last update 4 sept 2022
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[VAX INEFFECTIVITY]
[MYOCARDITIS RISK]
[ADE - Antibody-dependent enhancement]
[OAS - Original antigenic sin]
[ADCC - Antibody-dependent cellular cytotoxicity]
[SPIKE PROTEIN - Antibody escape]
[SPIKE PROTEIN - TOXICITY and ACE2 infectivity]
[DIFFERENCES BETWEEN VACCINE SPIKES and VIRUS SPIKES]
[EVOLUTIONARY PRESSURE LEADS TO MORE VIRULENT VARIANTS]
[CANCER - p53-blocking mechanism]
[PRION DISEASES - ALZHEIMER]
[AMYLOIDOSIS - ALZHEIMER]
[VIRAL and VACCINE SHEDDING]
[CELLULLAR SENESCENCE]
[INFERTILITY - placenta, testes, pregnancy, miscarriage, menstrual problems]
[LIPID NANOPARTICLES]
[NEVER STOPS REPLICATING - DNA reverse transcriptase, 3utr 5utr shenanigans]
[OTHERS]
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[VAX INEFFECTIVITY]
[CONTEXT]
mRNA vaccines provide a fast waning immunity (around four months).
mRNA vaccines produce no monoclonal protection.
Imperfect vaccination can enhance the transmission of highly virulent pathogens.
Non neutralizing antibodies put evolutionary pressure on the pathogen towards antibody escape.
An imperfect vaccination strategy can lead to ADE (Antibody-dependent enhancement - antibodies INCREASE the infection), OAS (Original Antigenic Sin - the immune system will still produce the "old" antibodies against a new variant).
Booster strategy is USELESS in the long run (through ADE, OAS or other).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4516275
Imperfect Vaccination Can Enhance the Transmission of Highly Virulent Pathogens [2015]
Read et al
[2021]
vaccine-elicited memory immune response do not produce neutralizing antibodies
https://www.biorxiv.org/content/10.1101/2021.07.29.454333v1
Antibody Evolution after SARS-CoV-2 mRNA Vaccination
Cho et al
memory B cell evolution differs in important ways between infection and mRNA vaccination.
Both natural infection and mRNA vaccination produce memory antibodies that evolve increased affinity, but the increase in affinity is more modest after vaccination
This difference is consistent with the observation that vaccine-elicited memory antibodies fail to show the increased neutralizing breadth that developed after natural infection
[2022]
vax produces no monoclonal protection:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185186/
SARS-CoV-2 mRNA vaccination induces functionally diverse antibodies to NTD, RBD, and S2
Amanat et al
vax has a waning protective effect:
https://cris.tau.ac.il/en/publications/waning-of-sars-cov-2-booster-viral-load-reduction-effectiveness
Waning of SARS-CoV-2 booster viral-load reduction effectiveness
Matan Levine-Tiefenbrun et al
becomes small and insignificant in the third to fourth months.
https://pubmed.ncbi.nlm.nih.gov/35442459/
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2791312
Rates of COVID-19 Among Unvaccinated Adults With Prior COVID-19
Ridgway et al
between october 2020 and november 2021
natural immunity was associated with similar protection against mild and severe disease. mRNA vaccines are associated with similar prolonged protection from severe COVID-19 as found in our study, although vaccine-associated protection from mild COVID-19 has been shown to wane at 6 months
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(22)00089-7/fulltext
Risk of infection, hospitalisation, and death up to 9 months after a second dose of COVID-19 vaccine: a retrospective, total population cohort study in Sweden
Nordström et al
We found progressively waning vaccine effectiveness against SARS-CoV-2 infection of any severity across all subgroups, but the rate of waning differed according to vaccine type.
https://www.medrxiv.org/content/10.1101/2021.12.30.21268565v1.full.pdf
Effectiveness of COVID-19 vaccines against Omicron or Delta infection
Buchan et al
Two doses of COVID-19 vaccines are unlikely to protect against infection by Omicron. A third dose provides some protection in the immediate term, but substantially less than against Delta.
https://pubmed.ncbi.nlm.nih.gov/34915551/
Neutralization of SARS-CoV-2 Omicron variant by sera from BNT162b2 or Coronavac vaccine recipients
Lu et al
Omicron variant escapes neutralizing antibodies elicited by BNT162b2 or Coronavac.
https://www.biorxiv.org/content/10.1101/2022.02.03.479037v1
mRNA-1273 or mRNA-Omicron boost in vaccinated macaques elicits comparable B cell expansion, neutralizing antibodies and protection against Omicron
Gagne et al
Therefore, an Omicron boost may not provide greater immunity or protection compared to a boost with the current mRNA-1273 vaccine.
PFIZER STUDY that acknowledges the lower effectiveness of their vaccine against Omicron:
Effectiveness of mRNA-1273 against SARS-CoV-2 omicron and delta variants
Tseng et al
Our findings demonstrate high, durable 3-dose VE against delta infection but lower effectiveness against omicron infection, particularly among immunocompromised people.
mRNA vaccines have no effect on mortality:
https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4072489
Randomised Clinical Trials of COVID-19 Vaccines: Do Adenovirus-Vector Vaccines Have Beneficial Non-Specific Effects?
Ben et al
Randomized trials show all-cause mortality reduction from the AZ/J&J/S adenovirus-vector vaccines (RR=0.37, 95%CI:0.19-0.70) but not from the Pfizer/Moderna mRNA vaccines (RR=1.03, 95%CI 0.63-1.71).
Why aren't the vaccines effective? because they do not create non-neutralizing antibodies:
https://pubmed.ncbi.nlm.nih.gov/33758878/
The plasmablast response to SARS-CoV-2 mRNA vaccination is dominated by non-neutralizing antibodies and targets both the NTD and the RBD
Fatima Amanat et al
Polyclonal antibody responses in vaccinees were robust
However [..] at the monoclonal level, we found that the majority of vaccine-induced antibodies did not have neutralizing activity
Why aren't the vaccines effective? because they do not create non-neutralizing antibodies:
https://www.medrxiv.org/content/10.1101/2022.01.03.21268582v1
Mapping the antigenic diversification of SARS-CoV-2
van der Straten et al
we studied SARS-CoV-2 antigenic drift by assessing neutralizing activity against variants-of-concern (VOCs) of a unique set of sera from patients infected with a range of VOCs. Infections with ancestral or Alpha strains induced the broadest immunity, while individuals infected with other VOCs had more strain-specific responses. Omicron was substantially resistant to neutralization by sera elicited by all other variants.
Antigenic cartography revealed that all VOCs preceding Omicron belong to one antigenic cluster, while Omicron forms a new antigenic cluster associated with immune escape and likely requiring vaccine updates to ensure vaccine effectiveness.
Meanwhile natural immunity appears to be effective:
Persistence of neutralizing antibodies a year afterSARS-CoV-2 infection in humans
Haveri et al.
https://www.medrxiv.org/content/10.1101/2021.10.27.21265574v1
Boosting of Cross-Reactive Antibodies to Endemic Coronaviruses by SARS-CoV-2 Infection but not Vaccination with Stabilized Spike
Crowley et al
In this observational study of mucosal and systemic humoral immunity in acutely infected, convalescent, and vaccinated subjects, we tested for cross reactivity against endemic CoV spike (S) protein at subdomain resolution.
In contrast, vaccination with a stabilized spike mRNA vaccine did not robustly boost cross-reactive antibodies, suggesting differing antigenicity and immunogenicity.
https://www.medrxiv.org/content/10.1101/2021.10.30.21265693v1
Vaccine-induced humoral and cellular immunity against SARS-CoV-2 at 6 months post BNT162b2 vaccination
Kato et al
the levels of vaccine-induced antibodies dramatically declined at 6 months after vaccination
Spike Protein IgG titer was negatively correlated with age and alcohol consumption.
the only plan is to keep boosting:
https://www.medrxiv.org/content/10.1101/2022.02.01.22270232v1
Protection by 4th dose of BNT162b2 against Omicron in Israel
Bar-On et al
or approving drugs like PAXLOVID, MOLNUPIRAVID or REMDESIVIR with NO FINISHED STUDY ABOUT THEIR EFFECTIVENESS
https://www.ema.europa.eu/en/news/ema-issues-advice-use-paxlovid-pf-07321332-ritonavir-treatment-covid-19-rolling-review-starts
https://www.ema.europa.eu/en/documents/referral/paxlovid-pf-07321332-ritonavir-covid-19-article-53-procedure-assessment-report_en.pdf
Phase 1 studies 1012, 1013 and Phase 2/3 studies 1002 and 1006 are ongoing. An update of PK data from these studies will have to be presented at the time of the MAA.
Additional information is planned to be collected from studies performed in adult patients as presented in table 11 with three pivotal Phase 2/3 studies, with one completed, Study 1005 and two ongoing Studies 1002 and 1006.
Is the sequence of exposure(s) important? Vaccination thus had a negative effect on the formation of anti-N antibody:
https://www.medrxiv.org/content/10.1101/2022.04.18.22271936v1.full
Anti-nucleocapsid antibodies following SARS-CoV-2 infection in the blinded phase of the mRNA-1273 Covid-19 vaccine efficacy clinical trial
Follman et al
anti-N Abs may have lower sensitivity in mRNA-1273-vaccinated persons who become infected
double vax > infection > 40% anti-N
placebo > infection > 93% anti-N
infection > placebo > 95% anti-N
infection-> double vax -> 96% anti-N
Sub-cutaneous vax produces the same level of IgG than mRNA vaxes. No need for mRNA at all?
https://www.sciencedirect.com/science/article/pii/S0264410X21010100
Sub-cutaneous Pfizer/BioNTech COVID-19 vaccine administration results in seroconversion among young adults
Friedensohn et al
Subcutaneous injection of the BNT162b2 vaccine resulted in 98.2% seroconversion.
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[MYOCARDITIS RISK]
[CONTEXT]
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3370379/
Myocarditis
Uwe Kühl and Heinz-Peter Schultheiss
Non-fulminant active myocarditis has a mortality rate of 25% to 56% within 3 to 10 years, owing to progressive heart failure and sudden cardiac death, especially if symptomatic heart failure manifests early on (9– 11, e1).
[2020]
https://www.biorxiv.org/content/10.1101/2020.12.21.423721v1
The SARS-CoV-2 spike protein disrupts the cooperative function of human cardiac pericytes - endothelial cells through CD147 receptor-mediated signalling: a potential non-infective mechanism of COVID-19 microvascular disease
Avoilio et al
This paper from July 2020 says that between 7 and 23% of COVID patients get myocarditis.
https://www.sciencedirect.com/science/article/pii/S2589790X20300640
COVID-19 and Myocarditis: What Do We Know So Far?
Pirzada et al
0.7 in ~3000 for subclincal (they were picked up on mass testing). Which would translate into 1 in ~20,000 or so clinical.
[2021]
Preliminary Evidence on Long SARS-2 in children
https://www.medrxiv.org/content/10.1101/2021.01.23.21250375v1.full.pdf
Buonsenso et al
129 children diagnosed with COVID-19 between March and November, 2020 were enrolled (mean age of 11 ± 4.4 years, 62 (48.1%) female). Subsequently, three developed Multisystem Inflammaory Syndrome (2.3%) and two myocarditis (1.6%).
https://jamanetwork.com/journals/jamacardiology/fullarticle/2772399
Coronavirus Disease 2019 and the Athletic Heart Emerging Perspectives on Pathology, Risks, and Return to Play
Kim et al
Emerging observational data coupled with widely publicized reports of athletes in competitive sports with reported COVID-19–associated cardiac pathology suggest that myocardial injury may occur in cases of COVID-19 that are asymptomatic and of mild severity
So that's where the bruises come from:
https://www.medrxiv.org/content/10.1101/2021.05.31.21255594v1
Signatures of mast cell activation are associated with severe COVID-19
Janessa Tan et al
MC activation (...) significantly correlated with disease severity
other hematological changes and cardiovascular events (intra-vascular coagulation, endothelial damage with ischemic complications, the development of rashes that could be accentuated by damaged microvasculature, and increased incidence of myocardial infarction) - consistent with the effects of MCs in other sterile inflammatory conditions
including abnormalities of pulmonary blood flow leading to shunting and hypoxemia or loss of endothelial integrity leading to tissue edema.
https://sci-hub.hkvisa.net/doi.org/10.1016/j.yjmcc.2013.11.017
Angiotensin II induced proteolytic cleavage of myocardial ACE2 is mediated by TACE/ADAM-17: A positive feedback mechanism in the RAS
Patel et al
Inhibition of TACE prevents shedding of ACE2 in vitro and in vivo
https://jamanetwork.com/journals/jamacardiology/fullarticle/2781601
Myocarditis Following Immunization With mRNA COVID-19 Vaccines in Members of the US Military
Montgomery et al
While the observed number of myocarditis cases was small, the number was higher than expected among male military members after a second vaccine dose.
updated myocarditis data - July 2021
young males = 109 cases per million
cdc:
https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-07/05-COVID-Rosenblum-508.pdf
ontario:
https://www.publichealthontario.ca/-/media/documents/ncov/epi/covid-19-aefi-report.pdf?la=en
https://www.medrxiv.org/content/10.1101/2021.08.12.21261955v1
Cardiac Inflammation after COVID-19 mRNA Vaccines: A Global Pharmacovigilance Analysis
Chouchana et al
Increased relative risk of myocarditis in adolescents (22x) and 18-29 years old (7x) vs older people
https://www.nejm.org/doi/full/10.1056/NEJMc2115045
Adverse Effects after BNT162b2 Vaccine and SARS-CoV-2 Infection, According to Age and Sex
Letter to editor, Dagan et al
Myocarditis risk is cumulative based on spike exposure.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8541143/
Shedding the Light on Post-Vaccine Myocarditis and Pericarditis in COVID-19 and Non-COVID-19 Vaccine Recipients
Rima Hajjo et al
The frequencies of cardiac adverse events were affected by vaccine, vaccine type, vaccine dose, sex, and age of the vaccinated individuals.
Systems biology results suggested a central role of interferon-gamma (INF-gamma) in the biological processes leading to cardiac adverse events, by impacting MAPK and JAK-STAT signaling pathways.
TWICE THE JAB, DOUBLE THE MYOCARDITIS
https://www.medrxiv.org/content/10.1101/2021.12.23.21268276v1
Risk of myocarditis following sequential COVID-19 vaccinations by age and sex
Patone et al
Myocarditis risk was increased during 1-28 days following a third dose of BNT162b2 (IRR 2.02, 95%CI 1.40, 2.91).
Associations were strongest in males younger than 40 years for all vaccine types
3 (95%CI 1, 5) and 12 (95% CI 1,17) events per million (...) after first dose of BNT162b2 and mRNA-1273, respectively
14 (95%CI 8, 17), 12 (95%CI 1, 7) and 101 (95%CI 95, 104) additional events following a second dose of ChAdOx1, BNT162b2 and mRNA-1273, respectively;
and 13 (95%CI 7, 15) additional events following a third dose of BNT162b2,
compared with 7 (95%CI 2, 11) additional events following COVID-19 infection.
https://pubmed.ncbi.nlm.nih.gov/34341797/
Risk of Myocarditis from COVID-19 Infection in People Under Age 20: A Population-Based Analysis
Mendel E Singer, Ira B Taub, David C Kaelber
aggregating electronic health records from 48 mostly large U.S. Healthcare Organizations (HCOs)
primary COVID19 infection occurred at a rate as high as 450 per million in young males. Young males infected with the virus are up 6 times more likely to develop myocarditis as those who have received the vaccine.
Cetirizine as treatment
https://pubmed.ncbi.nlm.nih.gov/20682082/
Cetirizine a histamine H1 receptor antagonist improves viral myocarditis
Matsumori et al
These results suggest that cetirizine exerts its beneficial effects on viral myocarditis by suppressing expression of pro-inflammatory cytokines, genes related to cardiac remodeling in the hearts of mice.
[2022]
https://jamanetwork.com/journals/jamacardiology/fullarticle/2791253
SARS-CoV-2 Vaccination and Myocarditis in a Nordic Cohort Study of 23 Million Residents
Karlstad et al
numbers of excess events were 5.55 (95% CI, 3.70-7.39) events per 100000 vaccinees after the second dose of BNT162b2
and 18.39 (9.05-27.72) events per 100000 vaccinees after the second dose of mRNA-1273.
Estimates for pericarditis were similar.
https://pubmed.ncbi.nlm.nih.gov/33102537/
Prevalence of Myocardial Fibrosis in Intensive Endurance Training Athletes: A Systematic Review and Meta-Analysis
Zhang et al
reviews myocardial fibrosis (MF) in high-intensity endurance athletes measured by late gadolinium enhancement (LGE)
163/772 participants in the endurance athletes group showed LGE positive, compared with 19/587 participants in the comparison group
https://jamanetwork.com/journals/jama/fullarticle/2789793
The COVID Heart—One Year After SARS-CoV-2 Infection, Patients Have an Array of Increased Cardiovascular Risks
Jennifer Abbasi
the heightened risks were evident even among those who weren’t hospitalized with acute COVID-19
https://jamanetwork.com/journals/jama/fullarticle/2790421
Myocarditis Following a Third BNT162b2 Vaccination Dose in Military Recruits in Israel
Limor Friedensohn et al
2 weeks following a third vaccine dose
for males 18-24 years old only: 6.43 (95% CI, 0.13-12.73) and 11.25 (95% CI, 2.92-19.59) per 100000 vaccines
https://pubmed.ncbi.nlm.nih.gov/33360731/
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
Nuovo et al
It is concluded that ACE2+ endothelial damage is a central part of SARS-CoV2 pathology and may be induced by the spike protein alone.
https://www.sciencedirect.com/science/article/pii/S0048969721074222
Toxicity of spike fragments SARS-CoV-2 S protein for zebrafish: A tool to study its hazardous for human health?
VenturaFernandes et al
Zebrafish injected with SARS-CoV-2 rSpike protein shows several morphological alterations.
(The researchers attempted to study the incidence of myocarditis and pericarditis AFTER the COVID-19 infection, not during the acute phase which is when they manifest. The study is trying to understand if long-COVID is responsible for myocarditis and pericarditis rather than the actual infection - it's not really establishing a link between unvaccinated and vaccinated individuals.)
https://www.mdpi.com/2077-0383/11/8/2219?s=09
The Incidence of Myocarditis and Pericarditis in Post COVID-19 Unvaccinated Patients—A Large Population-Based Study
Ortal Tuvali et al
April 2022
Post COVID-19 infection was not associated with either myocarditis (aHR 1.08; 95% CI 0.45 to 2.56) or pericarditis (aHR 0.53; 95% CI 0.25 to 1.13). We did not observe an increased incidence of neither pericarditis nor myocarditis in adult patients recovering from COVID-19 infection
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[ADE - Antibody-dependent enhancement]
[CONTEXT]
The more time you expose yourselves to a disease-causing agent of the same serotype (read - vaccine), the more you set up your immune system (and in regards to ADE risks this would be specifically memory B cells) to respond just to it, and not adapt
More antibodies = more ADE (vaccines are making the virus MORE infective)
[2020]
https://www.cell.com/action/showPdf?pii=S0165-6147%2820%2930166-8
Fruitful neutralizing antibody pipeline brings hope to defeat SARS-Cov-2
Renn et al
SARS-CoV-2 may develop resistance to neutralizing antibodies through accumulating spontaneous mutations.
The neutralizing antibodies also may show antibody-dependent enhancement (ADE) and amplify disease progression.
https://onlinelibrary.wiley.com/doi/10.1111/ijcp.13795
Informed consent disclosure to vaccine trial subjects of risk of COVID-19 vaccines worsening clinical disease
Cardozo and Veazey
vaccines (..) may worsen COVID‐19 disease via antibody‐dependent enhancement (ADE). This risk is sufficiently obscured in clinical trial protocols and consent forms for ongoing COVID‐19 vaccine trials that adequate patient comprehension of this risk is unlikely to occur, obviating truly informed consent by subjects in these trials.
The specific and significant COVID‐19 risk of ADE should have been and should be prominently and independently disclosed to research subjects currently in vaccine trials
https://www.biorxiv.org/content/10.1101/2020.12.18.423358v1
An infectivity-enhancing site on the SARS-CoV-2 spike protein is targeted by SARS-2 patient antibodies
Liu et al
found that some of antibodies against the N-terminal domain (NTD) dramatically enhanced the binding capacity of the spike protein to ACE2, and thus increased SARS-CoV2 infectivity. Surprisingly, mutational analysis revealed that all the infectivity-enhancing antibodies recognized a specific site on the surface of the NTD. The antibodies against this infectivity-enhancing site were detected in all samples of hospitalized COVID-19 patients in the study. However, the ratio of infectivity-enhancing antibodies to neutralizing antibodies differed among patients
[2021]
https://archive.vn/vvfrv
Antibody-dependent enhancement and SARS-CoV-2 vaccines and therapies
Lee et al
Here, we describe key ADE mechanisms and discuss mitigation strategies for SARS-CoV-2 vaccines and therapies in development.
ADE in respiratory infections is included in a broader category named enhanced respiratory disease (ERD), which also includes non-antibody-based mechanisms such as cytokine cascades and cell-mediated immunopathology
https://www.biorxiv.org/content/10.1101/2020.12.31.424729v2
The functions of SARS-CoV-2 neutralizing and infection-enhancing antibodies in vitro and in mice and nonhuman primates
Li et al
three of 31 monkeys infused with enhancing antibodies had higher lung inflammation scores compared to controls
anti-NTD antibodies force the RBD into open confirmation more fit for ACE2 binding
https://www.frontiersin.org/articles/10.3389/fimmu.2021.640093/full
Two Different Antibody-Dependent Enhancement (ADE) Risks for SARS-CoV-2 Antibodies
Ricke
moderate and severe SARS and COVID-19 diseases fits a proposed model of antibody-dependent infection of macrophages as the key gate step in disease progression from mild to moderate and severe symptoms contributing to dysregulated immune responses (53) including apoptosis for some T cells/T cell lymphopenia, proinflammatory cascade with macrophage accumulation, and cytokine and chemokine accumulations in lungs with a cytokine storm in some patients.
Infected phagocytic immune cells may enable the virus to spread to additional organs prior to viral sepsis (Figure 2).
Exposure of non-neutralizing spike antibodies through breastmilk
https://www.medrxiv.org/content/10.1101/2021.05.03.21256416v1
Non-neutralizing secretory IgA and T cells targeting SARS-CoV-2 spike protein are transferred to the breastmilk upon BNT162b2 vaccination
Gonçalves et al
Immune transfer via milk to suckling infants occurs by spike-reactive SIgA and T cells
Spike-reactive SIgA in the breastmilk is non-neutralizing and T-cell independent
ADE mechanism Furin-Cleavage-independent: since it's likely age related then everyone vaccinated in that group are basically primed for this type of ADE. Once titers drop enough so that neutralizing don't do anything and they're exposed, then they get severe infection right from the beginning and they'll make more aberrant antibodies, so double severe.
https://www.cell.com/cell/fulltext/S0092-8674(21)00662-0
An infectivity-enhancing site on the SARS-CoV-2 spike protein targeted by antibodies
Liu et al
SARS-CoV-2 infectivity is enhanced by specific antibodies independent of the Fc receptor
we screened a series of anti-spike monoclonal antibodies from COVID-19 patients, and found that some of antibodies against the N-terminal-domain (NTD) induced the open conformation of receptor binding domain (RBD) and thus enhanced the binding capacity of the spike protein to ACE2 and infectivity of SARS-CoV-2
These findings demonstrate that not only neutralizing antibodies but also enhancing antibodies are produced during SARS-CoV-2 infection.
Although the ADE induced by the enhancing antibodies is relatively lower than the Fc-receptor mediated ADE observed in other viruses such as dengue virus, Fc receptors are not involved in this new type of ADE.
another report on an ADE case
https://casereports.bmj.com/content/14/2/e240496
A case of SARS-CoV-2 reinfection in a patient with obstructive sleep apnea managed with telemedicine
Sicsic wt al
https://journals.asm.org/doi/10.1128/mBio.01987-21
Antibody-Dependent Enhancement of SARS-CoV-2 Infection Is Mediated by the IgG Receptors FcγRIIA and FcγRIIIA but Does Not Contribute to Aberrant Cytokine Production by Macrophages
Maemura et al
We found that FcγRIIA and FcγRIIIA mediated modest ADE of infection against SARS-CoV-2.
SARS-CoV-2 infection thus produces antibodies that elicit ADE of infection, but these antibodies do not contribute to excess cytokine production by macrophages.
ADE-inducing antibodies may exist for at least 6months after SARS-CoV-2 infection
not the type of ADE expected:
https://www.biorxiv.org/content/10.1101/2021.10.14.464464v1
Opsonization by non-neutralizing antibodies can confer protection to SARS-CoV-2 despite Spike-dependent modulation of phagocytosis
Bahnan et al
we show that Spike-specific antibodies, dependent on concentration, can either enhance or reduce Spike-bead phagocytosis by monocytes independently of the antibody neutralization potential.
These results suggest that the levels of anti-Spike antibodies could influence monocyte-mediated immune functions and propose that non-neutralizing antibodies could confer protection to SARS-CoV-2 infection by mediating phago-cytosis.
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[OAS - Original antigenic sin]
[CONTEXT]
Trapped by immune memory: the immune system will still produce the "old" antibodies against a new variant of the pathogen, creating an ineffective response.
Failure to generate N-protein antibodies is a likely marker of OAS.
[2021]
OAS from a SARS-CoV-2 infection creates antibodies against hCoV, which would in theory lead to poorer viral clearance:
https://www.cell.com/cell/fulltext/S0092-8674(21)00160-4
Seasonal human coronavirus antibodies are boosted upon SARS-CoV-2 infection but not associated with protection
Anderson et al
Our studies suggest that SARS-CoV-2 infection boosts antibodies reactive to the S2 domain of the OC43 S protein. Further studies are needed to precisely map the footprints of these antibodies, and additional studies need to be completed to determine whether these antibodies help resolve infections or whether they enhance disease in COVID-19 patients.
probable OAS due to the high immunogenicity:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8396729/
Original antigenic sin responses to Betacoronavirus spike proteins are observed in a mouse model, but are not apparent in children following SARS-CoV-2 infection
Lapp et al
mice primed with HKU1 spike and boosted with SARS-CoV-2 spike were unable to mount neutralizing antibodies to SARS-CoV-2
https://www.jci.org/articles/view/150613
Seasonal coronavirus–specific B cells with limited SARS-CoV-2 cross-reactivity dominate the IgG response in severe COVID-19
Aguinal-Bretones et al
These findings support a boost of poorly protective coronavirus-specific antibodies in COVID-19 patients that correlates with disease severity, revealing original antigenic sin.
[2022]
OAS confirmed:
https://www.biorxiv.org/content/10.1101/2022.02.03.479037v1
mRNA-1273 or mRNA-Omicron boost in vaccinated macaques elicits comparable B cell expansion, neutralizing antibodies and protection against Omicron
Gagne et al
Therefore, an Omicron boost may not provide greater immunity or protection compared to a boost with the current mRNA-1273 vaccine.
OAS confirmed:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8786601/
Immune imprinting, breadth of variant recognition, and germinal center response in human SARS-CoV-2 infection and vaccination
Röltgen et al
Viral variant infection elicits variant-specific antibodies, but prior mRNA vaccination imprints serological responses toward Wuhan-Hu-1 rather than variant antigens.
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[ADCC - Antibody-dependent cellular cytotoxicity]
tl:dr any cell expressing the Spike protein will be targeted for destruction by Natural Killer Cells
Any tissue that takes up the mRNA will express Spike protein. They can even cross the blood brain barrier.
[CONTEXT]
A mechanism of cell-mediated immune defense whereby an effector cell of the immune system actively lyses a target cell, whose membrane-surface antigens have been bound by specific antibodies.[1] It is one of the mechanisms through which antibodies, as part of the humoral immune response, can act to limit and contain infection.
It is involved in some autoimmune diseases.
They're the only 3 viruses that have ADCC via afucosylated IgG. They also share many clinical aspects in how many are mild and some are severe, with the severe individuals having trouble in the initial stages of infection.
*RSV-specific afucosylated immunoglobulin G (IgG) has been shown to induce ADCC
*Dengue-specific afucosylated immunoglobulin G (IgG) has been shown to induce ADCC
*Corona-specific afucosylated immunoglobulin G (IgG) has been shown to induce ADCC
If you're unlucky enough to be prone to making afucosylated IgG and your innate immune system can't keep Corona's viral levels down, you get fucked up by 40-fold.
Do not confuse this with Antibody Enhancement (ADE), which is an entirely different process altogether.
[2020]
https://www.medrxiv.org/content/10.1101/2020.11.12.20230508v1
Asymptomatic and symptomatic SARS-CoV-2 infections elicit polyfunctional antibodies
Dufloo et al
asymptomatic SARS-CoV-2 infection elicits polyfunctional antibodies neutralizing the virus and targeting infected cells. - Sera from convalescent COVID-19 patients activate the complement and kill infected cells by ADCC. - Asymptomatic and symptomatic SARS-CoV-2-infected individuals harbor polyfunctional antibodies. - Antibody levels and functions are slightly lower in asymptomatic individuals - The different antiviral activities of anti-Spike antibodies are correlated regardless of disease severity. - Functions of anti-Spike antibodies have similar kinetics of induction and contraction.
[2022]
https://onlinelibrary.wiley.com/doi/abs/10.1002/eji.202149470
Natural killer cell-mediated ADCC in SARS-CoV-2-infected individuals and vaccine recipients
Hagemann et al
serum samples from individuals that received the BNT162b2 vaccine induced strong CD107a expression by NK cells that increased with the second vaccination and was significantly higher than observed in infected individuals
==============================================================
==============================================================
[SPIKE PROTEIN - Antibody escape]
[CONTEXT]
The spike protein of SARS-CoV-2 is made up of two portions. The S1 binds to the ACE2 receptor on the human cell surface, and S2 initiates membrane fusion to complete cell infection.
[2020]
https://archive.is/NyRhf
Distinct conformational states of SARS-CoV-2 spike protein
Cai et al
Intriguingly, they also found that the spike protein sometimes goes from its original "before" shape into the "after" form prematurely, without the virus binding to the ACE2 receptor.
Being able to assume this alternate shape even without binding to a cell may help keep SARS-CoV-2 viable in the environment, preventing it from breaking down when it lands on a surface for example. The postfusion shape could induce antibodies that do not neutralize the virus. In effect, the spikes in this form may act as decoys that distract the immune system.
We propose that there are two routes for the conformational changes. One is ACE2 dependent, and allows the virus to enter a host cell. The second is ACE2 independent.
The researchers speculate that having some spikes assume the post-fusion form prematurely may also protect SARS-CoV-2 from our immune system, inducing antibodies that are non-neutralizing and ineffective in containing the virus.
http://archive.is/9m4Uz
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
Rossi et al
Receptor-binding domain (RBD) of the S protein may constantly switch between a “lying-down” and a “standing-up” position. In SARS-CoV-2, RBD is mostly in the “lying-down” position, a state associated with not only ineffective receptor binding, but also immune evasion. In SARS-CoV, RBD is mostly in “standing-up” position, a state associated with not only high effective receptor binding, but also immune recognition
[2021]
https://www.biorxiv.org/content/10.1101/2020.12.17.423313v1
A human coronavirus evolves antigenically to escape antibody immunity
Eguia et al
These results show that the coronavirus is evolving antigenically, so immunity elicited against older CoV-229E is eroded by mutations in spike. For instance, this serum collected in 1995 neutralizes viral spikes from before then, but has reduced activity against new spikes.
https://www.biorxiv.org/content/10.1101/2020.10.30.352914v1
Evidence for adaptive evolution in the receptor-binding domain of seasonal coronaviruses
Kistler, Bedford
CoV spike RBD is mutationally tolerant & selection can strongly favor mutations in seasonal CoV spikes, enabling antigenic evolution
https://www.biorxiv.org/content/10.1101/2020.11.19.389916v2
Recurrent deletions in the SARS-CoV-2 spike glycoprotein drive antibody escape
Maccarthy et al
Deletions in RDRs confer resistance to neutralizing antibodies. By altering stretches of amino acids, deletions appear to accelerate SARS-CoV-2 antigenic evolution and may, more generally, drive adaptive evolution.
https://www.medrxiv.org/content/10.1101/2021.01.19.21249840v4
Impact of SARS-CoV-2 B.1.1.7 Spike variant on neutralisation potency of sera from individuals vaccinated with Pfizer vaccine BNT162b2
Collier et al
E484K mutation in a B.1.1.7 background to reflect newly emerging viruses in the UK led to a more substantial loss of neutralising activity by vaccine-elicited antibodies and mAbs (19 out of 31) over that conferred by the B.1.1.7 mutations alone. E484K emergence on a B.1.1.7 background represents a threat to the vaccine BNT162b.
https://www.biorxiv.org/content/10.1101/2021.01.27.428541v1
D614G Substitution of SARS-CoV-2 Spike Protein Increases Syncytium Formation and Viral Transmission via Enhanced Furin-mediated Spike Cleavage
Cheng et al
Our study provides a mechanistic explanation for the increased transmissibility of S-G614 containing SARS-CoV-2 through enhanced furin-mediated S cleavage, which increases membrane fusion and virus infectivity.
https://www.biorxiv.org/content/10.1101/2021.02.18.431897v1.full.pdf
Decreased neutralization of SARS-CoV-2 global variants by therapeutic anti-spike protein monoclonal antibodies
Tada et al
SARS-CoV-2 variants raises concerns that monoclonal antibody therapies could lose effectiveness
Analysis of spike protein mutations that occurred in a treated immunocompromised patient revealed additional mutations that allowed for escape from either antibody
https://pubmed.ncbi.nlm.nih.gov/33609494/
A potential interaction between the SARS-CoV-2 spike protein and nicotinic acetylcholine receptors
Oliveira et al
The region of the spike responsible for binding contains a PRRA motif, a four-residue insertion not found in other SARS-like coronaviruses.
Estimates of binding energy suggest that Y674-R685 forms stable complexes with all three nAChR subtypes.
what prevents SARS-CoV-2's spike protein mutating out of being intercepted by the peptide though? the authors don't even address the possibility
https://science.sciencemag.org/content/early/2021/02/16/science.abf4896
Intranasal fusion inhibitory lipopeptide prevents direct-contact SARS-CoV-2 transmission in ferrets
deVries et al
designed highly stable lipoprotein fusion inhibitors complementary to a conserved repeat in the C terminus of S that integrate into host cell membranes and inhibit conformational changes in S necessary for membrane fusion
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963733/
Engineering a Novel Antibody-Peptide Bispecific Fusion Protein Against MERS-CoV
Wang et al
https://www.medrxiv.org/content/10.1101/2020.11.17.20233726v2
Risk of evolutionary escape from neutralizing antibodies targeting SARS-CoV-2 spike protein
Van Egeren et al
SARS-CoV-2 will evolve quickly to evade widely deployed spike RBD-targeting monoclonal antibodies, requiring combinations that rely on at least three antibodies targeting distinct epitopes to suppress viral immune evasion
(A.C., M.S., and U.T. are employees and shareholders of Fractal Therapeutics. D.V.E., A.N., B.Z., and D.J.-M. are shareholders of Fractal Therapeutics.)
https://advances.sciencemag.org/content/early/2021/04/22/sciadv.abg7607
SARS-CoV-2 recruits a haem metabolite to evade antibody immunity
Rosa et al
We show that SARS-CoV-2 spike binds biliverdin and bilirubin
Our results indicate that the virus co-opts the haem metabolite for the evasion of humoral immunity via allosteric shielding of a sensitive epitope and demonstrate the remarkable structural plasticity of the NTD.
possible mutations pressured by ivermectin
https://iv.iiarjournals.org/content/34/5/3023
Ivermectin Docks to the SARS-CoV-2 Spike Receptor-binding Domain Attached to ACE2
Lehrer and Rheinstein
Binds to spike protein regions leucine 91, histidine 378
in vitro stuff showing spike evolution on the background of antibodies:
https://www.biorxiv.org/content/10.1101/2021.07.12.452002v1
SARS-CoV-2 Spike Protein Mutations and Escape from Antibodies: a Computational Model of Epitope Loss in Variants of Concern
Triveri et al
The list of studied proteins is further enriched by a laboratory-evolved escape S-variant, obtained by Rappuoli and coworkers by co-incubating the SARS-CoV-2 virus with a highly neutralizing plasma from a COVID-19 convalescent patient. Interestingly, after several passages this strategy generated a variant completely resistant to plasma neutralization.This “artificial” variant is labeled here as the PT188-EM variant.
https://www.biorxiv.org/content/10.1101/2021.08.12.456173v1
Delta spike P681R mutation enhances SARS-CoV-2 fitness over Alpha variant
Liu et al
Spike mutations that potentially affect furin cleavage efficiency must be closely monitored for future variant surveillance.
https://www.biorxiv.org/content/10.1101/2021.08.16.456470v1.full.pdf
Peptide Scanning of SARS-CoV and SARS-CoV-2 Spike Protein Subunit 1 Reveals Potential Additional Receptor Binding Sites
Lin et al
https://www.biorxiv.org/content/10.1101/2021.06.17.448820v2
SARS-CoV-2 spike P681R mutation, a hallmark of the Delta variant, enhances 2 viral fusogenicity and pathogenicity
Saito et al
S protein loses the ability tobind, if you fuck around with its FCS
https://www.biorxiv.org/content/10.1101/2020.07.25.221036v1
No evidence for basigin/CD147 as a direct SARS-CoV-2 spike binding receptor
Shilts et al
As previously described, the full spike ectodomain was mutated at its polybasic protease cleavage site (682-685 RRAR to SGAG), had a proline stabilizing mutation introduced (986-987 KV to PP), and to mimic the natural trimerized structure of the spike had a foldon trimerization domain introduced at its C-terminus. The ACE2 ectodomain spanned M1-S740, retaining its endogenous signal peptide
https://www.biorxiv.org/content/10.1101/2021.09.18.460924v1
Spike-independent replication of coronaviruses provides an alternative route for infection of host species that don't share common cell-entry receptors.
Lins et al
Deep sequencing of isolate 2613 showed that the majority population had acquired additional nucleotide insertions in the spike resulting in an additional codon that restores spike function.
https://www.medrxiv.org/content/10.1101/2021.10.27.21265574v1
Boosting of Cross-Reactive Antibodies to Endemic Coronaviruses by SARS-CoV-2 Infection but not Vaccination with Stabilized Spike
Crowley et al
In this observational study of mucosal and systemic humoral immunity in acutely infected, convalescent, and vaccinated subjects, we tested for cross reactivity against endemic CoV spike (S) protein at subdomain resolution.
In contrast, vaccination with a stabilized spike mRNA vaccine did not robustly boost cross-reactive antibodies, suggesting differing antigenicity and immunogenicity.
[2022]
https://www.biorxiv.org/content/10.1101/2022.01.03.474721v1
Hydrodynamics of spike proteins dictate a transport-affinity competition for SARS-CoV-2 and other enveloped viruses
Moreno et al
Our results revealed that the diffusional mechanism of SARS-CoV-2 is strongly influenced by the size and distribution of its spikes.
https://pubmed.ncbi.nlm.nih.gov/34139176/
An infectivity-enhancing site on the SARS-CoV-2 spike protein targeted by antibodies
Liu et al
some of antibodies against the N-terminal domain (NTD) induced the open conformation of RBD and thus enhanced the binding capacity of the spike protein to ACE2 and infectivity of SARS-CoV-2.
not only neutralizing antibodies but also enhancing antibodies are produced during SARS-CoV-2 infection
https://pubmed.ncbi.nlm.nih.gov/15367630/
Retroviruses pseudotyped with the severe acute respiratory syndrome coronavirus spike protein efficiently infect cells expressing angiotensin-converting enzyme 2
Moore et al
Here we show that codon optimization of the SARS-CoV S-protein gene substantially enhanced S-protein expression. We also found that two retroviruses, simian immunodeficiency virus (SIV) and murine leukemia virus, both expressing green fluorescent protein and pseudotyped with SARS-CoV S protein or S-protein variants, efficiently infected HEK293T cells stably expressing ACE2.
Infection mediated by an S-protein variant whose cytoplasmic domain had been truncated and altered to include a fragment of the cytoplasmic tail of the human immunodeficiency virus type 1 envelope glycoprotein was, in both cases, substantially more efficient than that mediated by wild-type S protein. Using S-protein-pseudotyped SIV, we found that the enzymatic activity of ACE2 made no contribution to S-protein-mediated infection.
Finally, we show that a soluble and catalytically inactive form of ACE2 potently blocked infection by S-protein-pseudotyped retrovirus and by SARS-CoV.
==============================================================
==============================================================
[SPIKE PROTEIN - TOXICITY and ACE2 infectivity]
tl;dr the spike protein by itself (without being part of the corona virus) can damage endothelial cells and disrupt the blood-brain barrier
[CONTEXT]
The spike protein of SARS-CoV-2 is made up of two portions. The S1 binds to the ACE2 receptor on the human cell surface, and S2 initiates membrane fusion to complete cell infection.
Dopamine-release mechanisms in the brain may play a major role in SARS-CoV-2 infection.
It is possible that after the initial binding or attachment of the SARS-CoV2 to ACE2 receptors, the spike protein of the virus binds to dopaminergic receptors of adjacent cells. Since the brain has dopamine receptors, it plays an integral regulatory role in local immunity, such as the release of lymphocytes and cytokines.
Dopamine at certain concentrations can disrupt lymphocytic function. When there is an influx of dopamine, it further decreases both innate and adaptive immunity. This causes neural symptoms, including fatigue, dizziness, encephalopathy, and loss of consciousness.
Dopamine is also a regulator of immune function. The virus may manipulate the immune system by elevating the levels of dopamine to help them enter cells.
**but the s proteins produced by the vaccine are locked in a stabilized prefusion conformation so all these studies are irrelevant
Cai et al found that the spike protein sometimes goes from its original "before" shape into the "after" form prematurely, without the virus binding to the ACE2 receptor.
https://www.science.org/doi/10.1126/science.abd4251
Distinct conformational states of SARS-CoV-2 spike protein
Cai et al
We propose that there are two routes for the conformational changes. One is ACE2 dependent, and allows the virus to enter a host cell. The second is ACE2 independent.
The researchers speculate that having some spikes assume the post-fusion form prematurely may also protect SARS-CoV-2 from our immune system, inducing antibodies that are non-neutralizing and ineffective in containing the virus.
Our study raises several potential concerns about the current vaccine strategies.
First, vaccines using the full-length wild-type sequence of the S protein may produce the various forms in vivo that we have observed here. The postfusion conformations could expose immunodominant, non-neutralizing epitopes that distract the host immune system, as documented for other viruses such as HIV-1 and RSV (46, 47).
Second, the approach to stabilizing the prefusion conformation by introducing proline mutations at residues 986 and 987 may not be optimal because the K986P mutation may break a salt bridge between protomers that contributes to trimer stability. The resulting S trimer structure with a relaxed apex may induce antibodies that could not efficiently recognize S trimer spikes on the virus, although it may be more effective in inducing anti-RBD–neutralizing responses than the closed form.
Third, considering the possibility that the postfusion S2 is present on infectious virions, vaccines using β-propiolactone–inactivated viruses may require additional quality control tests.
and if you read the pfizer leaks from 2021, they are aware of this
https://web.archive.org/web/20210305053725/https://www.slideshare.net/enave2609/ss-242999249
Three-dimensional classification of the dataset showed a class of particles that was in the conformation one RBD ‘up’ and two RBD ‘down”. This partly open conformation represented 20.4% of the trimeric molecules. The remainder were in the all RBD ‘down’ conformation. Although potent neutralizing epitopes have been described when the RBD is in the “heads down” closed conformation, the “heads up” receptor accessible conformation exposes a potentially greater breadth of neutralizing antibody targets.
[2020]
Petition:
https://2020news.de/en/dr-wodarg-and-dr-yeadon-request-a-stop-of-all-corona-vaccination-studies-and-call-for-co-signing-the-petition/
The vaccinations are expected to produce antibodies against spike proteins of SARS-CoV-2. However, spike proteins also contain syncytin-homologous proteins, which are essential for the formation of the placenta in mammals such as humans. It must be absolutely ruled out that a vaccine against SARS-CoV-2 could trigger an immune reaction against syncytin-1, as otherwise infertility of indefinite duration could result in vaccinated women.
https://www.biorxiv.org/content/10.1101/2020.12.04.409144v1
SARS-CoV-2 Spike Protein Impairs Endothelial Function via Downregulation of ACE2
Lei et al
S protein alone can damage vascular endothelial cells (ECs) in vitro and in vivo, manifested by impaired mitochondrial function, decreased ACE2 expression and eNOS activity, and increased glycolysis. The underlying mechanism involves S protein downregulation of AMPK and upregulation of MDM2, causing ACE2 destabilization.
Thus, the S protein-exerted vascular endothelial damage via ACE2 downregulation overrides the decreased virus infectivity
Spike expression disrupts lysosome function:
https://www.biorxiv.org/content/10.1101/2020.12.08.417022v1
The D614G Mutation Enhances the Lysosomal Trafficking of SARS-CoV-2 Spike
Guo et al
Spike trafficking to lysosomes is resistant to inhibitors of endocytosis, microtubules, and secretion but sensitive to V-ATPase inhibition
https://www.biorxiv.org/content/10.1101/2020.12.02.408153v1
LL-37 fights SARS-CoV-2: The Vitamin D-Inducible Peptide LL-37 Inhibits Binding of SARS-CoV-2 Spike Protein to its Cellular Receptor Angiotensin Converting Enzyme 2 In Vitro
Roth et al
We have revealed a biochemical link between vitamin D, LL-37, and COVID-19 severity. SPR analysis demonstrated that LL-37 binds to SARS-CoV-2 S protein and inhibits binding to its receptor hACE2, and most likely viral entry into the cell. This study supports the prophylactic use of vitamin D to induce LL-37 that protects from SARS-CoV-2 infection, and the therapeutic administration of vitamin D for the treatment of COVID-19 patients.
https://www.biorxiv.org/content/10.1101/2020.12.21.423721v1
The SARS-CoV-2 spike protein disrupts the cooperative function of human cardiac pericytes (PC)s - endothelial cells through CD147 receptor-mediated signalling
Avolio et al
We show, for the first time, that the recombinant S protein alone elicits functional alterations in cardiac PCs.
This was documented as:
(1) increased migration,
(2) reduced ability to support EC network formation on Matrigel,
(3) secretion of pro-inflammatory molecules typically involved in the cytokine storm; and
(4) production of pro-apoptotic factors responsible for EC death.
The SARS-CoV-2 spike protein disrupts the cooperative function of human cardiac pericytes - endothelial cells through CD147 receptor-mediated signalling: a potential non-infective mechanism of COVID-19 microvascular disease
[2021]
https://www.biorxiv.org/content/10.1101/2020.12.23.424283v1
The SARS-CoV-2 S1 spike protein mutation N501Y alters the protein interactions with both hACE2 and human derived antibody
Fratev
Free energy perturbation (FEP) and Molecular dynamics (MD) calculations
the spike S1 receptor binding domain (RBD)-ACE2 interaction was increased whereas those with the STE90-C11 antibody significantly decreased (over about 160 times). This may explain the observed in UK more spread of the virus but also emerge an important question about the possible human immune response and already available vaccines
(but SARS-CoV-2 is the only coronavirus with a superantigen insert in the spike protein tho)
https://www.biorxiv.org/content/10.1101/2021.01.28.428642v1
Coronavirus associated molecular mimicry common to SARS-CoV-2 peptide
Adiguzel
Results imply autoimmunity risk in COVID-19 patients with HLA*A02:01 and HLA*A24:02 serotypes in general, through molecular mimicry. This is also common to other coronaviruses than SARS-CoV-2
https://twitter.com/Daoyu15/status/1356922492766441472/
FCS hypersensitizes the Spike toward antibody-mediated irreversible inactivation by allowing the Spike to be fired prematurely and
Irreversibly inactivated even in it’s first host. This is especially pronounced with an already-immune reservoir animal
https://www.biorxiv.org/content/10.1101/2021.02.25.432853v1
Pyroptosis of syncytia formed by fusion of SARS-CoV-2 Spike and ACE2 expressing cells
Ma et al
We found that Caspase-9 was activated after syncytia formation, and Caspase-3/7 was activated downstream of Caspase-9, but it triggered GSDME-dependent pyroptosis rather than apoptosis.
We propose that pyroptosis is the fate of syncytia formed by SARS-CoV-2 infected host cells and ACE2-positive cells, which indicated that lytic death of syncytia may contribute to the excessive inflammatory responses in severe COVID-19 patients.
[pfizer leak 2.0]
https://web.archive.org/web/20210305053725/https://www.slideshare.net/enave2609/ss-242999249
https://www.slideshare.net/enave2609/ss-242999249
zero clues on how stable their mRNA are
risk of autoimmune problems from modRNA - brought up
needed research and data to assess safety - not
re-presenting the spike triggers the inflammation
re-presenting the RBD does not
https://pubmed.ncbi.nlm.nih.gov/33328624/
The S1 protein of SARS-CoV-2 crosses the blood-brain barrier in mice
Rhea et al
When injected into the bloodstream [of mice], (..) the spike proteins were gradually cleared from the blood but got uptaken by the brain.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827936/
SARS-CoV-2 spike protein-mediated cell signaling in lung vascular cells
Suzuki et al
S1 portion of SARS-CoV-2 spike protein — without the whole virion or genome — triggered growth signals in cultured human blood vessels from the lungs
suggests that SARS-CoV-2 spike proteins may activate blood vessel growth, leading to vascular thickening.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827936
SARS-CoV-2 Spike Protein Elicits Cell Signaling in Human Host Cells: Implications for Possible Consequences of COVID-19 Vaccines
Suzuki et al
we note that human host cells sensitively respond to the spike protein to elicit cell signaling. Thus, it is important to be aware that the spike protein produced by the new COVID-19 vaccines may also affect the host cells
In addition to cardiovascular cells, other cells that express ACE2 have the potential to be affected by the SARS-CoV-2 spike protein, which may cause adverse pathological events.
Thus, it is important to consider the possibility that the SARS-CoV-2 spike protein produced by the new COVID-19 vaccines triggers cell signaling events that promote PAH, other cardiovascular complications, and/or complications in other tissues/organs in certain individuals.
https://www.medrxiv.org/content/10.1101/2021.03.05.21252960v1.full
SARS-CoV-2 spike protein S1 induces fibrin(ogen) resistant to fibrinolysis: Implications for microclot formation in COVID-19
Grobbelaar et al
Here we study the effect of isolated SARS-CoV-2 spike protein S1 subunit as potential inflammagen sui generis.
directly to cause blood hypercoagulation.
https://www.salk.edu/news-release/the-novel-coronavirus-spike-protein-plays-additional-key-role-in-illness/
The novel coronavirus’ spike protein plays additional key role in illness
This binding disrupted ACE2’s molecular signaling to mitochondria (organelles that generate energy for cells), causing the mitochondria to become damaged and fragmented
Dr Frankenstein I presume:
https://www.biorxiv.org/content/10.1101/2021.04.30.442139v1
Cell-free glycoengineering of the recombinant SARS-CoV-2 spike glycoprotein
Ruhnau et al
In the future, this in-vitro glycoengineering approach can be used to efficiently generate a wide range of N-glycans on antigens considered as vaccine candidates for animal trials and preclinical testing to better characterize the impact of N-glycosylation on immunity and to improve the efficacy of protein subunit vaccines.
https://www.sciencedirect.com/science/article/pii/S0006291X21007889
SARS-Cov-2 spike protein fragment 674–685 protects mitochondria from releasing cytochrome c in response to apoptogenic influence
Kalashnyk et al
Our data suggest that the α7 nAChR-binding portion of SARS-Cov-2 spike protein prevents mitochondria-driven apoptosis when the virus is uncoated inside the cell and, therefore, supports the infected cell viability before the virus replication cycle is complete.
SARS peptide does not protect intact U373 cells from apoptosis.
https://archive.is/QSy9s
Functional autoantibodies against G-protein coupled receptors in patients with persistent Long-COVID-19 symptoms
Autoantibodies target β2- and α1-adrenoceptors, angiotensin II AT1-, muscarinic M2-, MAS-, nociceptin- and ETA-receptors.
Such autoantibody patterns have previously been seen in COVID independent neurological deficits and cardiovascular disease.
The Sars-CoV-2 spike protein is a potential epitopic target for biomimicry-induced autoimmunological processes [25]. Therefore, we feel it will be extremely important to investigate whether GPCR-fAABs will also become detectable after immunisation by vaccination against the virus.
Sars-CoV-2, to protect the spike from antibodies binding to it, ends up binding hydrophobic molecules (including, but not limited to, molecules responsible for bruise coloration) to NTD. Researchers find an antibody targeting that site and shill it as effective anyway:
https://www.biorxiv.org/content/10.1101/2021.06.29.450397v1
Neutralizing antibody 5-7 defines a distinct site of vulnerability in SARS-CoV-2 spike N-terminal domain
Cerutti et al
the mRNA vaccines may have been a worse idea than anyone realized:
https://elifesciences.org/articles/65962
SARS-CoV-2 requires cholesterol for viral entry and pathological syncytia formation
Sanders et al
The spike protein of SARS-CoV-2 interacts with cholesterol and ACE2 to induce viral entry and pathological cell-cell fusion
the data suggests that spike potentially associates with a specific population of cholesterol, which is biochemically distinct from the sphingomyelin-associated lipid complexes enriched in canonical rafts
https://www.sciencedirect.com/science/article/abs/pii/S0006291X2100499X
SARS-CoV-2 spike protein interactions with amyloidogenic proteins: Potential clues to neurodegeneration
Idrees et al.
SARS-CoV-2 Spike S1 protein receptor binding domain (SARS-CoV-2 S1 RBD) binds to heparin and heparin binding proteins.
Heparin binding accelerates the aggregation of the pathological amyloid proteins present in the brain.
SARS-CoV-2 S1 RBD binds to a number of aggregation-prone, heparin binding proteins including Aβ, α-synuclein, tau, prion, and TDP-43 RRM.
Heparin-binding site on the S1 might assist the binding of amyloid proteins to the viral surface and thus could leads to neurodegeneration in brain.
https://archive.is/zIBMf
Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV
Ou et al
we confirm that human angiotensin converting enzyme 2 (hACE2) is the receptor for SARS-CoV-2, find that SARS-CoV-2 enters 293/hACE2 cells mainly through endocytosis, that PIKfyve, TPC2, and cathepsin L are critical for entry
if it's not the spike, they imply (i guess) it's the adenovirus what causes the blood clots?
https://ashpublications.org/blood/article-abstract/doi/10.1182/blood.2021012938/476422/Anti-Platelet-Factor-4-Antibodies-Causing-VITT-do
Vaccine-induced immune thrombotic thrombocytopenia (VITT)
Anti-Platelet Factor 4 Antibodies Causing VITT do not Cross-React with SARS-CoV-2 Spike Protein
Andreas Greinacher et al.
In conclusion, antibodies against PF4 induced by vaccination do not cross-react with the SARS-CoV-2 spike protein, indicating that the intended vaccine-induced immune response against SARS-CoV-2 spike protein is not the trigger of VITT.
Testing RRRKR mutants. Notice the damage done to the cells and look at the only one that's somewhat comparable:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194065/
A Multibasic Cleavage Site in the Spike Protein of SARS-CoV-2 Is Essential for Infection of Human Lung Cells
Hoffman et al
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833556/
The polybasic insert, the RBD of the SARS-CoV-2 spike protein, and the feline coronavirus – evolved or yet to evolve
Budhraja et al
https://pubmed.ncbi.nlm.nih.gov/33053430/
The SARS-CoV-2 spike protein alters barrier function in 2D static and 3D microfluidic in-vitro models of the human blood-brain barrier
Buzhdygan et al
S1 promotes loss of barrier integrity in an advanced 3D microfluidic model of the human BBB
suggest that SARS-CoV-2 spike proteins trigger a pro-inflammatory response on brain endothelial cells that may contribute to an altered state of BBB function
https://www.biorxiv.org/content/10.1101/2021.08.01.454605v1
The spike protein of SARS-CoV-2 induces endothelial inflammation through integrin α5β1 and NF-κB
Robles et al
spike stimulates leukocyte adhesion to endothelial cells (EC)
spike alone activates the proinflammatory program in EC and suggest that the RGD sequence located in the spike receptor-binding domain is responsible for this effect
https://www.biorxiv.org/content/10.1101/2021.10.12.464152v1
SARS-CoV-2 spike protein induces abnormal inflammatory blood clots neutralized by fibrin immunotherapy
Ryu et al
Spike protein from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to the blood coagulation factor fibrinogen and induces structurally abnormal blood clots with heightened proinflammatory activity
https://www.biorxiv.org/content/10.1101/2021.12.16.472920v1
Amyloidogenesis of SARS-CoV-2 Spike Protein
Nyström et al
Full-length folded S-protein did not form amyloid fibrils, but amyloid-like fibrils with evident branching were formed during 24 h of S-protein coincubation with the protease neutrophil elastase (NE) in vitro.
Modena vaccine uploaded to genbank:
https://www.ncbi.nlm.nih.gov/nucleotide/OK120841.1
Synthetic construct HCV1146 Moderna (mRNA-1273) SARS-CoV-2 vaccine sequence
GenBank: OK120841.1
SARS-CoV-2 spike mRNA vaccine sequences circulate in blood up to at least 28 days after COVID-19 vaccination
[2022]
spike is toxic:
https://www.sciencedirect.com/science/article/pii/S0925443921001939#!
SARS-CoV-2 spike promotes inflammation and apoptosis through autophagy by ROS-suppressed PI3K/AKT/mTOR signaling
Fei Li et al
SARS-CoV-2 spike triggers autophagy and apoptosis in ACE2-expressing cells.
SARS-CoV-2 spike induces autophagy through ROS-suppressed PI3K/AKT/mTOR pathway.
SARS-CoV-2 spike-induced autophagy promotes inflammatory responses and apoptosis.
https://www.mdpi.com/1999-4915/13/10/2056/htm?s=08
SARS–CoV–2 Spike Impairs DNA Damage Repair and Inhibits V(D)J Recombination In Vitro
Jiang et al
we found that the spike protein localizes in the nucleus and inhibits DNA damage repair by impeding key DNA repair protein BRCA1 and 53BP1 recruitment to the damage site.
Our findings reveal a potential molecular mechanism by which the spike protein might impede adaptive immunity and underscore the potential side effects of full-length spike-based vaccines.
tl;dr spike blocks p53-related tumor suppresion at nuclear level, see
https://www.frontiersin.org/articles/10.3389/fmed.2021.798095/full
Rapid Progression of Angioimmunoblastic T Cell Lymphoma Following BNT162b2 mRNA Vaccine Booster Shot: A Case Report
Goldman et al
https://www.sciencedirect.com/science/article/abs/pii/S0046817718301941
TP53 mutations in peripheral mature T and NK cell lymphomas: a whole-exome sequencing study with correlation to p53 expression
Huang et al.
https://www.sciencedirect.com/science/article/pii/S0048969721074222
Toxicity of spike fragments SARS-CoV-2 S protein for zebrafish: A tool to study its hazardous for human health?
VenturaFernandes et al
Zebrafish injected with SARS-CoV-2 rSpike protein shows several morphological alterations.
https://pubmed.ncbi.nlm.nih.gov/33360731/
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
Nuovo et al
ACE2+ endothelial damage is a central part of SARS-CoV2 pathology and may be induced by the spike protein alone
spike toxicity
https://link.springer.com/article/10.1007/s10875-022-01228-2
First Identified Case of Fatal Fulminant Eosinophilic Myocarditis Following the Initial Dose of the Pfizer-BioNTech mRNA COVID-19 Vaccine (BNT162b2, Comirnaty): an Extremely Rare Idiosyncratic Necrotizing Hypersensitivity Reaction Different to Hypersensitivity or Drug-Induced Myocarditis
Nicholas G. Kounis
fulminant eosinophilic myocarditis as an extremely rare idiosyncratic necrotizing hypersensitivity reaction
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7799037/
SARS-CoV-2 spike protein binds to bacterial lipopolysaccharide and boosts proinflammatory activity
Petruk et al
There is a link between high lipopolysaccharide (LPS) levels in the blood and the metabolic syndrome, and metabolic syndrome predisposes patients to severe COVID-19.
our results provide an interesting molecular link between excessive inflammation during infection with SARS-CoV-2 and comorbidities involving increased levels of bacterial endotoxins.
https://www.sciencedirect.com/science/article/pii/S027869152200206X
Innate immune suppression by SARS-CoV-2 mRNA vaccinations: The role of G-quadruplexes, exosomes, and MicroRNAs
Seneff et al
mRNA vaccines promote sustained synthe