IMMUNOLOGY PERSPECTIVE ON COVID19 VACCINE - ASSIST PROF SIRA NANTHAPISAL MD PHD DEPARTMENT OF PAEDIATRICS, FACULTY OF MEDICINE
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Immunology perspective on
COVID19 vaccine
Assist Prof Sira Nanthapisal MD PhD
Department of Paediatrics, Faculty of Medicine
Protein complexity Protein synthesis
The antigen
The genomic structure of Severe Acute Respiratory Syndrome Coronavirus-2
1st case in
human
Genetic
reported sequencing
Jan 2020
Nov/Dec 2019 22 Feb 2020
Viral
samplings
Front. Chem., 05 January 2021
Summary of current knowledge of immunity against SARS-CoV-2
Antigen
• Spike protein is immunodominant and is the target of
neutralizing antibodies and T cells
• S-RBD is a prominent but not exclusive protective
epitope; enabled development of potent monoclonal Ab
cocktail therapies
• Various mutations e.g. D614G
• Genetic drift has been observed
• Variant match vaccine is ideal
Computational epitope map of
SARS-CoV-2 spike protein
Fergie J and Srivastava A (2021) Front. Immunol. 12:654165.
S glycoprotein trimer with site-specific glycosylation
Glycoprotein protect
S protein from
Ab recognition
Grant et al. Scientific Reports | (2020) 10:14991
VOCs immune evasion driven by Spike RBD electrostatic surface changes
Relative binding free energies of RBDs complexed to hACE
SARS-CoV-2 VOCs immune evasion
from previously elicited neutralizing
antibodies is mainly driven by lower
cross-reactivity due to Spike RBD
electrostatic surface changes
Ferraz, Matheus et al.; ChemRxiv. Preprint. https://doi.org/10.26434/chemrxiv.14343743.v1
the alignments of the RBD sequences of MERS, SARS, and CoV-2 spike protein
ORF play a role in
interferon antagonism
Grant et al. Scientific Reports | (2020) 10:14991
Cell entry mechanisms
• Th e h igh h ACE2 b in d in g a ffin it y
o f t h e RBD
• Fu r in p r e a ct iva t io n o f t h e s p ik e
• We ll h id d e n RBD in t h e s p ik e
Maintain efficient cell
entry while evading
immune surveillance
PNAS May 26, 2020 117 (21) 11727-11734
Immune response following natural infection
Infected epithelial cells
Activated alveolar macrophage
ACE2: target for Spike protein (S1 subunit) of SARS-CoV2
TMPRSS2: host serine protease which is required
to process the SARS-CoV-2 spike protein and
facilitate host cell entry
Tay et al. Nature https://doi.org/10.1038/s41577-020-INNATE: macrophages, monocytes,
Activation of Epithelial cells complement, NK cells
& Endothelial cells ADAPTIVE: T cells: CD8+, CD4+
B Cells: antibody production
TNF-a, IL-1, IL-6, IL-8, and IL-12
Dysfunctional immune response
• Excessive infiltration of monocytes, macrophages and T
cells
• Systemic cytokine storm
• Pulmonary oedema and pneumonia
• Widespread inflammation and multi-organ damage
Tay et al. Nature https://doi.org/10.1038/s41577-020-0311-8Evidence of Endothelial cell infection and endotheliitis in COVID-19
Viral inclusion bodies
Capillary • Caspase 3 positive • Apoptotic
containing cells endothelial cells
viral • Mononuclear in lung with large
particles infiltration in blood arterial vessel
vessels in bowel injury
Varga et al Lancet. 2020 May 2;395(10234):1417-1418 ŠIBÍKOVÁ et al. Folia Biologica (Praha) 64, 113-124 (2018)Innate immune response to SARS-CoV2
Cytokine responses -> IFN, IL-6
Park, A., & Iwasaki, A. (2020) Cell Host & Microbe.
Anne Rowley Nature Reviews Immunology 2020
doi:10.1016/j.chom.2020.05.008Interferon responses might control innate and adaptive
immunity to SARS-CoV-2.
Nature Reviews | ImmunologyAdaptive immune system in response to SARS-CoV2 infection
Vabret et al. Immunity 52, June 16, 2020
Ying et al. Signal Transduction and Targeted Therapy (2020) 5:128Variable region, heavy chain
Anti S-RBD IgG Variable region, light chain
Cell 2020 Aug 20;182(4):828-842.e16Dynamics of SARS-CoV-2 neutralising antibody responses and duration of
immunity: a longitudinal study
Neutralising antibody level, measured by percentage inhibition of sVNT readings in 164 patients
1. negative 3. Slow waning 5. delayed response
2. Rapid waning 4. Persistent
19 (12%) 44 (27%) 46 (28%) 52 (32.3%) 3 (2%)
Logistic regression analysis of
predictors of persistent antibody trend (n=161)
Chia et al, Lancet, March 23, 2021 https://doi.org/10.1016/S2666-5247(21)00025-2Immunological memory consists of antibodies, memory B cells,
memory CD8+ T cells, and memory CD4+ T cells
• Memory B cells against SARS-CoV-
2 spike increased between 1 -8
months after infection
• S-RBD Ab declined moderately
over 8 months
• memory CD4+ T cells and Memory
CD8+ T cells declined with an
initial half-life of 3 to 5 months
Dan et al., Science 371, eabf4063 (2021)The decay of immune memory to coronavirus infections
Nature Reviews Immunology volume 21, pages395–404 (2021)The decay of immune memory to coronavirus infections
Ab decay following infection with SARS-CoV or hCoV and following vaccine-induced VS natural immunity
mild-to-moderate SARS-CoV-2 infection to SARS-CoV-2
Nature Reviews Immunology volume 21, pages395–404 (2021)The vaccine and immune response
https://www.nytimes.com/interactive/2020/science/coronavirus-vaccine-tracker.html
Comparison of vaccine platforms
Inactivated Protein subunit Viral-vectored Nucleic acid
Advantage • Safety, as the • Safety during • Can induce robust • Scalability.
pathogen is dead. production. humoral and • Fast design and
• Transport and • Can be safe in cellular responses development.
storage. immunosuppressed with a single dose. • Extremely safe.
• No infectious agent • Good safety profile. • No infectious agent
handling is required handling is required.
• Can induce humoral
and cellular responses
Disadvantage • Large quantities of • Small size of antigens • Pre-existing • Storage issues
the pathogen need to diminishes their immunity against a • Long term AE unknown
be processed. uptake by APCs human viral vector
• The inactivation • Low immunogenicity. can attenuate
process can affect • Need several booster immune responses
the antigen doses and adjuvants. • Storage issues
immunogenicity. • Do not elicit cellular
• Antibody titers responses.
reduce over time. • Antigen integrity
• Need several booster needs to be
doses. confirmed
• Do not produce
cellular responsesSARS-CoV-2 proteins targeted by adaptive immune responses
Lancet 2020; 396: 1595–606Platform Viral antigen Adjuvant Administration
mRNA
Pfizer–BioNTech Synthesized 4 lipids including 30 ug, 2 doses, 21
COVID-19 vaccine nucleoside-modified PEGylated lipid to days apart
(BNT162b2, mRNA encodes form nanoparticles
tozinameran, mutated form of the which encapsulate
Comirnaty®) full-length spike mRNA
protein
Moderna, mRNA-1273 Synthesized 4 lipids including 100 ug, 2 doses, 28
nucleoside-modified PEGylated lipid to days apart
mRNA encodes form nanoparticles
mutated form of the which encapsulate
full-length spike mRNA
proteinmRNA vaccine Immune response
Cytotoxic T cells
LPN enhance immune reaction
• interact and stabilize antigens Vaccinated
APC
by ionic interactions Infected
• Promote dendritic cells CD8
cells
• Promote type I IFN response
Vaccinated AP cells
Lipid nanoparticle Th1
LPN Present spike
protein via HLA I/II
Macrophages
Infected cells
B cells
Protruding spike
protein
NK cells
Antibody productionRUMIANA TENCHOV, American chemical society, https://www.cas.org/resource/blog/understanding-nanotechnology-covid-19-vaccines
Comprehensive assessment of
humoral response after Pfizer
BNT162b2 mRNA Covid-19
vaccination: a three-case
series
IgG is still high but slightly
decline at 60 days
Clin Chem Lab Med 2021; aopDurability of Responses after SARS-CoV-2 mRNA-1273 Vaccination
RBD IgG persistently high > 3 mo
NT decline more significant
in elderly after 60 days
NEJM 384;1 nejm.org January 7, 2021Neutralizing Antibodies Against SARS-CoV-2 Variants After Infection and Vaccination
5-19 days after symptom onset 32-94 days after symptom onset 14 days post–second dose
of mRNA-1273 vaccine
JAMA May 11, 2021 Volume 325, Number 18Platform Viral antigen Adjuvan Administration
t
Viral vector
ChAdOx1-S Vector: Recombinant, replication- No 5 x 1010 viral particles per 0.5
(recombinant) deficient (nonreplicating) chimpanzee mL dose
AstraZeneca/Oxford adenovirus 2 doses, 4-16 weeks
University Antigen: SARS-CoV-2 spike (S)
glycoprotein
Johnson & Johnson, Vector: Recombinant, replication- No 5 x 1010 viral particles per 0.5
Janssen Inc. incompetent mL dose, single dose
(non-replicating) adenovirus 26
Antigen: Pre-fusion SARS-CoV-2 spike
(S) glycoprotein
Sputnik V, Gamaleya Vector: Recombinant, replication- No 10¹¹ viral particles per 0.5 mL
incompetent 2 doses, 21 days
recombinant adenovirus types 26 Lancet. 2020 26 September-2 October;
and 5 396(10255): 887–897
Antigen: SARS-CoV-2 S protein cDNA
Convidecia, Cansino Recombinant Ad5 No 0.5 mL dose, single doseDNA inside an adenovirus
Antigen presenting process of viral-vector vaccine
Vaccinated
AP cells
Vaccinated AP cells
nucleus
Present spike
protein via HLA I/II
RNA mRNA
DNA
Protruding spike
protein
https://www.nytimes.com/interactive/2020/health/oxford-astrazeneca-covid-19-vaccine.htmlModel for the Immune Response Mechanism Against Vector-based vaccine
Innate immune
response due to vector
Adaptive immune response to both
Antigenic target and Vector
Molecular Therapy Vol. 28 No 3 March 2020T cell and antibody responses induced by
a single dose of ChAdOx1 nCoV-19 (AZD1222) vaccine
IgG Continuously increase at W8
Nature Medicine | VOL 27 | February 2021 | 270–278T cell and antibody responses induced by
a single dose of ChAdOx1 nCoV-19 (AZD1222) vaccine
Activated Th1 Th2 Activated CD8 (predominated IFNγ)
Nature Medicine | VOL 27 | February 2021 | 270–278Prevalence of Ad5 neutralizing titer by level of titer
100
13.9 14.2
18.9 12.2
9.7
22.9
80 14.9
19.6
38.7
38
40.7 30.1
60 42.9 20.2
44.2
42.8
39.2
40
30.6 21.5
34
31.9 41.7
32.7
20 26.9
17.5 23.3
13.2 26.4
0 10 38.7
12.2 13.7
11 30.9
Brazil
(627) Botswana
Cameroon
6
(204) Malawi 14.8
(301) South
(49) Thailand
Africa
(300) Europe
(236) United
(93)
States Overall
(94) (1904)
1000 Vaccine28 (2010) 950–95Prevalence of Ad26 neutralizing titer by level of titer
4.1 0 4 2.1
10.4 6.3 1.1
1.1
8.2
18 9.63
0 32.7 29.2 14.6
24.5
60
66.7
32.7 43.8
40 66 45.8 28.6
88.3
20
30.6
22.9
22.9 35.4 38.8
0 12
Brazil
Botswana
(627) Cameroon
(204) Malawi
(301) South Africa
(49) Thailand
(236) United States
(300)
(94)
1000
Vaccine28 (2010) 950–95Single injection of the Ad5-vectored
COVID-19 vaccine of 1×10¹¹ or 5×10¹⁰ vp
Number of interferon-γ
266/508 (52%) who had pre-existing releasing cells pre/post vaccination
anti-Ad5 nAb > 200 had approx. 2
times lower of both RBD IgG and NT
Day 14 than those with anti-Ad5 nAb ≤ 200 Ad5 Ab
≤ 1:200
NT to live SARS-CoV2
80
Day 28
1*1011 vp
60
Seroconversion 76% 76% 30% 33% 0 0 5*1011 vp
Placebo
40
Ad5 Ab
> 1:200
20
Day 28
0
0
0
o
o
00
00
20
20
eb
eb
:2
:2
1:
1:
ac
ac
>1
>1
≤
≤
Pl
Pl
b
b
b
b
A
A
A
A
d5
d5
d5
d5
A
A
A
A
g
g
g
g
in
in
tin
tin
st
st
is
is
xi
xi
ex
ex
e
e
Seroconversion 98% 100% 94% 95% 0 0
e-
e-
e-
e-
Pr
Pr
Pr
Pr
Pre-existing ≤ 1:200 > 1:200 placebo
Ad5 Ab
Lancet 2020; 396: 479–88Platform Viral antigen Adjuvant Administration
Inactivated
CoronaVac Inactivated by Beta- aluminum- 2 doses, 3 weeks at
(Sinovac) propiolactone based least
compound
BBIBP-CorV, Inactivated by Beta- aluminum- 2 doses, 3 weeks at
Sinopharm propiolactone based least
compound
Covaxin, Bharat Inactivated by Beta- aluminum- 2 doses, 4 weeks
propiolactone based
compoundInactivated virus vaccines generally only
induce antibody-mediated immunity (not
cell-mediated immunity)
Anti S Ab
B
cells Ab Role on Anti N Ab?
Helper Helper
T cells T cells
ACS Pharmacol. Transl. Sci. 2020, 3, 5, 844–858High
Moderate
N = 43
Low
Unpublished data, with permission from Dr. Peera Jaruampornpan BIOTECHigh
Moderate
Low
Unpublished data, with permission from Dr. Peera Jaruampornpan BIOTECPlatform Viral antigen Adjuvant Administration
Inactivated
CoronaVac (Sinovac) Inactivated by Beta-propiolactone aluminum-based 2 doses, 3 weeks at least
compound
BBIBP-CorV, Sinopharm Inactivated by Beta-propiolactone aluminum-based 2 doses, 3 weeks at least
compound
Covaxin, Bharat Inactivated by Beta-propiolactone aluminum-based 2 doses, 4 weeks
compound
3rd dosePlatform Viral antigen Adjuvant Administration
Protein subunit
Novavax COVID-19 Baculovirus containing Matrix-M 5ug recombinant
vaccine modified spike protein -> nanoparticles protein, 2 doses, 3
cultured in moth cells to based on weeks
produce Spike protein then saponin
attach with synthetic lipid
nanoparticle
Active innate immune response
e.g. TLR2 TLR 4 IFN-α
Coming soon -> Sanofi-GSK recombinant spike protein vaccine (Phase III)patients
N Engl J Med 2020; 383:2320-2332Efficacy of NVX-CoV2373 Covid-19 Vaccine against the B.1.351 Variant
16 sites in
South Africa
NEJM 384;20 nejm.org May 20, 2021Heterologous prime-boost: breaking the protective immune response bottleneck of COVID-19 vaccine
candidates
Emerging Microbes & Infections 2021, VOL. 10• Vaccine efficacy ranges from 60-95% depend on several factors
including candidates, variants, public health policy
• Post infection and vaccination, clearance of SARS-CoV2 in the lung Is
better than nasal passage
• Reduced vaccine efficacy in regions with high circulation of variants
Fergie J and Srivastava A (2021) Front. Immunol. 12:654165.THANK YOU
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