Édité le 27 septembre 2022
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last update 27 sept 2022
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[VAX INEFFECTIVITY]
[MYOCARDITIS RISK - proposed mechanism, myocarditis after vax (yes and no), myocarditis after infection (yes and no) ]
[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 - modified immune response, DNA damage, p53-blocking mechanism]
[PRION DISEASES - ALZHEIMER - infection, spike protein, possible treatments]
[AMYLOIDOSIS - ALZHEIMER - infection, spike, treatments]
[CELLULLAR SENESCENCE - Ciliopathy,telomere dysfunction, cellullar senescence]
[INFERTILITY - menstrual problems, pregnancy and miscarriage, placenta, maternal transmission, testes]
[MATERNAL TRANSMISSION TO THE FETUS/BABY]
[VIRAL and VACCINE SHEDDING]
[LIPID NANOPARTICLES - blood-brain barrier, LNP toxicity, depression of the immune system]
[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).

*be prepared for high-risk autoimmune triggering by each extra vaccination dose with an obsolete antigen
*keep boosting your non-binding antibodies
*sounds like a good plan :D

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:
https://www.medrxiv.org/content/10.1101/2021.12.20.21267966
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:
https://onlinelibrary.wiley.com/doi/abs/10.1002/eji.202149535
Persistence of neutralizing antibodies a year after SARS-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.

*or approving new bivalent vax after testing it IN EIGHT (8) MICE and zero (0) humans
https://www.fda.gov/media/159496/download
https://www.fda.gov/media/159492/download
https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-moderna-pfizer-biontech-bivalent-covid-19-vaccines-use


*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.

https://pubmed.ncbi.nlm.nih.gov/36074486/
COVID-19-Associated Hospitalizations Among Vaccinated and Unvaccinated Adults 18 Years or Older in 13 US States, January 2021 to April 2022
Havers et al
hospitalization rates were 10.5 times higher in unvaccinated persons and 2.5 times higher in vaccinated persons with no booster dose, respectively, compared with those who had received a booster dose. Among sampled cases, vaccinated hospitalized patients with COVID-19 were older than those who were unvaccinated (median [IQR] age, 70 [58-80] years vs 58 [46-70] years, respectively; P < .001) and more likely to have 3 or more underlying medical conditions (1926 [77.8%] vs 4124 [51.6%], respectively; P < .001).

*this study suggests not only that the vaccines give negative ‘protection’ after a few months but also that they destroy the protection that should have been provided by natural immunity (see chart B negative effectiveness,Charts C and D erasure of natural immunity):
https://www.nejm.org/doi/full/10.1056/NEJMoa2117128
Effectiveness of Covid-19 Vaccines over a 9-Month Period in North Carolina
Lin et al
273,157 children
among previously uninfected children, vaccine effectiveness reached 63.2% (95% confidence interval [CI], 61.0 to 65.2) at 4 weeks after the first dose and decreased to 15.5% (95% CI, 8.1 to 22.8) at 16 weeks;
among previously infected children, vaccine effectiveness reached 69.6% (95% CI, 57.4 to 78.3) at 4 weeks after the first dose and decreased to 22.4% (95% CI, 13.0 to 30.8) at 16 weeks

*mRNA vaccines like Pfizer’s inhibit the immune system response to other pathogens:
https://www.medrxiv.org/content/10.1101/2021.05.03.21256520v1.full
The BNT162b2 mRNA vaccine against SARS-CoV-2 reprograms both adaptive and innate immune responses
Föhse et al
BNT162b2 vaccine induces complex functional reprogramming of innate immune responses
BNT162b2 vaccine can also modulate innate immune responses.
a potential to interfere with the responses to other vaccinations, as known for other vaccines to be as ‘vaccine interference’

*Letter (uh-oh - never stop boosting) :
https://www.cell.com/trends/molecular-medicine/fulltext/S1471-4914(22)00188-5
COVID-19 mRNA vaccine-induced adverse effects: unwinding the unknowns
Trougakos et al
If recent findings revealing the existence of vaccine mRNA in lymph nodes, and of S antigen in lymph nodes and blood, for 2 months post-SARS-CoV-2 mRNA vaccination [4.] are confirmed, then the mechanistic details of S mRNA persistence and protein production for such a prolonged period in human tissues should be prioritized for investigation.
In fact, the idea of ‘fading’ protection (increased risk of serious COVID-19 outcomes) from boosting doses should be viewed (excluding conditions of immunosuppression) as a significant paradox given the durable extremely high titers of anti-S antibodies post boosting vaccination [11.].

*what's the point then?
https://www.medrxiv.org/content/10.1101/2022.08.30.22279344v1
Recent SARS-CoV-2 infection abrogates antibody and B-cell responses to booster vaccination
Buckner et al
Thus, B-cell responses to booster vaccines are impeded by recent infection.

*Denmark. No vaxx under 50
https://www.sst.dk/en/English/Corona-eng/Vaccination-against-COVID-19
The Danish Health Authority expects that the number of covid-19 infections will increase during autumn and winter. Therefore, we recommend vaccination of people aged 50 years and over as well as selected risk groups. Read more about the autumn vaccination programme here.

*each vaccine was associated with a distinctive toxic profile (CHAdOx1 vs BNT162b2):
https://pubmed.ncbi.nlm.nih.gov/36043937/
Disproportionality analysis of adverse neurological and psychiatric reactions with the ChAdOx1 (Oxford-AstraZeneca) and BNT162b2 (Pfizer-BioNTech) COVID-19 vaccines in the United Kingdom
Otero-Losada et al
AEFIs more frequently reported after CHAdOx1 compared with BNT162b2 vaccination were Guillain-Barré syndrome (OR, 95% CI= 2.53, 1.82-3.51), freezing (6.66, 3.12-14.22), cluster headache (1.53, 1.28-1.84), migraine (1.23,1.17-1.30), postural dizziness (1.24,1.13-1.37), tremor (2.86, 2.68-3.05), headache (1.40, 1.38-1.43), paresthesia (1.11, 1.06-1.16), delirium (1.85, 1.45-2.36), hallucination (2.20, 1.82-2.66), poor quality sleep (1.53, 1.26-1.85), and nervousness (1.54, 1.26-1.89) Reactions less frequently reported with ChAdOx1 than with BNT162b2 were Bell's palsy (0.47, 0.41-0.55), anosmia (0.58, 0.47-0.71), facial paralysis (0.35, 0.29-0.41), dysgeusia (0.68, 0.62-0.73), presyncope (0.48, 0.42-0.55), syncope (0.63, 0.58-0.67), and anxiety (0.75 (0.67-0.85).

*monoclonal antibodies escape confirmed
*this is bad (see T-cell exhaustion)
*any monoclonal antibody therapy we have so far will fail
*thank you, vaccine interventions, for teaching me the true meaning of convergent evolution
https://www.biorxiv.org/content/10.1101/2022.09.16.508299v2
Omicron sublineage BA.2.75.2 exhibits extensive escape from neutralising antibodies
Sheward et al
In recent serum samples from blood donors in Stockholm, Sweden, BA.2.75.2 was neutralised, on average, at titers approximately 6.5-times lower than BA.5, making BA.2.75.2 the most neutralisation resistant variant evaluated to date
BQ.1.1 escapes evusheld and bebtelovimab
BA.2.75.2 was resistant to neutralisation by Evusheld (tixagevimab + cilgavimab), but remained sensitive to bebtelovimab.


*In conclusion, COVID-19 vaccination is a major risk factor for infections in critically ill patients:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9167431/
Adverse effects of COVID-19 vaccines and measures to prevent them
Kenji Yamamoto
frequent COVID-19 booster shots could adversely affect the immune response
caused by several factors such as N1-methylpseudouridine, the spike protein, lipid nanoparticles, antibody-dependent enhancement, and the original antigenic stimulus
Several practical measures to prevent a decrease in immunity have been reported. These include limiting the use of non-steroidal anti-inflammatory drugs, including acetaminophen to maintain deep body temperature, appropriate use of antibiotics, smoking cessation, stress control, and limiting the use of lipid emulsions, including propofol, which may cause perioperative immunosuppression.
In conclusion, COVID-19 vaccination is a major risk factor for infections in critically ill patients.

*1.be young 2.dont be sick 3.have interferon
https://pubmed.ncbi.nlm.nih.gov/36129445/
Impaired immune response drives age-dependent severity of COVID-19
Beer et al
age-dependent disease severity is caused by the disruption of a timely and well-coordinated innate and adaptive immune response due to impaired interferon (IFN) immunity
Our data suggest that highly vulnerable individuals could benefit from immunotherapy combining IFN-&#947; and IFN-&#955;.


https://www.medrxiv.org/content/10.1101/2022.04.18.22271936v1
Anti-nucleocapsid antibodies following SARS-CoV-2 infection in the blinded phase of the mRNA-1273 Covid-19 vaccine efficacy clinical trial
Follmann et al
The hypothesis tested was that mRNA-1273 recipients have different anti-N Ab seroconversion and/or seroreversion profiles after SARS-CoV-2 infection, compared to placebo recipients.
As a marker of recent infection, anti-N Abs may have lower sensitivity in mRNA-1273-vaccinated persons who become infected.
seroconversion to anti-N Abs at a median follow up of 53 days post diagnosis occurred in 21/52 (40%) of the mRNA-1273 vaccine recipients vs. 605/648 (93%) of the placebo recipients (p < 0.001).

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[MYOCARDITIS RISK - proposed mechanism, myocarditis after vax (yes and no), myocarditis after infection (yes and no) ]
*tl;dr TWICE THE JAB, DOUBLE THE MYOCARDITIS

[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).

*Meta-review analysis on atheletes
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


[MYOCARDITIS: PROPOSED MECHANISM BEHIND INCREASED MYOCARDITIS RISK]
[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

https://www.sciencedirect.com/science/article/pii/S2589790X20300640
COVID-19 and Myocarditis: What Do We Know So Far?
Pirzada et al

[2021]
*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://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.

*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.

[MYOCARDITIS: PAPERS THAT SHOW AN INCREASE OF MYOCARDITIS RISK AFTER VACCINATION]
[2021]
*Sample size:23
*Cases 43/100K (second dose, young males)
https://jamanetwork.com/journals/jamacardiology/fullarticle/2781601
Myocarditis Following Immunization With mRNA COVID-19 Vaccines in Members of the US Military
Montgomery et al
436K second doses to male military members, 19 cases myocarditis (expected 0 to 8)
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 (10,8 cases/100K)
*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

*VAERS report analysis:
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

*Letter to editor:
https://www.nejm.org/doi/full/10.1056/NEJMc2115045
Adverse Effects after BNT162b2 Vaccine and SARS-CoV-2 Infection, According to Age and Sex
Dagan et al
Myocarditis risk is cumulative based on spike exposure.

*VAERS report analysis:
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
*Sample size:42 Million
*Cases after second dose: 14/100K (Oxford/AZ) 12/100K (Pfizer/BNT162b2) and 101/100K (Moderna/mRNA-1273)
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.

[2022]
*Sample size:23 Million
*Cases after second dose: 5.5/100K(Pfizer/BNT162b2) and 18/100K (Moderna/mRNA-1273)
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.

*Sample size:156K
*Cases after third dose: 11/100K(Pfizer/BNT162b2)
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

*Sample size:301
https://www.mdpi.com/2414-6366/7/8/196
Cardiovascular Manifestation of the BNT162b2 mRNA COVID-19 Vaccine in Adolescents
Mansanguan et al
301 participants
Cardiovascular manifestations were found in 29.24% of patients
tachycardia (7.64%), shortness of breath (6.64%), palpitation (4.32%), chest pain (4.32%), and hypertension (3.99%).
Myopericarditis was confirmed in one patient after vaccination. Two patients had suspected pericarditis and four patients had suspected subclinical myocarditis.

*Population study (VAERS)
*Cases after second dose: 16.2/100K(ages 12-15)
*Cases after second dose: 9.3/100K(ages 12-15)
https://www.medrxiv.org/content/10.1101/2021.08.30.21262866v2
SARS-CoV-2 mRNA Vaccination-Associated Myocarditis in Children Ages 12-17: A Stratified National Database Analysis
Høeg et al
Stratified cardiac adverse event (CAE) rates were reported for age, sex and vaccination dose number.
For boys 12-17 without medical comorbidities, the likelihood of post vaccination dose two CAE is 162.2 and 93.0/million respectively.

*back in 2021, the FDA acknowledged in their models 1/5000 cases of myocarditis in young males
https://www.fda.gov/media/151733/download
an estimated excess risk approaching 200 cases per million vaccinated males 16-17 years of age

*before it was 1 in 5000 doses caused servere adverse events
*1/5000 = 20/100K
*now its 1 in ~3000
*1/3000 = 33/100K
Paul Erlich Institute:
https://www.pei.de/DE/newsroom/dossier/coronavirus/arzneimittelsicherheit.html
*0.046 per 1000 vaccine doses in the first report
*0.046 per 1000 = 4,6/100K doses.
*Now its 0.3 per 1000 = 30/100K
https://www.pei.de/SharedDocs/Downloads/DE/newsroom/dossiers/sicherheitsberichte/sicherheitsbericht-27-12-bis-31-12-20.pdf?__blob=publicationFile&v=6

*Sample size:324
*620/100K after fourth dose
https://pubmed.ncbi.nlm.nih.gov/36097844/
A Prospective Study on Myocardial Injury after BNT162b2 mRNA COVID-19 Fourth Dose Vaccination in Healthy Persons
Levi et al
324 participants
Vaccine-related myocardial injury was demonstrated in two (0.62%) participants, one had mild symptoms and one was asymptomatic
an increase in serum troponin levels

*follow up of 519 patients
*after 90 days, 32% were NOT cleared for physical activity
https://www.thelancet.com/journals/lanchi/article/PIIS2352-4642(22)00244-9/fulltext
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
Kracalik et al
An abnormality was noted among 81 (54%) of 151 patients with follow-up cardiac MRI

*HK myocarditis data
*3.37/100K after first dose
*21.22/100K after second dose
*5.57/100K after first dose in young males
*37.32/100K after second dose in young males
https://pubmed.ncbi.nlm.nih.gov/34849657/
Epidemiology of Acute Myocarditis/Pericarditis in Hong Kong Adolescents Following Comirnaty Vaccination
Chua et al
There is a significant increase in the risk of acute myocarditis/pericarditis following Comirnaty vaccination among Chinese male adolescents, especially after the second dose.

*VSD data
*9.5/100K after second doses, patients age 12-39
https://www.medrxiv.org/content/10.1101/2021.12.21.21268209v1
Risk of Myopericarditis following COVID-19 mRNA vaccination in a Large Integrated Health System: A Comparison of Completeness and Timeliness of Two Methods
Sharff et al

[MYOCARDITIS: PAPERS THAT DO NOT SHOW AN INCREASE OF MYOCARDITIS RISK AFTER INFECTION]
[2022]
*(Note: 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.)
Sample size:590K
https://www.mdpi.com/2077-0383/11/8/2219/htm
The Incidence of Myocarditis and Pericarditis in Post COVID-19 Unvaccinated Patients—A Large Population-Based Study
Ortal Tuvali et al
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
limitations:
(1 small sample size) This was mainly attributed to the limitation of a relatively short follow-up period due to the initiation of the massive vaccination program
(2 only hospitalizations) outpatient medical records were excluded from the study. This could possibly omit a small number of patients with mild disease.

[MYOCARDITIS: PAPERS THAT SHOW AN INCREASE OF MYOCARDITIS RISK AFTER INFECTION]
[2020]
*Meta-review, refers to Wang et al:Sample-size: 138
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.
https://jamanetwork.com/journals/jama/fullarticle/2761044
Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus–Infected Pneumonia in Wuhan, China
Wang et al

[2021]
*Sample size:129
*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 Inflammatory Syndrome (2.3%) and two myocarditis (1.6%).

*Sample size:186
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

*electronic health records analysis
*as high as 45/100K
https://www.medrxiv.org/content/10.1101/2021.07.23.21260998v2
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.

[2022]
*Sample size:154K
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://europepmc.org/article/pmc/pmc8938267
Long-term cardiovascular outcomes of COVID-19.
Xie et al




==============================================================
==============================================================
[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)

*FYI:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901381/
Vaccine-associated enhanced disease: Case definition and guidelines for data collection, analysis, and presentation of immunization safety data [2021]
Munoz et al
>Case definition of vaccine associated enhanced disease (VAED)
>Cytokine activation/storm and enhanced disease (SARS, MERS, SARS-CoV-2)
>Knowledge gaps in current understanding of potential VAED in the context of SARS-CoV-2
>>Mechanisms, >>Animal Models, >>Vaccine Platforms, >>Adjuvants, >>Diagnosis, >>Disease Severity
>Diagnostic tests
>>Evidence inadequate or unbalanced neutralizing antibody responses (Low or inappropriate total binding (IgG, IgM, IgA) antibody titers; Low neutralizing antibody titers; Low ratio of neutralizing to binding antibody; Low absolute affinity of IgG antibody to receptor binding domain (RBD); Lack of acquisition or loss of affinity of IgG to RBD; Increased viral load
>>Evidence of inadequate or inappropriately biased cellular immune responses (Lymphopenia or lymphocytosis; High CD4 lymphocyte subset; Low CD8 lymphocyte subset; Th2 (IL-4, IL-5, IL-13) CD4 T cell predominant response over Th1 (INFg, TNF) responses (testing in vitro stimulation with viral peptides or proteins, ELISPOT, or intracellular cytokine staining assays); Low virus-specific cytotoxic T-cells (CTL))
>>Evidence of exuberant inflammatory responses (Elevated IL-1, IL-6, IL-8; Increased pro-inflammatory chemo/cytokines: INF-g, type 1-INF, TNF, CCL2, CCL7; Reduced expression of type I interferons (eg. IFN-&#945;, INF-b); Elevated C-reactive protein, Ferritin, Lactate dehydrogenase (LDH), D-dimers)
>>Evidence of immunopathology in target organs involved, by histopathology (Present or elevated tissue eosinophils in tissue; Elevated pro-inflammatory Th2 cytokines in tissue (IL4, IL5, IL10, IL13); C4d tissue deposition (evidence for complement activation through immune complex deposition); C1q assessments of immune complexes in fluids; Low C3 levels as evidence complement consumption)


[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&#8208;19 disease via antibody&#8208;dependent enhancement (ADE). This risk is sufficiently obscured in clinical trial protocols and consent forms for ongoing COVID&#8208;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&#8208;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 independent of Furin-Cleavage: since it's likely age-related then everyone vaccinated in that age-group are basically primed for this type of ADE. Once titers drop enough so that neutralizing don't do anything and they're exposed, they'll 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 case report on ADE
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 et 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 Fc&#947;RIIA and Fc&#947;RIIIA but Does Not Contribute to Aberrant Cytokine Production by Macrophages
Maemura et al
We found that Fc&#947;RIIA and Fc&#947;RIIIA 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.

*ADE confirmed, with time
https://pubmed.ncbi.nlm.nih.gov/36114224/
https://rdcu.be/cVODF
Reevaluation of antibody-dependent enhancement of infection in anti-SARS-CoV-2 therapeutic antibodies and mRNA-vaccine antisera using FcR- and ACE2-positive cells
Shimizu et al
we demonstrate that certain monoclonal Abs (mAbs) approved as therapeutic neutralizing anti-S-protein mAbs for human usage have the potential to cause ADE in a narrow range of Ab concentrations. Although sera collected from mRNA-vaccinated individuals exhibited neutralizing activity, some sera gradually exhibited dominance of ADE activity in a time-dependent manner. None of the sera examined exhibited neutralizing activity against infection with the Omicron strain.
These results suggest that the rapid spread of Omicron around the world may in part result from the lack of cross-neutralization against Omicron and some ADE activity of sera after vaccination.

https://pubmed.ncbi.nlm.nih.gov/31826992/
Molecular Mechanism for Antibody-Dependent Enhancement of Coronavirus Entry
Wan et al
we identify a novel mechanism for ADE: a neutralizing antibody binds to the surface spike protein of coronaviruses like a viral receptor, triggers a conformational change of the spike, and mediates viral entry into IgG Fc receptor-expressing cells through canonical viral-receptor-dependent pathways.


==============================================================
==============================================================
[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.ncbi.nlm.nih.gov/pmc/articles/PMC7871851/
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.

==============================================================
==============================================================
[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

*case report:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9385769/
COVID-19 mRNA vaccine BNT162b2 induces autoantibodies against type I interferons in a healthy woman
Ning et al
plasma levels of IgG against type I interferons (IFNs) were increased specifically among the 103 autoantibodies tested following the second shot of COVID-19 vaccine BNT162b2 compared to pre-vaccination and further increased following the third shot of BNT162b2 in a healthy woman. Unlike COVID-19 mediated autoimmune responses, vaccination in this healthy woman did not induce autoantibodies against autoantigens associated with autoimmune diseases.

*case report
https://www.hindawi.com/journals/ad/2022/9171284/
Autoimmune Diseases Induced or Exacerbated by COVID-19: A Single Center Experience
Ishay et al
six patients
following severe SARS-CoV-2 infection
Several theories
The molecular mimicry theory revolves around the concept that shared structural elements between self-antigens and infectious antigens may drive the immune system to attack the former. Growing evidence supports this theory as human peptide sequences are found to be shared with SARS-CoV-2 proteins, for example, a heptapeptide shared between the human proteome and the viral spike glycoprotein [3]. Some evidence supports this theory, as in the case of acute myocarditis induced by group A Streptococcus (GAS) infection due to structural similarities between M-protein of GAS and the myocardium [14].
Another suggested mechanism is the adjuvant or bystander effect. Proponents of this theory cite the infection-driven inflammatory state as sufficient for providing a “second-hit” for self-antigen recognition by latent immune cells, which are potentially self-reactive
Lastly, viral persistence, as suggested by its name, is another underlying mechanism. Uncleared infection persisting in affected cells, whether still causing cellular damage or quiescent, may stimulate the immune system, particularly via cytotoxic lymphocytes. Immune cells may continue to mediate viral clearance after the symptomatic infection has resolved, causing inflammation and tissue damage via their cytolytic effects.

*case report
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9420842/pdf/fimmu-13-967226.pdf
https://www.frontiersin.org/articles/10.3389/fimmu.2022.967226/full
Four cases of cytokine storm after COVID-19 vaccination: Case report
Murata et al
Using RNA sequencing, we identified genes that were differentially expressed between our post-vaccination cases and a control group that died of blood loss and strangulation.
Three hundred and ninety genes were found to be upregulated and 115 genes were downregulated in post-vaccination cases compared with controls. Importantly, genes involved in neutrophil degranulation and cytokine signaling were upregulated.
Our results suggest that immune dysregulation occurred following vaccination.
Careful observation and care may be necessary if an abnormally high fever exceeding 40°C occurs after vaccination, even with antipyretic drugs.

*case report
https://pubmed.ncbi.nlm.nih.gov/34839563/
Genital necrosis with cutaneous thrombosis after COVID-19 mRNA vaccination
Kuzumi et al

==============================================================
==============================================================
[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.
*A human coronavirus evolves antigenically to escape antibody immunity

*why previous CoV vaccines failed in 2005:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371592/
Vaccine development against coronavirus (2003 to present): An overview, recent advances, current scenario, opportunities and challenges
Badgujar et al
some reports showed inflammation to liver and lung, neutrophil influx, and pro-inflammatory cytokine after getting challenge in animal model [33,34]. Besides this, it has drawbacks such as unsuitability of vaccination to immunologically sensitive population, requirement of multiple, frequent or high dosages of vaccination, reversing to virulence and appearance of low response in immune-compressed hosts which having comorbidities [21,30,32,34].
Several efforts have been attempted in the last 17 years to design a successful vaccine against coronavirus. However, NO vaccine is approved till date against coronavirus.

[ANTIBODY ESCAPE]
[2020]
*sometimes spike protein sometimes goes from "before" shape into "after", without binding:
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

*Free energy perturbation (FEP) and Molecular dynamics (MD) calculations:
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
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

*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 to bind, 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 HEK29

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