Anti-virale Immunität und Sars-Cov2 Impfstoffe - HH Peter 22.3.21 Museumsgesellschaft
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Anti-virale Immunität und
Sars-Cov2 Impfstoffe
HH Peter
22.3.21 Museumsgesellschaft
Klassifikation Humane Coronaviren
RNA-Virus
From: Liu DX, 2020
Paul-Ehrlich-Institut
Immunogene Strukturen des Sars-Cov2 Virus
Review
(Krammer F. Sars-CoV-2 Vaccines in development. Nature 586: 516-527, 2020)
a SARS-CoV-2 b RBD of the c Inactivated vaccines d Live attenuated va
Matrix protein spike protein contain SARS-CoV-2 are made of genet
RBD, Receptor
that is Binding Domäne
grown in cell (S2)version
weakened
culture and then SARS-CoV-2 that
RBD
chemically inactivated grown in cell cultu
Wirtszelle
mit ACE-
Rezeptor
f Recombinant g VLPs carry no genome bu
RBD-based display the spike protein o
vaccines their surface
Spike Protein
Spike protein (S1)
Envelope protein Nucleoprotein
Nucleoprotein (NP)
und virale
and viral RNA
RNA
i Replication-competent vector vaccines j Inactivated virus vector vaccines carry k DNA vaccines consist of plasmid
can propagate to some extent in the copies of the spike protein on their surface DNA encoding the spike gene unde
cells of the vaccinated individual and but have been chemically inactivated a mammalian promoter
express the spike protein within them
Rolle von Typ 1 Interferonen (IFN-!, IFN-") in der antiviralen Abwehr
1. IFN-!, IFN-" Sekretion ->machen
ACE-
Zellen resistent gegen Virusreplikation
Receptor
2. Typ I-IFN aktivieren NK-Zellen
zur Abtötung Virus-Infizierter Zellen
4. MHC I + Viruspeptide aktivieren CD8+T-Killer Zellen
3. IFN steigern Oberflächen-Expression
von MHC-I und MHC-II Molekülen samt 5. MHC-II + Viruspeptide aktivieren CD4+T-Helfer Zellen und
den in ihnen gebundenen Virus-Peptiden induzieren eine anti-virale Antikörper-Produktion in B-Zellen
MHC Klasse I Moleküle (ca. 125)
Auf allen Körperzellen exprimiert
außer den Keimzellen Interferone
(Hoden, Ovarien) steigern die
Expression von
MHC I und MHC II
Molekülen.
MHC Klasse II Moleküle (ca. 150)
Nur auf Zellen des Immunsystems
exprimiert:
Ø Monozyten (++)
Ø Makrophagen (++)
Ø Granulozyten (+)
Ø Dendritische Zellen (+++)
Ø B-Lymphozyten (++)
Ø T-Lymphozyten (+)
CD8+ T-Killer
CD4+ T-Helfer
MHC-I Molekül MHC-II Molekül 1. Aufnahme von Virus-Partikeln
über Phagozytose (exogener Weg)
in das Phagolysosom der Antigen
präsentierenden Zellen (APC):
Makrophagen, DC, B-Zellen.
Peptid-spezifische 2. Präsentation von viralen
Abtötung von Virus Peptiden in MHCII –Molekülen
Infizierten Zellen an Viruspeptid spezifische
CD4+ T-Helfer Zellen.
3. Diese stimulieren B-Zellen zur
Ausreifung und spezifischen
Antikörperbildung, z.B. gegen
Virusà APC das Spike-Protein veranlassen.
Endogener Weg. Exogener Weg
Ontogenese der Abwehrzellen
T-cytotox.
CD8+
TC
Erworbenes (adaptive) T reg
Immunsystem TC CD4+CD25+
Thymus TC
T-Helper
Lymphoid
TC CD4+
SC BC Plasmacell C‘
BC C‘ CC
C
C‘ C C
BC B-memory cell
Knochenmark SC
C CC
Fetale Leber DC
SC Dendritic cell: pDC, mDC
Angeborenes (innate) Myeloid Makrophage
MΦ (Monozyt)
Immunsystem NK
NK cell G Granulocyte
(PMN, Eo, Baso)
Periphere, sekundäre Immunorgane
Lymphknoten
Tonsillen
Milz
Milz
Peyer’sche
Plaques
S. Gadola
Funktionelle Organisation des Immunsystems
Bacteria, Pilze
Viren 1
Granulocytes Angeborenes Immunsystem:
2 DC ..….. 4
A. Frühwarnsystem durch Wächterzellen
NK
2. Dendritische Zellen u. Mastzellen
Dendritic cells 3. NK-Zellen
3
B. Schnelle Eingreiftruppe mit
Macrophages Abbräumfunktion
Mast cell
DC 4. Granulozyten und
Makrophagen
5 Adaptives Immunsystem
T T- and B- lymphocytes
5. T-B-Zell-Interaktion
B 6 7 C‘ 6. B-Zell-Reifung
C‘ CC 7. Plasmazellen -> AK Bildung
PC C
C‘ C C
Effektor T-cells Plasma cells C CC 8. Gedächtnis B-Zellen
Antibodies -> Abheilung nach 7-10 Tagen
Bm
8
HHP
B-Zellen und Plasmazellen produzieren Immunglobulin Klassen
und repräsentieren die Antikörper-Immunität
Subklassen IgG IgD IgE
Gegen Viren
Bakterien, Allergie
Toxine
60%. 25%. 10% 5% IgA Dimer IgM Pentamer
IgG 7.0-16.0 g/l < 5.0 g/l
IgG1 5.2-8.5 g/l
IgG2 2.5-4.0 g/l Schleimhaut
IgG3 0.5-1.6 g/l Immunität
IgG4 0.2-0.5 g/l
IgA 0.7-4.5 g/l < 0.7 g/l
IgM 0.4-2.3 g/l < 0.4 g/l
IgE 0.0001g/l (10-100 IU/ml)
IgD 0.03 g/lRisiken für ungünstige COVID-Verläufe
Beeinflussung durch Lebens- Einflüsse durch Immunsystem
Umstände und Vorkrankheiten und Virus-Mutanten
• Alter >65 • Störungen der Interferon-Antwort
• Übergewicht • Störungen der NK-und CD8+ T-
• Nieren-/Leberkrankheiten Killerzell Antwort
• Diabetes • Bildung von Autoantikörper gegen
Interferon Typ I
• Herz/Lungen-Vorkrankheiten • Antikörper-Bildungsstörungen (PID)
• Allergien • Verhältnis von Antikörpern gegen
• Einige Immunsuppressiva Spike zu Nukleoprotein
• Neigung zu Autoimmunität-> • Virus-Protein-Mutanten im Bereich
Thrombosen, Late COVID Syndrom, von RBD (B1.1.7, B1.351 „E484K“) ->
Fatigue höhere InfektionsrateSchwächung der anti-viralen Immunantwort begünstigen einen aggressiven Verlauf der COVID-19 1. Auf Ebene der Typ I-Interferone: Ø Inborn errors of type I IFN immunity in life-threatening Covid-19 Q. Zhang et al., Science 10.1126/science.abd4570 (2020) Ø Autoantibodies against type I IFNs in life-threatening Covid-19 P. Bastard et al., Science 10.1126/science.abd4585 (2020). 2. Auf Ebene der NK-Zellen und CD8+ Killer T-Zellen Ø Rasche Erschöpfung von NK- und CD8+Killer T-Zellen: Indikatoren für schlechte Prognose Li M, Guo W, Dong Y et al Front. Immunol. 11:580237. doi: 10.3389/fimmu.2020.580237
V or MERS-CoV infection (16, 17). whether SARS-CoV-2 infects any immune cells is still unknown.
NK cells are innate lymphoid cells, which can directly kill In our study, we found that the counts and frequencies of CD4+T
cted cells and contribute to the activation and orientation cells, CD8+ T cells, and NKT cells were significantly lower in
adaptive immune response (18). Human NK cells can severe cases than mild cases. More importantly, the significantly
subdivided into various subsets based on the relative elevated expression levels of PD-1 and CD244 on CD8+ T cells
Rasche Erschöpfung von NK und CD8 Killer T-Zellen als Indikatoren
einer Covid-19 Progression mit schlechter Prognose
Perforin ↓
Granzyme↓
CD27 ↓
PD-1 ↑
CD244 ↑
Li M, Guo W, Dong Y et al Elevated Exhaustion Levels of NK and CD8+ T Cells as Indicators for Progression and
Prognosisofof
GURE 5 | Schematic depiction COVID-19
alterations Disease.
in NK Front.
cells and Immunol.
T cells 11:580237.
observed doi: 10.3389/fimmu.2020.580237
during SARS-CoV-2 infection.
tiers in Immunology | www.frontiersin.org 8 October 2020 | Volume 11 | Article 580237Review
Antikörperbildung nach Sars-CoV2 Exposition
a Natural
Natürliche Ø IgA Antikörper vermitteln die Schleimhaut-Immunität
infection Types of vaccine in development
Infektion Mostly slgA1 (IgA1
More than 180 im
vaccine oberen
candidates, Atemwegstrakt,
based IgA2 im Darm)
on several different platforms
Mostly lgG1 (Fig. 3), are currently in development against SARS-CoV-232 (Fig. 4). The
World Health Organization (WHO) maintains a working document32
Ø IgG und IgM Antikörper repräsentieren die Immunität
that includes most of the vaccines in development and is available at
imReview
Gewebe
https://www.who.int/publications/m/item/draft-landscape-of-covid-
19-candidate-vaccines. The platforms can be divided into ‘traditional’
a SARS-CoV-2
approaches (inactivated b have
or live-virus vaccines), platforms that RBD of the c Inactivated
recently resulted in licensed vaccines (recombinant
Matrix protein spike protein
protein vaccines contain SA
b Intramuscular/ that is gro
and vectored vaccines), and platforms that have yet to result in a
Intramuskuläre
intradermal RBD
culture an
licensed vaccine (RNA and DNA vaccines). chemically
Impfung
vaccination
Inactivated vaccines
Inactivated vaccines (Fig. 3c) are produced by growing SARS-CoV-2 in
cell culture, usually on Vero cells, followed by chemical inactivation of
the virus33,34. They can be produced relatively easily; however, their yield
could be limited by the productivity of the virus in cell culture and the
requirement for production facilities at biosafety level 3. Examples of
inactivated vaccine candidates include CoronaVac (initially known as
Intranasale
c Intranasal PiCoVacc), which is under development by Sinovac Biotech in China34,35
vaccination f Recom
Impfung and is further discussed below, as well as several other candidates that RBD-ba
are being developed in China, by Bharat Biotech in India and by the vaccine
Research Institute for Biological Safety Problems in Kazakhstan. TheseSpike protein
vaccines are usually administered intramuscularly and can contain
Spike proteine
alum (aluminium hydroxide) or other adjuvants. Because the whole
virus is presented to the immune system, immune responses are likely
to target not only the spike protein of SARS-CoV-2 but also the matrix,
Envelope protein
envelope and nucleoprotein. Nucleo
Nucleoprotein
Several inactivated
and viral
proteine
vaccine
RNA
candidates
Krammer
Fig.F.2 | Sars-CoV-2 Vaccinesimmune
Mucosal and systemic in development.
responses toNature 586: 516-527,
natural infection have entered clinical trials, with three candidates from China in phase
with 2020
respiratory viruses and to vaccination. The lower human respiratory tract III trials, and one from India, one from Kazakhstan and two from China
is thought to be mostly protected by IgG (IgG1 is most prevalent), the main type in phase I or II iclinical trials32 (Fig. 4). vector vaccines
Replication-competent j Inactivated virus vector vaccines carry
of antibody in serum, which is transported into the lung. The upper respiratory can propagate to some extent in the copies of the spike protein on their surface
tract is thought to be mostly protected by secretory IgA1 (sIgA1). a, Natural Live attenuatedcells
vaccines
of the vaccinated individual and but have been chemically inactivated
infection with respiratory viruses induces both a systemic immune response, express the
Live attenuated vaccines spike
(Fig. 3d)protein within them
are produced by generating a geneti-
dominated by IgG1, as well as a mucosal immune response in the upperSegregation der Covid-Verläufe mit Antikörper-Antworten
Atyeo C et al Distinct early serological signatures track with Sars-Cov2 survival. doi.org/10.1016/j.immuni.2020.07.020
Antikörper gegen das Spikeprotein (S) und die
Rezeptor Bindungsdomaine (RBD) sind
neutralisierend, da das Virus nicht mehr an den
zellständigen ACE Rezeptor andocken kann.
Erhöhte Anti-S-Titer der IgG1, IgA1 und IgM
Klassen finden sich vermehrt bei Überlebenden.
Antikörper gegen das Nukleoprotein (NP) finden
sich mehr bei Patienten mit schlechter Prognose.
Ungünstig:
IgG1 anti NP
Günstig: IgA1 anti NP
IgG1 anti S IgM anti NP
IgA1 anti S Anti-NP ADCP/ADNP
IgM anti S Anti-S NK- activationVerhältnis von Spike- zu Nucleoprotein- Antikörpernll ist
signifikant
Report höher bei Überlebenden OPEN ACCESS
A B
C
(Atyeo C et al https://doi.org/10.1016/j.immuni.2020.07.020)
Figure 4. Converging Shift in Immunity across a Second Acute Infection Cohort
(A and B) The Nightingale rose plots show the mean percentile of the spike:nucleocapsid (S:N) ratio of each readout are depicted for (A) the Seattle or discovery
cohort and (B) the Boston or validation cohort for convalescents (left) and deceased (right). Titers are shown as pink wedges and functions as blue wedges.
(C) The whisker boxplots show the number of S features that are greater than their N counterparts for all individuals in the Seattle or discovery cohort (left) and the
Boston or validation cohort (right). Differences across the 2 groups were assessed using a one-sided Mann-Whitney U test.Von der Entdeckung bis zur Entwicklung und Zulassung
von Impfstoffen für SARS-CoV-2
31.12.2019: China informiert die WHO über das Auftreten von Fällen von
‘Viraler Pneumonie unbekannter Ursache’ in Wuhan
12.01.2020: Veröffentlichung der genetischen Sequenz des neuartigen
Coronavirus SARS-CoV-2
16.03.2020: Erste klinische Prüfung im Menschen beginnen
Ab 01.10.2020 Rolling Review der ersten Impfstoffe beginnt bei der EMA
26.10.2020 über 240 Impfstoffe für SARS-CoV-2 in der Entwicklung (ref
LSHTM vaccine tracker)
Source: WHO, LSHTM (https://vac-lshtm.shinyapps.io/ncov_vaccine_landscape/)
Paul-Ehrlich-Institut 3Impfstoff-Varianten (Krammer F. Sars-CoV-2 Vaccines in development. Nature 586: 516-527, 2020)
Review
a SARS-CoV-2 b RBD of the c Inactivated vaccines d Live attenuated vaccines e Recombinant spike-
Matrix protein spike protein contain SARS-CoV-2 are made of genetically protein-based vaccines
that is grown in cell weakened versions of
culture and then SARS-CoV-2 that is
RBD
chemically inactivated grown in cell culture
4 Novavax,
Longcom
3 Wuhan, Sinovac
f Recombinant g VLPs carry no genome but h Replication-incompetent vector
RBD-based display the spike protein on vaccines cannot propagate in the
vaccines their surface cells of the vaccinated individual but
Spike protein express the spike protein within them
5 Glaxo 2 Astra,CanSino,
Sputnik, Jansson
Spike
gene
Envelope protein Nucleoprotein
and viral RNA
i Replication-competent vector vaccines j Inactivated virus vector vaccines carry k DNA vaccines consist of plasmid l RNA vaccines consist of RNA encoding
can propagate to some extent in the copies of the spike protein on their surface DNA encoding the spike gene under the spike protein and are typically
cells of the vaccinated individual and but have been chemically inactivated a mammalian promoter packaged in LNPs
express the spike protein within them 1 Biontec, Moderna
CureVac
Spike
gene
Fig. 3 | Vaccine platforms used for SARS-CoV-2 vaccine development. SARS-CoV-2 vaccine candidates include inactivated virus vaccines (c), live
a, A schematic of the structural proteins of the SARS-CoV-2 virion, including attenuated vaccines (d), recombinant protein vaccines based on the spike
the lipid membrane, the genomic RNA covered by the nucleoprotein on the protein (e), the RBD (f) or on virus-like particles (g), replication-incompetent
inside, the envelope and matrix proteins within the membrane, and the spike vector vaccines (h), replication-competent vector vaccines (i), inactivated
protein on the surface of the virus. b, The structure of the spike protein; one virus vector vaccines that display the spike protein on their surface ( j), DNABeispiel COVID-19 Impfstoffe mit möglicher Relevanz für EU
Firmen Impfstofftyp Dosen, Route Phase der Stand Zulassungs-
Impfintervall Entwicklung verfahren
BioNTech/ mRNA eingeschlossen in 2 Dosen, i.m. Phase 3 Rolling Review ab
Pfizer/Fosun Lipid-Nanopartikel 0, 21 Tage 05. 10.2020
Moderna/ mRNA eingeschlossen in 2 Dosen, i.m. Phase 3 Rolling Review ab
Lonza/NIH Lipid-Nanopartikel 0, 28 Tage 16.11.2020
Curevac mRNA eingeschlossen in 2 Dosen, i.m. Phase 1/2 Im rolling review
Lipid-Nanopartikel 0, 28 Tage Verfahren
Oxford/ Vektor-basiert (ChAdOx1) (1-)2 Dosen i.m. Phase 3 Rolling Review ab
AstraZeneca nicht replizierend 0, 28 Tage 01.10.2020
J&J/Janssen Vektor-basiert (hAd26) 1-2 Dosen, i.m. Phase 3
0, 56 Tage Zugelassen 3/21
nicht replizierend
Novavax Rekombinant hergestelltes 2 Dosen, i.m. Phase 3
Protein, adjuvantiert 0, 21 Tage
Sanofi Rekombinant hergestelltes 2 Dosen, i.m. Phase 1/2
Eingestellt
Pasteur/GSK Protein, adjuvantiert 0, 28 Tage
Paul-Ehrlich-Institut 820.11.2020
20.11.2020
BioNTech/Pfizer:
BioNTech/Pfizer:Immunogenität
Immunogenität
S1-Binding
S1-BindingIgG
IgG Neutralisierende
NeutralisierendeAntikörper
Antikörper(NT
(NT50%)
50%)
18-55 Jahre
18-55 Jahre 65-85
65-85Jahre
Jahre 18-55 Jahre
18-55 Jahre 65-85 Jahre
65-85 Jahre
Hohe
Hoheneutralisierende
neutralisierendeAntikörpertiter
Antikörpertiterim
imVergleich
Vergleichzu
zuRekonvaleszentenseren
Rekonvaleszentenseren
77 Tage nach der 2. Impfung auch bei Älteren; TH1 gerichteteImmunantwort
Tage nach der
Paul-Ehrlich-Institut
2. Impfung auch bei Älteren; TH1 gerichtete Immunantwort
Paul-Ehrlich-InstitutNebenwirkungen des BioNtec Impfstoffes Lokal Allgemein • Schmerzen und Rötungen an • Abgeschlagenheit (40-70% Einstichstelle (50-90%) • Schüttelfrost, Fieber (10-20% • Häufiger bei jüngeren • Kopfschmerzen (10-20%) Probanden (
BNT162b2 mRNA Covid-19 Vaccine in a Nationwidem eMass
ne w engl a nd jou r na l dicine
Vaccination Setting.
The of
N Dagan , N.Barda et al NEJM Feb 24, 2021
Unvaccinated Vaccinated
A Documented SARS-CoV-2 Infection B Symptomatic Covid-19
3
Infektionsrate 2.0
Symptomatische COVID19
Cumulative
Cumulative
1.5
Incidence
Incidence
2
(%)
(%)
1.0
1
0.5
0 0.0
0 7 14 21 28 35 42 0 7 14 21 28 35 42
Days Days
No. at Risk No. at Risk
Unvaccinated 596,618 413,052 261,625 186,553 107,209 37,164 4132 Unvaccinated 596,618 413,768 262,662 187,784 108,242 37,564 4204
Vaccinated 596,618 413,527 262,180 187,702 108,529 38,029 4262 Vaccinated 596,618 414,140 263,179 188,740 109,261 38,299 4288
Cumulative No. of Events Cumulative No. of Events
Unvaccinated 0 2362 3971 5104 5775 6053 6100 Unvaccinated 0 1419 2393 3079 3433 3582 3607
Vaccinated 0 1965 3533 4124 4405 4456 4460 Vaccinated 0 1103 1967 2250 2373 2387 2389
C Covid-19 Hospitalization D Severe Covid-19
0.20 0.20
KH-Rate Schwere COVID19 Verläufe
Cumulative
Cumulative
0.15 0.15
Incidence
Incidence
(%)
(%)
0.10 0.10
0.05 0.05
0.00 0.00
0 7 14 21 28 35 42 0 7 14 21 28 35 42
Days Days
No. at Risk No. at Risk
Unvaccinated 596,618 414,865 264,377 189,808 109,867 38,432 4309 Unvaccinated 596,618 414,898 264,437 189,874 109,929 38,467 4310
Vaccinated 596,618 414,916 264,482 189,972 110,054 38,561 4321 Vaccinated 596,618 414,933 264,516 190,000 110,076 38,571 4322
Cumulative No. of Events Cumulative No. of Events
Unvaccinated 0 58 125 198 244 256 259 Unvaccinated 0 17 57 114 157 171 174
Vaccinated 0 31 77 98 108 110 110 Vaccinated 0 6 26 45 52 55 55
E Death Due to Covid-19
0.05
0.04
Cumulative
Incidence
0.03
(%)
0.02
0.01Danke für Ihre Aufmerksamkeit
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