ADE – PRIMING, bronnen en vertalingen

paradoxically more severe disease course: Immune enhancement


Seasonal Influenza Vaccine and Increased Risk of Pandemic A/H1N1-Related Illness: First Detection of the Association in British Columbia, Canada

Conclusions. An outbreak investigation in British Columbia during the late spring of 2009 provided the first indication of an unexpected association between receipt of TIV and pH1N1 illness. This led to 5 additional studies through the summer 2009 in Canada, each of which corroborated these initial findings.

1 november 2010


first exposure to influenza virus shapes the outcome of subsequent exposures to antigenically related strains. When an individual is infected by an ‘evolved’ strain with a new dominant antigen, slightly different from the ‘original’ strain against which the person has been vaccinated, the immune system produces antibodies against the ‘original’ strain through preformed high-affinity memory B cells that inhibit activation of naïve B cells resulting in a weak immune response against the new ‘dominant’ strain. Hence, the risk of infection paradoxically increased in vaccinated individuals as compared to naïve individuals

viruses are known to interfere with the circulation of other viruses. For example, there is evidence that the circulation of rhinovirus in the community interferes and decreases the spread of seasonal and pandemic influenza viruses [3,4]. Viral interference is also well-known to interfere with “take” of oral polio vaccine. However, more recently a new phenomenon, ‘vaccine-associated virus interference’ has been suggested whereby a vaccine can paradoxically increase the circulation of other viruses. That is, vaccinated individuals may be at increased risk for other respiratory viruses because they do not receive the non-specific immunity associated with natural infection

JUNE 2020

Immune enhancement of the disease

ADE-Antibody Dependent Enhancement:

Na vaccinatie kan een productie van inefficiente antilichamen volgen. Deze niet-neutraliserende antilichamen kunnen binden aan FcReceptor van het virus. Het virus kan zo gemakkelijk toegang krijgen tot de cel.

Dit probleem kwam eerder naar voren tijdens de ontwikkeling van vaccins tegen RSV, Dengue, Ebola, HIV, feline coronavirus, en tijdens in in-vitro studies mbt het SARS-CoV-1 vaccin.

VAERD: Vaccine-associated enhanced respiratory disease
verkeerde antigenen in vaccin kan leiden tot veel bindende antilichamen
(via zelfde systeem als OAS?) Allergische ontstekingen


Clinical trials need to evaluate the potential harms in addition to the efficacy. Sometimes, the disease runs a more severe course paradoxically in individuals who are vaccinated. There are two immune-mediated mechanisms of such a phenomenon: first, an Ab-dependent enhancement (ADE), in which there is increased binding efficiency of virus-antibody complexes to FcR-bearing cells, which triggers viral entry. Thus, the viral entry might be facilitated by these antibodies, bypassing the specific receptor-mediated entry. 50 This phenomenon reflects the production of ‘inefficient’ antibodies by the vaccine which are incapable of thoroughly neutralizing the virus owing to low affinity or low concentration or nonspecific nature (“cross-reactive antibodies”). 51 These inefficient antibodies, along with a type-2 T-helper cell (Th-2)-biased immune response lead to Ab-mediated enhancement of infection. Such a phenomenon has been noted with RSV, Dengue, Ebola, and human immunodeficiency virus (HIV) vaccine candidates, feline coronavirus vaccine, and in in-vitro studies of the SARS-CoV-1 vaccine. 51–53 Very recently, similar concerns regarding vaccine enhancement of disease have been raised regarding certain SARS-CoV-2 vaccine candidate approaches. 30 There is a weak binding of human antibodies against common-cold causing coronaviruses and S-protein of SARS-CoV-1. 54 Lv et al. demonstrate similar cross-reactivity between SARS-CoV-1 and SARS-CoV-2 infected patients and immunized mice. However, these antibodies were non-neutralizing to conserved epitopes in the ‘S’ protein of SARS-CoV-2. 55 Whether such non-neutralizing antibodies can lead to an ‘ADE’ like response in the future cannot be ruled out and hence needs to be evaluated carefully in the clinic.

The second mechanism is ‘vaccine-associated enhanced respiratory disease’ (VAERD). It is a distinct clinical syndrome that was noted in young children in the 1960s when inactivated measles virus and respiratory syncytial virus (RSV) vaccines were tested. This happened because the vaccines contained conformationally incorrect antigens, resulting in a relatively high ratio of binding Ab to neutralizing antibody that causes immune complex deposition and complement activation leading to worsening of respiratory disease. Another mechanism of VAERD could be allergic inflammation associated with the vaccine. 56

Additional mutations in the virus may lead to a phenomenon referred to as ‘original antigenic sin’ in influenza immunology parlance with resultant disease enhancement after exposure that may render vaccines ineffective.

JULI 2020

Niet-neutraliserende of sub-neutraliserende antilichamen kunnen binden aan virusdeeltjes. Deze virus-antilichaam immuun complexen kunnen worden opgenomen door de gastheercellen middels interactie tussen de antilichaam Fc regio en de Fc receptor van de gast cel. Opgenomen immuuncomplexen kunnen daarnaast de immuunreactie van cellen onderdrukken. Cellen als Monocyten en Macrofagen kunnen op deze wijze gekaapt worden. ipv virusdeeltjes vernietigers kunnen ze zelfs virusfabriekjes worden. Dit leidt tot sterkere vermeerdering van virusdeeltjes en een ernstiger ziektebeeld.
De waargenomen verslechtering van Covid- patienten na 7 tot 14 dagen ziekte zou hiermee samen kunnen hangen. De door ADE gevormde immuuncomplexen activeren de monocyten/macrofagen en kunnen de zgn cytokinestorm triggeren.


VAERD wordt veroorzaakt door een vaccinatie met verkeerde type antigenen.

Bij een hoge viral load kunnen immuuncomplexen gevormd worden en ophopen in het longweefsel. En er kunnen cytokines gevormd worden waardoor er ontstekingsreacties ontstaan. VAERD werd waargenomen na vaccinatie tegen mazelen en RSV bij kinderen en SARS bij dieren.

11 november 2020

The basic condition of a common use of a vaccine in healthy people is safety. At present, there is a risk that vaccination could make subsequent SARS-CoV-2 infection more severe (29-31). There are two different antibody-mediated syndromes. One is antibody-dependent enhancement (ADE) of infection and the other is vaccine-associated enhanced respiratory disease (VAERD). ADE phenomenon conditions the presence of non-neutralizing or sub-neutralizing antibodies, which bind to the virus particles. Virus-antibody immune complexes are internalized into host cells via interaction of the antibody Fc region with the cellular Fc receptors (30,32). So, in ADE mechanism the target cells are myeloid lineage cells with Fc receptors expression. In contrast, SARS-CoV-2 primarily infects pulmonary, endothelial, renal, and intestinal parenchymal cells that express ACE2. Therefore, Fc receptor mediated ADE not only intensifies the infection of already susceptible cells but also can expand tropism to, e.g., monocytes and macrophages. Moreover, internalized immune complexes can cause suppression of the cellular innate antiviral response (32). In the consequence, this leads to the enhancement of viral replication and exacerbation of clinical symptoms. In some patients with COVID-19, approximately 7th to 14th day of illness a dramatic decline in respiratory function occurs. It is suggested that the pathomechanism of this phenomenon is similar to Fc receptor-mediated ADE, the formation of immune complexes may activate monocytes/macrophages to trigger a cytokine storm (32-34). The above data, and the earlier in vitro tests with the use of serum from SARS-CoV patients with S protein-specific antibodies indicate that the therapeutic use of convalescents’ plasma with anti-SARS-CoV-2 antibodies could facilitate infecting monocytes/macrophages and in the consequence cause disease exacerbation (35,36). ADE has been described after immunizing cats with a vaccine against veterinary coronavirus (37,38).

VAERD is a distinct clinical syndrome, it mainly occurs after the use of a vaccine containing conformationally incorrect antigens. VAERD may be the result of two major mechanisms of immunological phenomenon, which are associated with enhanced respiratory disease (30,32). One of them is conditional upon immune complex formation and complement deposition in lungs tissue (in the presence of high viral load). Whereas the other is associated with complement activation, expression of proallergic cytokines and in the result, with the development of allergic inflammation (39). VAERD was demonstrated in humans immunized with vaccines for measles and respiratory syncytial virus (RSV) and in animals for SARS (40-42).

Type Monoclonaal antilichaam : CT-P59 mAb

A therapeutic neutralizing antibody targeting receptor binding domain of SARS-CoV-2 spike protein.

Vaccines and therapeutics are urgently needed for the pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we screen human monoclonal antibodies (mAb) targeting the receptor binding domain (RBD) of the viral spike protein via antibody library constructed from peripheral blood mononuclear cells of a convalescent patient. The CT-P59 mAb potently neutralizes SARS-CoV-2 isolates including the D614G variant without antibody-dependent enhancement effect. Complex crystal structure of CT-P59 Fab/RBD shows that CT-P59 blocks interaction regions of RBD for angiotensin converting enzyme 2 (ACE2) receptor with an orientation that is notably different from previously reported RBD-targeting mAbs. Furthermore, therapeutic effects of CT-P59 are evaluated in three animal models (ferret, hamster, and rhesus monkey), demonstrating a substantial reduction in viral titer along with alleviation of clinical symptoms. Therefore, CT-P59 may be a promising therapeutic candidate for COVID-19.

CT-P59 mAb kan SARS-Cov-2 neutraliseren, ook D614G variant zonder ADE effect

12 JANUARI 2021


COVID-19 Vaccines: A Primer for Clinicians


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the identified cause of coronavirus disease 2019 (COVID-19), continues unabated. This fact, coupled with recurrence of COVID-19 in areas where it had been controlled, highlights the critical need for a safe and effective vaccine to prevent and mitigate this novel virus. The spike protein of SARS-CoV-2 is important in its lifecycle as well as in the development of immunity after human infection. This has prompted the selection of this antigen as a focus in developing COVID-19 vaccines. This article provides (1) a summary of the host immune responses to SARS-CoV-2 infection, (2) the vaccine platforms being used with COVID-19 vaccine candidates undergoing, or about to undergo, Phase III clinical trial testing, and (3) an overview of the key criteria necessary for COVID-19 vaccine efficacy and safety. In addition, the unique concept of vaccine-enhanced disease will be discussed. [Pediatr Ann. 2020;49(12):e532–e536.]

(Formalin-inactivation RSV resulted in the formation of conformationally incorrect antigens which in turn brought about a high ratio of binding antibody to neutralizing antibody. In the presence of … )


Vaccine-enhanced disease
Available data do not indicate a risk of vaccine-enhanced disease, and conversely suggest
effectiveness against severe disease within the available follow-up period. However, risk of
vaccine-enhanced disease over time, potentially associated with waning immunity, remains
unknown and needs to be evaluated further in ongoing clinical trials and in observational studies
that could be conducted following authorization and/or licensure.
blz 49

Vaccines and Related Biological Products Advisory Committee Meeting
December 10, 2020
FDA Briefing Document
Pfizer-BioNTech COVID-19 Vaccine


2.3.1. Risk Assessment

Potential Risk of Clinical
Summary of Data/Rationale for Risk Mitigation Strategy
Study Intervention: BNT162 RNA-Based COVID-19 Vaccine
Potential for local reactions (injection
site redness, injection site swelling,
and injection site pain) and systemic
events (fever, fatigue, headache,
chills, vomiting, diarrhea, muscle
pain, and joint pain) following
These are common adverse reactions seen
with other vaccines, as noted in the FDA
Center for Biologics Evaluation and
Research (CBER) guidelines on toxicity
grading scales for healthy adult volunteers
enrolled in preventive vaccine clinical
The Phase 1 study design includes the use of controlled vaccination and
dose escalation to closely monitor and limit the rate of enrollment to ensure
participant safety. The study employs the use of a reactogenicity e-diary to
monitor local reactions and systemic events in real time. Stopping rules are
also in place. The first 5 participants in each group in Phase 1 will be
observed for 4 hours after vaccination to assess any immediate AEs. All
other participants will be observed for at least 30 minutes after vaccination.
Unknown AEs and laboratory
abnormalities with a novel vaccine.
This study is one of the first 2
parallel-running clinical studies with the
BNT162 vaccine candidates and as such
there are no clinical data available for this
The Phase 1 study design includes the use of controlled vaccination and
dose escalation to closely monitor and limit the rate of enrollment to ensure
participant safety. An IRC (in Phase 1) and DMC (throughout the study)
will also review safety data. Stopping rules are also in place. The first 5
participants in each group in Phase 1 will be observed for 4 hours after
vaccination to assess any immediate AEs. All other participants will be
observed for at least 30 minutes after vaccination.
Potential for COVID-19
Disease enhancement has been seen
following vaccination with respiratory
syncytial virus (RSV), feline coronavirus,
and Dengue virus vaccines.
Phase 1 excludes participants with likely previous or current COVID-19. In
Phase 2/3, temporary delay criteria defer vaccination of participants with
symptoms of potential COVID-19. All participants are followed for any
potential COVID-19 illness, including markers of severity, and have blood
samples taken for potential measurement of SARS-CoV-2 antigen-specific
antibody and SARS-CoV-2 neutralizing titers.

In fase 1 werden geen deelnemers met Covid of een Covid historie toegelaten.

in fase 2/3 temporary delay criteria defer vaccination of participants with
symptoms of potential COVID-19

5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:

5. Previous clinical (based on COVID-19 symptoms/signs alone, if a SARS-CoV-2 NAAT
result was not available) or microbiological (based on COVID-19 symptoms/signs and a
positive SARS-CoV-2 NAAT result) diagnosis of COVID-19.

blz 41

Diagnostic Assessments:
18. Phase 1 only: Positive serological test for SARS-CoV-2 IgM and/or IgG antibodies at
the screening visit.

21. Phase 1 only: SARS-CoV-2 NAAT-positive nasal swab within 24 hours before receipt of
study intervention

7.1. Discontinuation of Study Intervention
Note that a positive SARS-CoV-2 NAAT result
without symptoms does not meet exclusion criterion 5 and should not result in
discontinuation of study intervention, whereas a COVID-19 diagnosis does meet exclusion
criterion 5 and should result in discontinuation of study intervention (see Section 8.15).
Note that discontinuation of study intervention does not represent withdrawal from the study.
Per the study estimands, if study intervention is definitively discontinued, the participant will
remain in the study to be evaluated for safety, immunogenicity, and efficacy.

Stopping Rule Criteria for Each BNT162 Vaccine Candidate:
5. If any participant dies or requires ICU admission due to SARS-CoV-2 infection; if this
stopping rule is met, all available clinical and preclinical safety and immunogenicity data
should be reviewed to evaluate for enhanced COVID-19.

8.2.4. Surveillance of Events That Could Represent Enhanced COVID-19 and Phase 2/3
Stopping Rule
Participants in all phases of the study will be surveilled for potential COVID-19 illness from
Visit 1 onwards (see
Section 8.13).
As this is a sponsor open-label study during Phase 1, the sponsor will conduct unblinded
reviews of the data during the course of the study, including for the purpose of safety
assessment. All NAAT-confirmed cases in Phase 1 will be reviewed contemporaneously by
the IRC and the DMC (see
Section 9.6).
In Phase 2/3, the unblinded team supporting the DMC, including an unblinded medical
monitor, will review cases of severe COVID-19 as they are received and will review AEs at
least weekly for additional potential cases of severe COVID-19. At any point, the unblinded
team may discuss with the DMC chair whether the DMC should review cases for an adverse
imbalance of cases of COVID-19 and/or severe COVID-19 between the vaccine and placebo
The purpose of these reviews will be to identify whether any features of each case appear
unusual, in particular greater in severity, compared to available information at the time of
review. Indicators of severity may include accelerated deterioration, need for hospitalization,
need for ventilation, or death. Observed rates of these indicators will be compared with what
could be expected in a similar population to the study participants based upon available
information at the time of review.
Stopping and alert rules will be applied as follows. The stopping rule will be triggered when
the 1-sided probability of observing the same or a more extreme case split is 5% or less when
the true incidence of severe disease is the same for vaccine and placebo participants, and alert
criteria are triggered when this probability is less than 11%. In addition, when the total
number of severe cases is low (15 or less), the unblinded team supporting the DMC will
implement the alert rule when a reverse case split of 2:1 or worse is observed. For example,
at 3 cases 2:1, at 4 cases 3:1, etc. Below 15 cases, this rule is more rigorous than requiring
the probability of an observed adverse split or worse be <11%. Further details can be found
Section 10.7.

8.13. COVID-19 Surveillance (All Participants)
• Surveillance of potential COVID-19 symptoms should continue even if a participant has
a positive SARS-CoV-2 test earlier in the study

8.11.1. Phase 1 Screening: (0 to 28 Days Before Visit 1)
Collect a blood sample (approximately 20 mL) for potential future serological
assessment and to perform a rapid test for prior COVID-19 infection.

Pfizer COVID Vaccine Trial Shows Alarming Evidence of Pathogenic Priming in Older Adults

– Eerdere blootstelling aan de proteines van een pathogeen veroorzaken “pathogenic priming” van het lichaam voor autoimmuniteit. Bij Covid-19 heeft ieder SARS-COV-2 proteine minstens 1 epitope dat overeenkomt met menselijke protienes in het menselijk lichaam. Ongeveer een derde van de epitopes in het SARS-COV-2 virus die overeenkomst hebben met menselijke proteines komen overeen met immuunsysteem proteines.

In documentatie van Pfizer mbt de vaccin tirals zijn verontrustende tekenen terug te vinden die zouden kunnen wijzen op Pathogenic Priming, vooral onder ouderen.
De onderzoeksopzet roept zelf ook wat vragen op.

Ten eerste het onderscheid tussen ernstige en milde bijwerkingen. Bell’s Palsy, zenuwontstekingen en trombose zijn geen milde bijwerkingen en kunnen na verloop van tijd ontwikkelen tot levensbedreigende aandoeningen, met een langdurig behandeltjaject en aanverwante kosten. In de korte termijn studie worden de mogelijkheden uitgesloten om op te kunnen merken of de eerste blootstelling aan de basis kan liggen van het ontwikkelen van levenslange chronische ziekte bij patienten. De bijwerkingen zoals die naar voren komen uit de studie van Pfizer kunnen op zichzelf al een teken van Pathogenische Priming zijn, vooral omdat er na de tweede dosis ernstigere bijwerkingen werden waargenomen.

Tweede punt is dat de studie opzet niet objectief is mbt het opmerken van bijwerkingen. Er wordt mbt de 4 Bell’s Palsy gevallen in de vaccingroep en geen in de placebogroep gemeld dat het aantal van 4 niet boven het aantal in de gemiddelde polulatie ligt. Deze vergelijking met de baseline is nutteloos. In de algemene populatie worden andere vaccins gebruikt. Het risico mbt Covid-vaccines komt bovenop of vermenigvuldigt zelfs het baseline risico op bijwerkingen.

Na de tweede dosis kwamen er in de deelnemers groep boven 55 jaar 10x meer Serious Adverse Events voor. Tegenover 3,6 x in de groep onder 55 jaar. Het betreft bij de studies gezonde deelnemers en is in die zin niet representatief voor mbt de situatie wanneer het vaccin op de markt komt.

In eerdere dierproeven bestond de eerste dosis uit een vaccin en de tweede uit een natuurlijke infectie. Dit leidde tot zeer ernstige bijwerkingen en vaak tot sterfte. In deze studies op mensen bestaan beide dosissen uit het vaccin. Daarmee kan dus niet uitgesloten worden dat er bij dit vaccin hetzelfde effect zou kunnen optreden dat bij dieren werd gezien.

De mensstudies sluiten pathogenic priming op geen enkele manier uit. Bij zowel Moderna als Pfizer dierstudies op niet-menselijke primaten werden er naast longweefsel geen organen onderzocht. En terwijl er onderzoek gedaan werd mbt potentiele markers voor Pathogenic priming, werd er niet gekeken naar interleukin-5. In eerdere coronavirus studies was IL-5 verhoogd in samengang met door Priming opgewekte ziekte versterking. (Disease Enhancement)

Tijdens dierstudies met eerdere COVID vaccins kwam naar voren dat pathogenic priming leident tot ziekte verterking meer bij oudere dieren voorkomt dan bij jongere. Dit kan betekenen dat oudere volwassenen het hoogste risico lopen op een ernstig ziekteverloop vanwege autoimmuunreactie ten gevolge van vaccin-opgewekte pathogenic priming. Dr Anthony Fauci heeft gezegd dat dat deze vaccins de overdracht geen halt toe roepen. Daaruit volgt dat de volgende dosis van virale proteines, via een natuurlijke infectie voor de onderzoeksdeelnemers wel eens hun laatste zou kunnen blijken. Het onderzoek moet verlengd worden tot lange termijn studie, daarbij zal iedere volgende vaccinatie of blootstelling aan SARS-COV-2 proteines via infectie inbegrepen moeten worden.


There’s been a serious terminology problem with this issue. The problem, of course, is not “immune enhancement,” which sounds like something helpful to the immune system.  In fact, it is quite the opposite. The problem is, in reality “disease enhancement”; in fact, that is what it was called in the original RSV study. Disease enhancement now appears to be caused by initial exposure to a pathogen’s proteins, or parts of proteins, which primes the body to autoimmunity. That is “pathogenic priming.” In COVID-19, every protein in the SARS-CoV-2 has at least one epitope that matches human proteins someplace in the human body. About one-third of the epitopes in SARS-CoV-2 virus that match human proteins match immune system proteins.

The Vaccines and Related Biological Products Advisory Committee Briefing Document on the Pfizer-BioNTech COVID-19 vaccine contains disturbing indications that might be a safety signal on pathogenic priming, especially in older adults. Before those are reviewed, there are fundamental issues with the classification of serious adverse events that reflect the short-term thinking and externalization-of-cost mindset of the vaccine safety science paradigm.

The first issue is the categorization of “Serious vs. Non-Serious” adverse events in the study and in the report. To a person experiencing neurologic adverse events including Bell’s Palsy, neuroinflammatory and thrombotic events, these events are not “non-serious” and can, over time, develop into life-threatening conditions that require continuous medical intervention and repeated billable office visits for care. The short-term study excludes any means of detecting whether the initial exposure may play a fundamental root cause role in setting up patients for life-long chronic illness. The vaccine adverse events themselves seen in the Pfizer study may be indicative of pathogenic priming, especially since more serious adverse events were seen with the second dose.

The second issue is that the design and analysis set-up of the study are biased against finding adverse events.

The report states:

Among non-serious unsolicited adverse events, there was a numerical imbalance of four cases of Bell’s palsy in the vaccine group compared with no cases in the placebo group, though the four cases in the vaccine group do not represent a frequency above that expected in the general population.”

The comparison to baseline rates is meaningless because other vaccines are in use in the population. Thus, any risk due to the COVID-19 vaccine adds to or multiplies existing risk present in the population from other vaccines.



7.1 Protocol Safety Review Team and the Data Safety Monitoring Board

Monitoring boundaries were established prior to study start to assess for lack of efficacy and for evidence of enhanced disease for both COVID-19 cases of any severity and severe cases of COVID-19.

blz 55/56

There was no evidence of enhanced disease as fewer cases of severe COVID-19 and COVID-19 were observed in participants who received mRNA-1273 than those who received placebo.

blz 56

Dit is geen uitspraak die betrekking heeft op disease enhancement… Enhanced Disease: COVID-19 and Severe COVID-19

The potential for the mRNA-1273 to cause enhanced disease was monitored by the DSMB, which received unblinded case counts on a continuous basis and monitored the study against prespecified boundary rules based on an imbalance in the number of severe COVID-19 cases and all COVID-19 cases starting when 1 and 9 cases had occurred from the time of first dose administration, respectively. The prespecified criteria for enhanced disease have not been met at any time from study onset through the interim analysis. There were fewer cases of severe COVID-19 or COVID-19 of any severity from time of randomization in participants who received mRNA-than in those who received placebo; thus, there was no evidence of vaccine-associated enhanced disease observed in the study.

– De mogelijkheid dat het vaccin een versterkt ziektebeeld zou kunnen veroorzaken werd gemonitord door de DSMB. Zij ontvingen continue niet-blinde data en vergeleken de studieresultaten met vooraf vastgestelde parameters gebaseerd op een disbalance in het aantal ernstige Covid gevallen en alle covid-gevallen. De vooraf gespecificeerde criteria voor versterkt ziektebeeld werden gedurende de tussentijdse analyses op geen enkel moment waargenomen. Er waren minder gevallen van ernstige Covid en Covid in deelnemers die het vaccin onvingen dan in de groep die de placebo toegedient kregen. Er was geen bewijs van vaccin geassocieerde verterkt ziekteverloop in de studie.

blz 70

17 DECEMBER 2020

A perspective on potential antibody-dependent enhancement of SARS-CoV-2

At present, there are no known clinical fndings, immunological assays or biomarkers that can diferentiate
any severe viral infection from immune-enhanced disease, whether by measuring
antibodies, T cells or intrinsic host responses. In vitro systems and animal models do
not predict the risk of ADE of disease, in part because protective and potentially
detrimental antibody-mediated mechanisms are the same and designing animal
models depends on understanding how antiviral host responses may become
harmful in humans.

13 JULY 2020



No evidence that COVID-19 vaccines cause more severe disease; antibody-dependent enhancement has not been observed in clinical trials

Dit is duidelijk een checking the fact-checkers gevalletje. Schiet op meerdere punten voorbij de inhoud van de discussie mbt ADE.
Conclusie: tot nog toe geen bewijs van ADE bij Covid vaccins (wat logisch is, gezien de studieopzet….)


Pathogenic priming likely contributes to serious and critical illness andmortality in COVID-19 via autoimmunity

Homology (genetische verwantschap) tussen menselijke en virale proteines vormen een bewezen factor in viraal- of vaccin veroorzaakte autoimmuniteit. Het falen van SARS en MERS vaccins bij dierstudies had betrekking op pathogenesis (ziekteontwikkeling) die overeenkwam met een immunologische priming die kon leiden tot autoimmuniteit in longweefsel, vanwege een eerdere blootstelling aan het SARS of MERS Spike proteine. Ontwikkeling van SARS-COV-2 blootstelling tot COVID-19 zal waarschijnlijk tot gelijke uitkomsten leiden.
Immunogenic peptides in virussen of bacterien die een match zijn met menselijke proteines zijn heel geschikt als pathogenic priming peptides ( zoals bij het bredere begrip immuun versterking).
Bij SARS werd een soort “priming” van het immuunsysteem waargenomen tijdens dierstudies naar SARS Spike proteine gebaseerde vaccins. Dit leidde tot verhoogde ziekte en sterfte in dieren die na vaccinatie werden blootgesteld aan wild SARS virus. Het probleem kwam in twee studies naar voren. Op Recombinant SARS Spike proteine gebaseerde vaccins faalden niet alleen in het voorkomen van SARS-Cov infectie maar de muizen ontwikkelden longpoblemen door immuunreacties. SARS-Cov gevaccineerde fretten ontwikkelden ernstige leverontstekingen. In beide studies werd een cellulaire immuun respons vermoed.
Een derde van de immunogenische proteines in SARS-COV-2 hebben potentieel problematische verwantschap tov proteines die een sleutelrol spelen bij het menselijke adaptive (specifieke) immuun systeem. Vele functies van het menselijke adaptive immuunsysteem kunnen geraakt worden via autoimmuniteit tegen deze proteines en waar die verder mee in verband staan.
Dit kan deels verklaren waarom er zoveel ernstige ziekte door SARS-COV-2 veroorzaakt wordt. Het kan ook een verklaring geven voor de lange asymptomatische periode die vooraf gaat aan de presentatie van karakteristieke COVID-19 symptomen.
SarS-CoV-2 kan in eerste instantie het immuunsysteem verzwakken. Na verloop van tijd kan het immuun systeem een aanval gaan inzetten op de verscheidenheid aan proteines.
De sterkte van pathogenic priming bij door vaccin- of infectie veroorzaakte imuun reacties zou afhankelijk kunnen zijn van het type proteine, vanwege ‘original antigenic sin’. De immunologische reactie tegen eigen-antigenen zou minder ernstig kunen zijn doordat snel evoluerende virussen van het originele vaccintype vandaan evolueren.
Het screenen van immunogenische epitopen op hun potentieel voor pathogenische priming via homology kan verbeterd worden door studies naar auto-antilichamen die een kruisreactie hebben met epitomen die onderdeel uitmaken van vaccins.
SarS-CoV-2 heeft wat tot nog toe onverklaarde pathogenische eigenschappen die gerelateerd kunnen zijn aan de lijst van vermoede pathogenic priming peptides. Blootstelling aan deze peptides- via infectie of vaccinatie- zou patienten kunnen primen voor een verhoogd risico op een ernstiger ziekteverloop tijdens toekomstige blootstelling vanwege een toekomstige pandemie of via universele vaccinatie programma’s.
Hoewel er nog weinig kennis is mbt het mechanisme achter de pathogenesis (ziekteontwikkeling) van COVID-19, is het ziekteverloop en de mortaliteit van COVID-19 uitvoerig bestudeerd. De rol van pathogenische priming bij herinfectie met COVID-19 is in theorie mogelijk. Er zijn nog geen SarS-CoV-2 vaccins getest op dieren en daarom is nog niet bekend of pathogenische priming verwacht kan worden. Deze studies moeten uitgevoerd worden voordat enig vaccin tegen SarS-CoV-2 bij mensen toegepast wordt.

Deel dit bericht