endothelial Inflammation through Integrin A5β1 and NF-ΚB Signaling. J. Biol. Chem. 2022, 298, 101695.
  23. Banks, W.A.; Sharma, P.; Bullock, K.M.; Hansen, K.M.; Ludwig, N.; Whiteside, T.L. Transport of Extracellular Vesicles across the Blood-Brain Barrier: Brain Pharmacokinetics and Effects of Inflammation. Int. J. Mol. Sci. 2020, 21, 4407.
  24. Chen, Y.Y.; Syed, A.M.; MacMillan, P.; Rocheleau, J.V.; Chan, W.C.W. Flow Rate Affects Nanoparticle Uptake into Endothelial Cells. Adv. Mater. 2020, 32, e1906274.
  25. Buzhdygan, T.P.; DeOre, B.J.; Baldwin-Leclair, A.; Bullock, T.A.; McGary, H.M.; Khan, J.A.; Razmpour, R.; Hale, J.F.; Galie, P.A.; Potula, R.; et al. The SARS-CoV-2 Spike Protein Alters Barrier Function in 2D Static and 3D Microfluidic in-Vitro Models of the Human Blood-Brain Barrier. Neurobiol. Dis. 2020, 146, 105131.
  26. Asandei, A.; Mereuta, L.; Schiopu, I.; Park, J.; Seo, C.H.; Park, Y.; Luchian, T. Non-Receptor-Mediated Lipid Membrane Permeabilization by the SARS-CoV-2 Spike Protein S1 Subunit. ACS Appl. Mater. Interfaces 2020, 12, 55649–55658.
  27. Malhotra, A. Curing the Pandemic of Misinformation on COVID-19 MRNA Vaccines through Real Evidence-Based Medicine—Part 1. J. Insul. Resist. 2022, 5, 8.
  28. Gill, J.R.; Tashjian, R.; Duncanson, E. Autopsy Histopathologic Cardiac Findings in 2 Adolescents Following the Second COVID-19 Vaccine Dose. Arch. Pathol. Lab. Med. 2022, 146, 925–929.
  29. Diaz, G.A.; Parsons, G.T.; Gering, S.K.; Meier, A.R.; Hutchinson, I.V.; Robicsek, A. Myocarditis and Pericarditis After Vaccination for COVID-19. JAMA 2021, 326, 1210–1212.
  30. Karlstad, Ø.; Hovi, P.; Husby, A.; Härkänen, T.; Selmer, R.M.; Pihlström, N.; Hansen, J.V.; Nohynek, H.; Gunnes, N.; Sundström, A.; et al. SARS-CoV-2 Vaccination and Myocarditis in a Nordic Cohort Study of 23 Million Residents. JAMA Cardiol. 2022, 7, 600–612.
  31. Patone, M.; Mei, X.W.; Handunnetthi, L.; Dixon, S.; Zaccardi, F.; Shankar-Hari, M.; Watkinson, P.; Khunti, K.; Harnden, A.; Coupland, C.A.C.; et al. Risks of Myocarditis, Pericarditis, and Cardiac Arrhythmias Associated with COVID-19 Vaccination or SARS-CoV-2 Infection. Nat. Med. 2022, 28, 410–422.
  32. Kracalik, I.; Oster, M.E.; Broder, K.R.; Cortese, M.M.; Glover, M.; Shields, K.; Creech, C.B.; Romanson, B.; Novosad, S.; Soslow, J.; et al. Outcomes at Least 90 Days since Onset of Myocarditis after MRNA COVID-19 Vaccination in Adolescents and Young Adults in the USA: A Follow-up Surveillance Study. Lancet Child Adolesc. Health 2022, 6, 788–798.
  33. Mansanguan, S.; Charunwatthana, P.; Piyaphanee, W.; Dechkhajorn, W.; Poolcharoen, A.; Mansanguan, C. Cardiovascular Manifestation of the BNT162b2 MRNA COVID-19 Vaccine in Adolescents. Trop. Med. Infect. Dis. 2022, 7, 196.
  34. Tai, W.; He, L.; Zhang, X.; Pu, J.; Voronin, D.; Jiang, S.; Zhou, Y.; Du, L. Characterization of the Receptor-Binding Domain (RBD) of 2019 Novel Coronavirus: Implication for Development of RBD Protein as a Viral Attachment Inhibitor and Vaccine. Cell Mol. Immunol. 2020, 17, 613–620.
  35. Jackson, C.B.; Farzan, M.; Chen, B.; Choe, H. Mechanisms of SARS-CoV-2 Entry into Cells. Nat. Rev. Mol. Cell Biol. 2022, 23, 3–20.
  36. Shin, Y.-H.; Jeong, K.; Lee, J.; Lee, H.J.; Yim, J.; Kim, J.; Kim, S.; Park, S.B. Inhibition of ACE2-Spike Interaction by an ACE2 Binder Suppresses SARS-CoV-2 Entry. Angew. Chem. Int. Ed. Engl. 2022, 61, e202115695.
  37. Fertig, T.E.; Chitoiu, L.; Marta, D.S.; Ionescu, V.-S.; Cismasiu, V.B.; Radu, E.; Angheluta, G.; Dobre, M.; Serbanescu, A.; Hinescu, M.E.; et al. Vaccine MRNA Can Be Detected in Blood at 15 Days Post-Vaccination. Biomedicines 2022, 10, 1538.
  38. Bahl, K.; Senn, J.J.; Yuzhakov, O.; Bulychev, A.; Brito, L.A.; Hassett, K.J.; Laska, M.E.; Smith, M.; Almarsson, Ö.; Thompson, J.; et al. Preclinical and Clinical Demonstration of Immunogenicity by MRNA Vaccines against H10N8 and H7N9 Influenza Viruses. Mol. Ther. 2017, 25, 1316–1327.
  39. Hanna, N.; Heffes-Doon, A.; Lin, X.; Manzano De Mejia, C.; Botros, B.; Gurzenda, E.; Nayak, A. Detection of Messenger RNA COVID-19 Vaccines in Human Breast Milk. JAMA Pediatr. 2022, 176, 1268.
  40. Nuovo, G.J.; Magro, C.; Shaffer, T.; Awad, H.; Suster, D.; Mikhail, S.; He, B.; Michaille, J.-J.; Liechty, B.; Tili, E. Endothelial Cell Damage Is the Central Part of COVID-19 and a Mouse Model Induced by Injection of the S1 Subunit of the Spike Protein. Ann. Diagn. Pathol. 2021, 51, 151682.
  41. Raghavan, S.; Kenchappa, D.B.; Leo, M.D. SARS-CoV-2 Spike Protein Induces Degradation of Junctional Proteins That Maintain Endothelial Barrier Integrity. Front. Cardiovasc. Med. 2021, 8, 687783.
  42. Lei, Y.; Zhang, J.; Schiavon, C.R.; He, M.; Chen, L.; Shen, H.; Zhang, Y.; Yin, Q.; Cho, Y.; Andrade, L.; et al. SARS-CoV-2 Spike Protein Impairs Endothelial Function via Downregulation of ACE 2. Circ. Res. 2021, 128, 1323–1326.
  43. Serviente, C.; Matias, A.; Erol, M.E.; Calderone, M.; Layec, G. The Influence of COVID-19-Based MRNA Vaccines on Measures of Conduit Artery and Microvascular Endothelial Function. FASEB J. 2022, 36.
  44. Castanares-Zapatero, D.; Chalon, P.; Kohn, L.; Dauvrin, M.; Detollenaere, J.; Maertens de Noordhout, C.; Primus-de Jong, C.; Cleemput, I.; Van den Heede, K. Pathophysiology and Mechanism of Long COVID: A Comprehensive Review. Ann. Med. 2022, 54, 1473–1487.
  45. Crook, H.; Raza, S.; Nowell, J.; Young, M.; Edison, P. Long Covid-Mechanisms, Risk Factors, and Management. BMJ 2021, 374, n1648.
  46. Xie, Y.; Xu, E.; Bowe, B.; Al-Aly, Z. Long-Term Cardiovascular Outcomes of COVID-19. Nat. Med. 2022, 28, 583–590.
  47. Raman, B.; Bluemke, D.A.; Lüscher, T.F.; Neubauer, S. Long COVID: Post-Acute Sequelae of COVID-19 with a Cardiovascular Focus. Eur. Heart J. 2022, 43, 1157–1172.
  48. Yonker, L.M.; Swank, Z.; Bartsch, Y.C.; Burns, M.D.; Kane, A.; Boribong, B.P.; Davis, J.P.; Loiselle, M.; Novak, T.; Senussi, Y.; et al. Circulating Spike Protein Detected in Post–COVID-19 MRNA Vaccine Myocarditis. Circulation 2023, 147, 867–876.
  49. Zhang, S.; Liu, Y.; Wang, X.; Yang, L.; Li, H.; Wang, Y.; Liu, M.; Zhao, X.; Xie, Y.; Yang, Y.; et al. SARS-CoV-2 Binds Platelet ACE2 to Enhance Thrombosis in COVID-19. J. Hematol. Oncol. 2020, 13, 120.
  50. Grobbelaar, L.M.; Venter, C.; Vlok, M.; Ngoepe, M.; Laubscher, G.J.; Lourens, P.J.; Steenkamp, J.; Kell, D.B.; Pretorius, E. SARS-CoV-2 Spike Protein S1 Induces Fibrin(Ogen) Resistant to Fibrinolysis: Implications for Microclot Formation in COVID-19. Biosci. Rep. 2021, 41, BSR20210611.
  51. Nyström, S.; Hammarström, P. Amyloidogenesis of SARS-CoV-2 Spike Protein. J. Am. Chem. Soc. 2022, 144, 8945–8950.
  52. Montgomery, J.; Ryan, M.; Engler, R.; Hoffman, D.; McClenathan, B.; Collins, L.; Loran, D.; Hrncir, D.; Herring, K.; Platzer, M.; et al. Myocarditis Following Immunization With MRNA COVID-19 Vaccines in Members of the US Military. JAMA Cardiol. 2021, 6, 1202–1206.
  53. Dennis, A.; Cuthbertson, D.J.; Wootton, D.; Crooks, M.; Gabbay, M.; Eichert, N.; Mouchti, S.; Pansini, M.; Roca-Fernandez, A.; Thomaides-Brears, H.; et al. Multi-Organ Impairment and Long COVID: A 1-Year Prospective, Longitudinal Cohort Study. J. R. Soc. Med. 2023, 116, 97–112.
  54. Mustafa Alhussein, M.; Rabbani, M.; Sarak, B.; Dykstra, S.; Labib, D.; Flewitt, J.; Lydell, C.P.; Howarth, A.G.; Filipchuck, N.; Kealey, A.; et al. Natural History of Myocardial Injury After COVID-19 Vaccine–Associated Myocarditis. Can. J. Cardiol. 2022, 38, 1676–1683.
  55. Abbott, M.G.; Allawi, Z.; Hofer, M.; Ansorge, O.; Brady, S.; Fadic, R.; Torres, G.; Knight, R.; Calvo, M.; Bennett, D.L.H.; et al. Acute Small Fiber Neuropathy after Oxford-AstraZeneca ChAdOx1-S Vaccination: A Report of Three Cases and Review of the Literature. J. Peripher. Nerv. Syst. 2022, 27, 325–329.
  56. Khokhar, F.; Khan, A.; Hussain, Z.; Yu, J. Small Fiber Neuropathy Associated With the Moderna SARS-CoV-2 Vaccine. Cureus 2022, 14, e25969.
  57. Frontera, J.A.; Tamborska, A.A.; Doheim, M.F.; Garcia-Azorin, D.; Gezegen, H.; Guekht, A.; Yusof Khan, A.H.K.; Santacatterina, M.; Sejvar, J.; Thakur, K.T.; et al. Neurological Events Reported after COVID-19 Vaccines: An Analysis of Vaccine Adverse Event Reporting System. Ann. Neurol. 2022, 91, 756–771.
  58. Ayoubkhani, D.; Bermingham, C.; Pouwels, K.B.; Glickman, M.; Nafilyan, V.; Zaccardi, F.; Khunti, K.; Alwan, N.A.; Walker, A.S. Trajectory of Long Covid Symptoms after COVID-19 Vaccination: Community Based Cohort Study. BMJ 2022, 377, e069676.
  59. Schwab, C.; Domke, L.M.; Hartmann, L.; Stenzinger, A.; Longerich, T.; Schirmacher, P. Autopsy-Based Histopathological Characterization of Myocarditis after Anti-SARS-CoV-2-Vaccination. Clin. Res. Cardiol. 2023, 112, 431–440.
  60. Rosenblum, H.G.; Gee, J.; Liu, R.; Marquez, P.L.; Zhang, B.; Strid, P.; Abara, W.E.; McNeil, M.M.; Myers, T.R.; Hause, A.M.; et al. Safety of MRNA Vaccines Administered during the Initial 6 Months of the US COVID-19 Vaccination Programme: An Observational Study of Reports to the Vaccine Adverse Event Reporting System and v-Safe. Lancet Infect. Dis. 2022, 22, 802–812.
  61. Dickerman, B.A.; Madenci, A.L.; Gerlovin, H.; Kurgansky, K.E.; Wise, J.K.; Figueroa Muñiz, M.J.; Ferolito, B.R.; Gagnon, D.R.; Gaziano, J.M.; Cho, K.; et al. Comparative Safety of BNT162b2 and MRNA-1273 Vaccines in a Nationwide Cohort of US Veterans. JAMA Intern. Med. 2022, 182, 739–746.
  62. Iddir, M.; Brito, A.; Dingeo, G.; Fernandez Del Campo, S.S.; Samouda, H.; La Frano, M.R.; Bohn, T. Strengthening the Immune System and Reducing Inflammation and Oxidative Stress through Diet and Nutrition: Considerations during the COVID-19 Crisis. Nutrients 2020, 12, 1562.
  63. Nakeshbandi, M.; Maini, R.; Daniel, P.; Rosengarten, S.; Parmar, P.; Wilson, C.; Kim, J.M.; Oommen, A.; Mecklenburg, M.; Salvani, J.; et al. The Impact of Obesity on COVID-19 Complications: A Retrospective Cohort Study. Int. J. Obes. 2020, 44, 1832–1837.
  64. Apicella, M.; Campopiano, M.C.; Mantuano, M.; Mazoni, L.; Coppelli, A.; Del Prato, S. COVID-19 in People with Diabetes: Understanding the Reasons for Worse Outcomes. Lancet Diabetes Endocrinol. 2020, 8, 782–792.
  65. Logette, E.; Lorin, C.; Favreau, C.; Oshurko, E.; Coggan, J.S.; Casalegno, F.; Sy, M.F.; Monney, C.; Bertschy, M.; Delattre, E.; et al. A Machine-Generated View of the Role of Blood Glucose Levels in the Severity of COVID-19. Front. Public Health 2021, 9, 695139.
  66. Holt, E.M.; Steffen, L.M.; Moran, A.; Basu, S.; Steinberger, J.; Ross, J.A.; Hong, C.-P.; Sinaiko, A.R. Fruit and Vegetable Consumption and Its Relation to Markers of Inflammation and Oxidative Stress in Adolescents. J. Am. Diet. Assoc. 2009, 109, 414–421.
  67. Cheng, Y.-C.; Sheen, J.-M.; Hu, W.L.; Hung, Y.-C. Polyphenols and Oxidative Stress in Atherosclerosis-Related Ischemic Heart Disease and Stroke. Oxidative Med. Cell. Longev. 2017, 2017, 8526438.
  68. Serino, A.; Salazar, G. Protective Role of Polyphenols against Vascular Inflammation, Aging and Cardiovascular Disease. Nutrients 2018, 11, 53.
  69. Belkaid, Y.; Hand, T.W. Role of the Microbiota in Immunity and Inflammation. Cell 2014, 157, 121–141.
  70. Yeoh, Y.K.; Zuo, T.; Lui, G.C.-Y.; Zhang, F.; Liu, Q.; Li, A.Y.; Chung, A.C.; Cheung, C.P.; Tso, E.Y.; Fung, K.S.; et al. Gut Microbiota Composition Reflects Disease Severity and Dysfunctional Immune Responses in Patients with COVID-19. Gut 2021, 70, 698–706.
  71. Zuo, T.; Liu, Q.; Zhang, F.; Lui, G.; Tso, E.; Yeoh, Y.K.; Chen, Z.; Boon, S.; Chan, F.K.L.; Chan, P.; et al. Depicting SARS-CoV-2 Faecal Viral Activity in Association with Gut Microbiota Composition in Patients with COVID-19. Gut 2021, 70, 276–284.
  72. Ferreira, C.; Viana, S.D.; Reis, F. Gut Microbiota Dysbiosis–Immune Hyperresponse–Inflammation Triad in Coronavirus Disease 2019 (COVID-19): Impact of Pharmacological and Nutraceutical Approaches. Microorganisms 2020, 8, 1514.
  73. Wang, C.; van Haperen, R.; Gutiérrez-Álvarez, J.; Li, W.; Okba, N.M.A.; Albulescu, I.; Widjaja, I.; van Dieren, B.; Fernandez-Delgado, R.; Sola, I.; et al. A Conserved Immunogenic and Vulnerable Site on the Coronavirus Spike Protein Delineated by Cross-Reactive Monoclonal Antibodies. Nat. Commun. 2021, 12, 1715.
  74. Li, F. Structure, Function, and Evolution of Coronavirus Spike Proteins. Annu. Rev. Virol. 2016, 3, 237–261.
  75. Pollard, T.D. A Guide to Simple and Informative Binding Assays. Mol. Biol. Cell 2010, 21, 4061–4067.
  76. Baer, A.; Kehn-Hall, K. Viral Concentration Determination Through Plaque Assays: Using Traditional and Novel Overlay Systems. J. Vis. Exp. 2014, 52065.
  77. Puren, A.; Gerlach, J.L.; Weigl, B.H.; Kelso, D.M.; Domingo, G.J. Laboratory Operations, Specimen Processing, and Handling for Viral Load Testing and Surveillance. J. Infect. Dis. 2010, 201 (Suppl. 1), S27–S36.
  78. Gillette, J.R. Problems in Correlating InVitro and InVivo Studies of Drug Metabolism. In Pharmacokinetics: A Modern View; Benet, L.Z., Levy, G., Ferraiolo, B.L., Eds.; Springer: Boston, MA, USA, 1984; pp. 235–252. ISBN 978-1-4613-2799-8.
  79. Faraoni, D.; Schaefer, S.T. Randomized Controlled Trials vs. Observational Studies: Why Not Just Live Together? BMC Anesth. 2016, 16, 102.
  80. De, R.; Dutta, S. Role of the Microbiome in the Pathogenesis of COVID-19. Front. Cell Infect. Microbiol. 2022, 12, 736397.
  81. Ramakrishnan, R.K.; Kashour, T.; Hamid, Q.; Halwani, R.; Tleyjeh, I.M. Unraveling the Mystery Surrounding Post-Acute Sequelae of COVID-19. Front. Immunol. 2021, 12, 686029.
  82. Haran, J.P.; Bradley, E.; Zeamer, A.L.; Cincotta, L.; Salive, M.-C.; Dutta, P.; Mutaawe, S.; Anya, O.; Meza-Segura, M.; Moormann, A.M.; et al. Inflammation-Type Dysbiosis of the Oral Microbiome Associates with the Duration of COVID-19 Symptoms and Long COVID. JCI Insight 2021, 6, e152346.
  83. Proal, A.D.; VanElzakker, M.B. Long COVID or Post-Acute Sequelae of COVID-19 (PASC): An Overview of Biological Factors That May Contribute to Persistent Symptoms. Front. Microbiol. 2021, 12, 698169.
  84. Hazan, S.; Stollman, N.; Bozkurt, H.S.; Dave, S.; Papoutsis, A.J.; Daniels, J.; Barrows, B.D.; Quigley, E.M.; Borody, T.J. Lost Microbes of COVID-19: Bifidobacterium, Faecalibacterium Depletion and Decreased Microbiome Diversity Associated with SARS-CoV-2 Infection Severity. BMJ Open Gastroenterol. 2022, 9, e000871.
  85. Gutiérrez-Castrellón, P.; Gandara-Martí, T.; Abreu Y Abreu, A.T.; Nieto-Rufino, C.D.; López-Orduña, E.; Jiménez-Escobar, I.; Jiménez-Gutiérrez, C.; López-Velazquez, G.; Espadaler-Mazo, J. Probiotic Improves Symptomatic and Viral Clearance in Covid19 Outpatients: A Randomized, Quadruple-Blinded, Placebo-Controlled Trial. Gut Microbes 2022, 14, 2018899.
  86. Chen, Y.; Gu, S.; Chen, Y.; Lu, H.; Shi, D.; Guo, J.; Wu, W.-R.; Yang, Y.; Li, Y.; Xu, K.-J.; et al. Six-Month Follow-up of Gut Microbiota Richness in Patients with COVID-19. Gut 2022, 71, 222–225.
  87. Zuo, T.; Wu, X.; Wen, W.; Lan, P. Gut Microbiome Alterations in COVID-19. Genom. Proteom. Bioinform. 2021, 19, 679–688.
  88. Hibino, S.; Hayashida, K. Modifiable Host Factors for the Prevention and Treatment of COVID-19: Diet and Lifestyle/Diet and Lifestyle Factors in the Prevention of COVID-19. Nutrients 2022, 14, 1876.
  89. Losso, J.N.; Losso, M.N.; Toc, M.; Inungu, J.N.; Finley, J.W. The Young Age and Plant-Based Diet Hypothesis for Low SARS-CoV-2 Infection and COVID-19 Pandemic in Sub-Saharan Africa. Plant Foods Hum. Nutr. 2021, 76, 270–280.
  90. Brown, R.B. Low Dietary Sodium Potentially Mediates COVID-19 Prevention Associated with Whole-Food Plant-Based Diets. Br. J. Nutr. 2022, 129, 1136–1141.
  91. Kim, H.; Rebholz, C.M.; Hegde, S.; LaFiura, C.; Raghavan, M.; Lloyd, J.F.; Cheng, S.; Seidelmann, S.B. Plant-Based Diets, Pescatarian Diets and COVID-19 Severity: A Population-Based Case–Control Study in Six Countries. BMJ Nutr. Prev. Health 2021, 4, 257–266.
  92. Benton, D.; Williams, C.; Brown, A. Impact of Consuming a Milk Drink Containing a Probiotic on Mood and Cognition. Eur. J. Clin. Nutr. 2007, 61, 355–361.
  93. de Falco, B.; Amato, M.; Lanzotti, V. Chia Seeds Products: An Overview. Phytochem. Rev. 2017, 16, 745–760.
  94. Mao, Y.-H.; Xu, Y.; Song, F.; Wang, Z.-M.; Li, Y.-H.; Zhao, M.; He, F.; Tian, Z.; Yang, Y. Protective Effects of Konjac Glucomannan on Gut Microbiome with Antibiotic Perturbation in Mice. Carbohydr. Polym. 2022, 290, 119476.
  95. Zhang, Y.; Zhao, Y.; Yang, W.; Song, G.; Zhong, P.; Ren, Y.; Zhong, G. Structural Complexity of Konjac Glucomannan and Its Derivatives Governs the Diversity and Outputs of Gut Microbiota. Carbohydr. Polym. 2022, 292, 119639.
  96. Thomas, R.; Aldous, J.; Forsyth, R.; Chater, A.; Williams, M. The Influence of a Blend of Probiotic Lactobacillus and Prebiotic Inulin on the Duration and Severity of Symptoms among Individuals with COVID-19. Infect. Dis. Diagn. Treat. 2021, 5, 1–12.
  97. Rossi, G.A.; Sacco, O.; Mancino, E.; Cristiani, L.; Midulla, F. Differences and Similarities between SARS-CoV and SARS-CoV-2: Spike Receptor-Binding Domain Recognition and Host Cell Infection with Support of Cellular Serine Proteases. Infection 2020, 48, 665–669.
  98. Petersen, E.; Koopmans, M.; Go, U.; Hamer, D.H.; Petrosillo, N.; Castelli, F.; Storgaard, M.; Khalili, S.A.; Simonsen, L. Comparing SARS-CoV-2 with SARS-CoV and Influenza Pandemics. Lancet Infect. Dis. 2020, 20, e238–e244.
  99. Mykytyn, A.Z.; Breugem, T.I.; Riesebosch, S.; Schipper, D.; van den Doel, P.B.; Rottier, R.J.; Lamers, M.M.; Haagmans, B.L. SARS-CoV-2 Entry into Human Airway Organoids Is Serine Protease-Mediated and Facilitated by the Multibasic Cleavage Site. eLife 2021, 10, e64508.
  100. Hoffmann, M.; Kleine-Weber, H.; Pöhlmann, S. A Multibasic Cleavage Site in the Spike Protein of SARS-CoV-2 Is Essential for Infection of Human Lung Cells. Mol. Cell 2020, 78, 779–784.e5.
  101. Coutard, B.; Valle, C.; de Lamballerie, X.; Canard, B.; Seidah, N.G.; Decroly, E. The Spike Glycoprotein of the New Coronavirus 2019-NCoV Contains a Furin-like Cleavage Site Absent in CoV of the Same Clade. Antivir. Res. 2020, 176, 104742.
  102. Hoffmann, M.; Kleine-Weber, H.; Schroeder, S.; Krüger, N.; Herrler, T.; Erichsen, S.; Schiergens, T.S.; Herrler, G.; Wu, N.-H.; Nitsche, A.; et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell 2020, 181, 271–280.e8.
  103. Hansen, T.; Titze, U.; Kulamadayil-Heidenreich, N.S.A.; Glombitza, S.; Tebbe, J.J.; Röcken, C.; Schulz, B.; Weise, M.; Wilkens, L. First Case of Postmortem Study in a Patient Vaccinated against SARS-CoV-2. Int. J. Infect. Dis. 2021, 107, 172–175.
  104. Polack, F.P.; Thomas, S.J.; Kitchin, N.; Absalon, J.; Gurtman, A.; Lockhart, S.; Perez, J.L.; Pérez Marc, G.; Moreira, E.D.; Zerbini, C.; et al. Safety and Efficacy of the BNT162b2 MRNA COVID-19 Vaccine. N. Engl. J. Med. 2020, 383, 2603–2615.
  105. Corbett, K.S.; Flynn, B.; Foulds, K.E.; Francica, J.R.; Boyoglu-Barnum, S.; Werner, A.P.; Flach, B.; O’Connell, S.; Bock, K.W.; Minai, M.; et al. Evaluation of the MRNA-1273 Vaccine against SARS-CoV-2 in Nonhuman Primates. N. Engl. J. Med. 2020, 383, 1544–1555.
  106. Bos, R.; Rutten, L.; van der Lubbe, J.E.M.; Bakkers, M.J.G.; Hardenberg, G.; Wegmann, F.; Zuijdgeest, D.; de Wilde, A.H.; Koornneef, A.; Verwilligen, A.; et al. Ad26 Vector-Based COVID-19 Vaccine Encoding a Prefusion-Stabilized SARS-CoV-2 Spike Immunogen Induces Potent Humoral and Cellular Immune Responses. Npj Vaccines 2020, 5, 91.
  107. Bangaru, S.; Ozorowski, G.; Turner, H.L.; Antanasijevic, A.; Huang, D.; Wang, X.; Torres, J.L.; Diedrich, J.K.; Tian, J.-H.; Portnoff, A.D.; et al. Structural Analysis of Full-Length SARS-CoV-2 Spike Protein from an Advanced Vaccine Candidate. Science 2020, 370, 1089–1094.
  108. Pallesen, J.; Wang, N.; Corbett, K.S.; Wrapp, D.; Kirchdoerfer, R.N.; Turner, H.L.; Cottrell, C.A.; Becker, M.M.; Wang, L.; Shi, W.; et al. Immunogenicity and Structures of a Rationally Designed Prefusion MERS-CoV Spike Antigen. Proc. Natl. Acad. Sci. USA 2017, 114, E7348–E7357.
  109. Watanabe, Y.; Mendonça, L.; Allen, E.R.; Howe, A.; Lee, M.; Allen, J.D.; Chawla, H.; Pulido, D.; Donnellan, F.; Davies, H.; et al. Native-like SARS-CoV-2 Spike Glycoprotein Expressed by ChAdOx1 NCoV-19/AZD1222 Vaccine. ACS Cent. Sci. 2021, 7, 594–602.
  110. Gao, Q.; Bao, L.; Mao, H.; Wang, L.; Xu, K.; Yang, M.; Li, Y.; Zhu, L.; Wang, N.; Lv, Z.; et al. Development of an Inactivated Vaccine Candidate for SARS-CoV-2. Science 2020, 369, 77–81.
  111. Lu, M.; Chamblee, M.; Zhang, Y.; Ye, C.; Dravid, P.; Park, J.-G.; Mahesh, K.; Trivedi, S.; Murthy, S.; Sharma, H.; et al. SARS-CoV-2 Prefusion Spike Protein Stabilized by Six Rather than Two Prolines Is More Potent for Inducing Antibodies That Neutralize Viral Variants of Concern. Proc. Natl. Acad. Sci. USA 2022, 119, e2110105119.
  112. Amanat, F.; Strohmeier, S.; Rathnasinghe, R.; Schotsaert, M.; Coughlan, L.; García-Sastre, A.; Krammer, F. Introduction of Two Prolines and Removal of the Polybasic Cleavage Site Lead to Higher Efficacy of a Recombinant Spike-Based SARS-CoV-2 Vaccine in the Mouse Model. mBio 2021, 12, e02648-20.
  113. Longo, V.D.; Mattson, M.P. Fasting: Molecular Mechanisms and Clinical Applications. Cell Metab. 2014, 19, 181–192.
  114. Bagherniya, M.; Butler, A.E.; Barreto, G.E.; Sahebkar, A. The Effect of Fasting or Calorie Restriction on Autophagy Induction: A Review of the Literature. Ageing Res. Rev. 2018, 47, 183–197.
  115. Brandhorst, S.; Longo, V.D. Protein Quantity and Source, Fasting-Mimicking Diets, and Longevity. Adv. Nutr. 2019, 10, S340–S350.
  116. Shuvayeva, G.; Bobak, Y.; Igumentseva, N.; Titone, R.; Morani, F.; Stasyk, O.; Isidoro, C. Single Amino Acid Arginine Deprivation Triggers Prosurvival Autophagic Response in Ovarian Carcinoma SKOV3. Biomed. Res. Int. 2014, 2014, 505041.
  117. Horne, B.D.; May, H.T.; Muhlestein, J.B.; Le, V.T.; Bair, T.L.; Knowlton, K.U.; Anderson, J.L. Association of Periodic Fasting with Lower Severity of COVID-19 Outcomes in the SARS-CoV-2 Prevaccine Era: An Observational Cohort from the INSPIRE Registry. BMJ Nutr. Prev. Health 2022, 5, 145–153.
  118. Mojtabavi, H.; Saghazadeh, A.; Rezaei, N. Interleukin-6 and Severe COVID-19: A Systematic Review and Meta-Analysis. Eur. Cytokine Netw. 2020, 31, 44–49.
  119. Kell, D.B.; Laubscher, G.J.; Pretorius, E. A Central Role for Amyloid Fibrin Microclots in Long COVID/PASC: Origins and Therapeutic Implications. Biochem. J. 2022, 479, 537–559.
  120. Pretorius, E.; Vlok, M.; Venter, C.; Bezuidenhout, J.A.; Laubscher, G.J.; Steenkamp, J.; Kell, D.B. Persistent Clotting Protein Pathology in Long COVID/Post-Acute Sequelae of COVID-19 (PASC) Is Accompanied by Increased Levels of Antiplasmin. Cardiovasc. Diabetol. 2021, 20, 172.
  121. Pretorius, E.; Venter, C.; Laubscher, G.J.; Kotze, M.J.; Oladejo, S.O.; Watson, L.R.; Rajaratnam, K.; Watson, B.W.; Kell, D.B. Prevalence of Symptoms, Comorbidities, Fibrin Amyloid Microclots and Platelet Pathology in Individuals with Long COVID/Post-Acute Sequelae of COVID-19 (PASC). Cardiovasc. Diabetol. 2022, 21, 148.
  122. Chang, J.C.; Hawley, H.B. Vaccine-Associated Thrombocytopenia and Thrombosis: Venous Endotheliopathy Leading to Venous Combined Micro-Macrothrombosis. Medicina 2021, 57, 1163.
  123. Mainous, A.G.; Rooks, B.J.; Orlando, F.A. The Impact of Initial COVID-19 Episode Inflammation Among Adults on Mortality Within 12 Months Post-Hospital Discharge. Front. Med. 2022, 9, 891375.
  124. Aydınyılmaz, F.; Aksakal, E.; Pamukcu, H.E.; Aydemir, S.; Doğan, R.; Saraç, İ.; Aydın, S.Ş.; Kalkan, K.; Gülcü, O.; Tanboğa, İ.H. Significance of MPV, RDW and PDW with the Severity and Mortality of COVID-19 and Effects of Acetylsalicylic Acid Use. Clin. Appl. Thromb. Hemost. 2021, 27, 10760296211048808.
  125. Bianconi, V.; Violi, F.; Fallarino, F.; Pignatelli, P.; Sahebkar, A.; Pirro, M. Is Acetylsalicylic Acid a Safe and Potentially Useful Choice for Adult Patients with COVID-19 ? Drugs 2020, 80, 1383–1396.
  126. Clissold, S.P. Aspirin and Related Derivatives of Salicylic Acid. Drugs 1986, 32, 8–26.
  127. Storstein, O.; Nitter-Hauge, S.; Enge, I. Thromboembolic Complications in Coronary Angiography: Prevention with Acetyl-Salicylic Acid. Acta Radiol. Diagn. 1977, 18, 555–560.
  128. Østerud, B.; Brox, J.H. The Clotting Time of Whole Blood in Plastic Tubes: The Influence of Exercise, Prostacyclin and Acetylsalicylic Acid. Thromb. Res. 1983, 29, 425–435.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Infectious Diseases
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Matthew T. J. Halma
,
Christof Plothe
,
Paul Marik
,
Theresa A. Lawrie
View Times: 598
Entry Collection: COVID-19
Revisions: 2 times (View History)
Update Date: 26 Jul 2023
Table of Contents
    1000/1000
    Hot Most Recent
    ScholarVision Creations
    Feedback