Antibody responses to natural infection and vaccines - Miles Davenport| COVID-19 Vaccines meeting, 22 February 2022
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Antibody responses to natural
infection and vaccines
Miles Davenport| COVID-19 Vaccines meeting, 22 February 2022
Declaration of potential conflicts
Funding this work:
National Health and Medical Research Council (NHMRC) (Australia)
Medical Research Futures Fund (Australia)
University of New South Wales (UNSW Sydney)
Other research funding:
Australian Research Council
NHMRC + UNSW Sydney Professor Davenport
National Institutes of Health (USA) receives no grants /
honoraria / travel support
European Union Horizon 2020 funds
from other bodies
Other funding:
eLife Journal - stipend (as Senior Editor)
Outline • Reconciling existing data on correlates • Using correlates • Correlates for severe disease 3 The Lancet 2020 3961595-1606DOI: (10.1016/S0140-6736(20)32137-1)
Reconciling correlates
Two current methods for detecting correlates
Vaccine comparison method Breakthrough infection method
Measure antibody titres Observe breakthrough
infection
Khoury et al, Nature Med (2021)
Initial titre
visit. cID50: ID50 nAb titer calibrated to the WHO International Standard.
Breakthrough infection studies:
The n e w e ng l a n d j o u r na l of m e dic i n e
A Peri-infection Neutralizing Antibody Level B Peak Neutralizing Antibody Level
105 105
104 104
Bergwerk (NEJM): BNT162b2 Israeli healthcare. 103 103
Titer
Titer
102 102
https://www.nejm.org/doi/full/10.1056/NEJMoa2109072 101 101
100 100
Breakthrough Case Control Breakthrough Case Control
C Peri-infection IgG Level D Peak IgG Level
100 100
10 10
Feng et al (Nature Med): ChAdOx1 trial.
Titer
Titer
1 1
https://www.nature.com/articles/s41591-021-01540-1 Breakthrough Case Control Breakthrough Case Control
Figure 2. Neutralizing Antibody and IgG Titers among Cases and Controls, According to Timing.
Among the 39 fully vaccinated health care workers who had breakthrough infection with SARS-CoV-2, shown are the
neutralizing antibody titers during the peri-infection period (within a week before SARS-CoV-2 detection) (Panel A)
and the peak titers within 1 month after the second dose (Panel B), as compared with matched controls. Also shown
are IgG titers during the peri-infection period (Panel C) and peak titers (Panel D) in the two groups. Each case of
breakthrough infection was matched with 4 to 5 controls according to sex, age, immunosuppression status, and
timing of serologic testing after the second vaccine dose. In each panel, the horizontal bars indicate the mean geo-
metric titers and the I bars indicate 95% confidence intervals. Symptomatic cases, which were all mild and did not
IgG: Immunoglobulin G; RBD: receptor binding domain.
Gilbert et al (Science): mRNA1273 trial.
require hospitalization, are indicated in red.
tested positive for Covid-19, most had few symp- unvaccinated persons, as has been reported pre-
toms, yet 19% had long Covid-19 symptoms 5 viously.4,5,17,18 Mandated isolation after positive
https://www.science.org/doi/10.1126/science.abm3425 (>6 weeks). results on RT-PCR assay regardless of vaccina-
Most of the infected health care workers had tion status could have contributed to this obser-
N gene Ct values that suggested they had been vation. Most important, we found that low titers
infectious at some point. These workers includ- of neutralizing antibody and S-specific IgG anti-
ed some who had been asymptomatic and thus body may serve as markers of breakthrough in-
who had infections that would not have been fection.
detected without the rigorous screening that fol- Identifying immune correlates of protection
lowed any minor known exposure. This factor (or lack thereof) from SARS-CoV-2 is critical to
suggests that at least in some cases, the vaccine predicting how the expected antibody decay will
Protection for symptomatic: Vaccine comparison: (Khoury et al, Nature Med) 50% protective threshold = 54 IU/ml (95% CI=30-96) Breakthrough infection: (Gilbert et al, Science) 70% protective threshold = 4 IU/ml
Protective threshold: Vaccine comparison: (Khoury et al, Nature Med) Geometric mean for mRNA-1273 = 1057 IU/ml Breakthrough infection: (Gilbert et al, Science) Geometric mean for mRNA-1273 = 247 IU/ml
Protective threshold:
Vaccine comparison: (Khoury et al, Nature Med)
Geometric mean for mRNA-1273 = 1057 IU/ml
Phase 2
Breakthrough infection: (Gilbert et al, Science)
Geometric mean for mRNA-1273 = 247 IU/ml
Phase 3Protective threshold:
Vaccine comparison: (Khoury et al, Nature Med)
Geometric mean for mRNA-1273 = 1057 IU/ml
Phase 2
Breakthrough infection: (Gilbert et al, Science)
Geometric mean for mRNA-1273 = 247 IU/ml
Phase 3distribution function (CDF) of the marker in baseline SARS-CoV-2 negative per-protocol vaccine
recipients. (B) Covariate-adjusted cumulative incidence of COVID-19 by 100 days post Day 57 by Day 57
Vaccine comparison Breakthrough infection
cID50 level. The dotted lines indicate bootstrap point-wise 95% CIs. (C) Vaccine efficacy by Day 57 cID50
level, estimated using the method of Gilbert, Fong, and Carone.39 The dashed lines indicate bootstrap
point-wise 95% CIs. In (B) and (C), covariate adjustment was based on an inverse probability sampling-
Vaccine comparison Breakthrough infection
weighted Cox model; the green histograms are an estimate of the density of Day 57 cID50 level in
baseline negative per-protocol vaccine recipients. LOD, limit of detection. cID50: ID50 nAb titer
calibrated to the WHO International Standard.
The n e w e ng l a n d j o u r na l of m e dic i n e
A Peri-infection Neutralizing Antibody Level B Peak Neutralizing Antibody Level
105 105
104 104
103 103
Titer
Titer
102 102
101 101
100 100
Breakthrough Case Control Breakthrough Case Control
C Peri-infection IgG Level D Peak IgG Level
100 100
Bergwerk
10 10
Gilbert
Titer
Titer
1 1
Breakthrough Case Control Breakthrough Case Control
Figure 2. Neutralizing Antibody and IgG Titers among Cases and Controls, According to Timing.
Among the 39 fully vaccinated health care workers who had breakthrough infection with SARS-CoV-2, shown are the
neutralizing antibody titers during the peri-infection period (within a week before SARS-CoV-2 detection) (Panel A)
and the peak titers within 1 month after the second dose (Panel B), as compared with matched controls. Also shown
are IgG titers during the peri-infection period (Panel C) and peak titers (Panel D) in the two groups. Each case of
breakthrough infection was matched with 4 to 5 controls according to sex, age, immunosuppression status, and
timing of serologic testing after the second vaccine dose. In each panel, the horizontal bars indicate the mean geo-
metric titers and the I bars indicate 95% confidence intervals. Symptomatic cases, which were all mild and did not
require hospitalization, are indicated in red.
tested positive for Covid-19, most had few symp- unvaccinated persons, as has been reported pre-
toms, yet 19% had long Covid-19 symptoms
(>6 weeks).
viously.4,5,17,18 Mandated isolation after positive
results on RT-PCR assay regardless of vaccina-
Feng
Most of the infected health care workers had tion status could have contributed to this obser-
N gene Ct values that suggested they had been vation. Most important, we found that low titers
infectious at some point. These workers includ- of neutralizing antibody and S-specific IgG anti-distribution function (CDF) of the marker in baseline SARS-CoV-2 negative per-protocol vaccine
recipients. (B) Covariate-adjusted cumulative incidence of COVID-19 by 100 days post Day 57 by Day 57
Vaccine comparison Breakthrough infection
cID50 level. The dotted lines indicate bootstrap point-wise 95% CIs. (C) Vaccine efficacy by Day 57 cID50
level, estimated using the method of Gilbert, Fong, and Carone.39 The dashed lines indicate bootstrap
point-wise 95% CIs. In (B) and (C), covariate adjustment was based on an inverse probability sampling-
Vaccine comparison Breakthrough infection
weighted Cox model; the green histograms are an estimate of the density of Day 57 cID50 level in
baseline negative per-protocol vaccine recipients. LOD, limit of detection. cID50: ID50 nAb titer
calibrated to the WHO International Standard.
The n e w e ng l a n d j o u r na l of m e dic i n e
A Peri-infection Neutralizing Antibody Level B Peak Neutralizing Antibody Level
105 105
104 104
103 103
Titer
Titer
102 102
101 101
100 100
Breakthrough Case Control Breakthrough Case Control
C Peri-infection IgG Level D Peak IgG Level
100 100
Bergwerk
10 10
Gilbert
Titer
Titer
1 1
Breakthrough Case Control Breakthrough Case Control
Figure 2. Neutralizing Antibody and IgG Titers among Cases and Controls, According to Timing.
Among the 39 fully vaccinated health care workers who had breakthrough infection with SARS-CoV-2, shown are the
neutralizing antibody titers during the peri-infection period (within a week before SARS-CoV-2 detection) (Panel A)
and the peak titers within 1 month after the second dose (Panel B), as compared with matched controls. Also shown
are IgG titers during the peri-infection period (Panel C) and peak titers (Panel D) in the two groups. Each case of
breakthrough infection was matched with 4 to 5 controls according to sex, age, immunosuppression status, and
timing of serologic testing after the second vaccine dose. In each panel, the horizontal bars indicate the mean geo-
metric titers and the I bars indicate 95% confidence intervals. Symptomatic cases, which were all mild and did not
require hospitalization, are indicated in red.
tested positive for Covid-19, most had few symp- unvaccinated persons, as has been reported pre-
toms, yet 19% had long Covid-19 symptoms
(>6 weeks).
viously.4,5,17,18 Mandated isolation after positive
results on RT-PCR assay regardless of vaccina-
Feng
Most of the infected health care workers had tion status could have contributed to this obser-
N gene Ct values that suggested they had been vation. Most important, we found that low titers
infectious at some point. These workers includ- of neutralizing antibody and S-specific IgG anti-Protection level (raw data)
‘Protection curves’
Vaccine comparison
Moderna study
Astra-Zeneca study
Native virus
Pseudovirus
Khoury et al, submittedProtection level (raw data)
‘Protection curves’
Vaccine comparison
Moderna study
Astra-Zeneca study
Native virus
Pseudovirus
Khoury et al, submittedProtection level (raw data)
‘Protection curves’
Vaccine comparison
Moderna study
Astra-Zeneca study
Native virus
Pseudovirus
Khoury et al, submittedVaccine comparison and breakthrough
infection approaches agree!
(where there is sufficient data in breakthrough)
Khoury et al, submittedVaccine comparison and breakthrough
infection approaches agree!
(where there is sufficient data in breakthrough)
• Breakthrough analysis should be
limited to where data is centred
• Vaccine comparison uses wider
range of input
Khoury et al, submittedUsing correlates
Predicting efficacy against new variants • Vaccine uses ancestral spike • Drop in titre to VOC
Predicting efficacy against new variants • Vaccine uses ancestral spike • Drop in titre to VOC
Scaling existing model
Ancestral Variant
Vaccine/Serum
100 Ad26.COV2.S
* BNT162b2
ChAdOx1 nCoV−19
Convalescent
Reported efficacy (%)
75
CoronaVac
Covaxin
* Gam−COVID−Vac
50 mRNA−1273
NVX−CoV2373
Variant
25 Ancestral
Alpha (B.1.1.7)
Beta (B.1.351)
Delta (B.1.617.2)
0
0.0625 0.125 0.25 0.5 1 2 4 8 Study Design
Neutralisation level against ancestral RCT
(/convalescent plasma) TNCC
Cromer et al, Lancet MicrobeScaling existing model
Ancestral Variant
Vaccine/Serum
100 Ad26.COV2.S
* BNT162b2
ChAdOx1 nCoV−19
Convalescent
Reported efficacy (%)
75
CoronaVac
Covaxin
* Gam−COVID−Vac
50 mRNA−1273
NVX−CoV2373
Variant
25 Ancestral
Alpha (B.1.1.7)
Beta (B.1.351)
Delta (B.1.617.2)
0
0.0625 0.125 0.25 0.5 1 2 4 8 Study Design
Neutralisation level against ancestral RCT
(/convalescent plasma) TNCC
Cromer et al, Lancet MicrobeScaling existing model
Ancestral Variant
Vaccine/Serum
100 Ad26.COV2.S
* BNT162b2
ChAdOx1 nCoV−19
Convalescent
Reported efficacy (%)
75
CoronaVac
Covaxin
* Gam−COVID−Vac
50 mRNA−1273
NVX−CoV2373
Variant
25 Ancestral
Alpha (B.1.1.7)
Beta (B.1.351)
Delta (B.1.617.2)
0
0.0625 0.125 0.25 0.5 1 2 4 8 Study Design
Neutralisation level against ancestral RCT
(/convalescent plasma) TNCC
Cromer et al, Lancet MicrobeOmicron If you know the vaccine (titre), the variant (drop in titre), and time since vaccination, can you predict efficacy?
Omicron 100
4 months
post primary
vaccination
6 months
post primary
vaccination
Following
boosted
Data (UK TNCC)
80
Model prediction
If you know the vaccine (titre), the
variant (drop in titre), and time since
Efficacy (%)
60
vaccination, can you predict efficacy? Vaccine Type
ChAdOx1 nCoV−19
40 BNT162b2
ChAdOx1 +
mRNA boosted
BNT162b2 +
20 mRNA boosted
0
Khoury et al, MedRxiv 2021
https://www.medrxiv.org/content/10.1101/2021.12.13.21267748v2Corelates for severe disease
“Any” symptomatic Severe
SARS-CoV-2 infection SARS-CoV-2 infection
34 Khoury, D., Cromer, D. Nature Medicine 2021“Any” symptomatic Severe
SARS-CoV-2 infection SARS-CoV-2 infection
50% protection
50% protection at 8 IU/ml
at 54 IU/ml (3% convalescent)
(20% convalescent)
35 Khoury, D., Cromer, D. Nature Medicine 2021Is 3% (8 IU/ml) mechanistic in protecting from severe infection?
Is 3% (8 IU/ml) mechanistic in protecting from severe infection?
Might it be a surrogate marker for antibody recall?perpetuity.
It is made available under a CC-BY-NC-ND 4.0 International license .
Kinetics of recall after infection
RBD ELISA B Neuts
A
Spike RBD Neutralization titer COR82
6 6 104
Reciprocal endpoint
Reciprocal endpoint
IC5050
CP105
titre )(1/10x)
titre (1/10 x
)
NeutralisationIC
5 5 CP106
x)
103
Neutralization
x
CP107
titer (10
titer (10
4 4
Endpoint
CP108
Endpoint
102 COR03
3 3
2 2 101
-3 0 3 6 9 12 15 18 25 35 -3 0 3 6 9 12 15 18 25 35 -3 0 3 6 9 12 15 18
Days post onset Days post onset Days post onset
Days after symptom onset
C D
Recall of antibody
Spike+ MBCresponse occurs around
ASCs 5 days POS (Delta infection)
#1
COR82
Established
8 8
e+ of IgD- B cells
(8 days post-exposure) CP105
#2 exposure
Spike+ of IgD- B cells
CD20lolo CD71 +
2-3 days prior
% CD20 CD71+
6 6
CP106
#3 to symptom
B Bcells
cells
onset
4 4 #4
CP107
of of
Koutsakos et al MedRxiv 2021. https://www.medrxiv.org/content/10.1101/2021.12.23.21268285v1
2 2time unknown -30
COR038
#6
C
-40 -40 -40
-3 0 3 6 9 12 15 18 -50 -50
Kinetics ofsymptom
Days after recallonsetafter infection
Days post onset 101 102 103
Neut IC50
Neutralization IC50
104 103 104
Spike IgG
Neut IC50
105
E Neutralization
NeutralisationIC50 SpikeSpike IgG
IgG Binding
10 2 1011 1022
10 101
Fold Δ from baseline
Fold Δ from peak
Viral load (2^Ct)
Antibody levels
10 0
10 1011
0
101 10 100
100 10-1-1
10 1000
10 10-1
10
10 -2 10-1 10
0 5 10 15 20 0 5 10 15 20
Days after exposure Days after exposure
Figure 4. of
Recall Immune recall
antibody and viral
response loadaround
occurs kinetics in SARS-CoV-2
5 days breakthrough
POS (Delta infection)
(8 days post-exposure)
infections. (A) Comparative kinetics of immune recall following vaccination of
seropositive individuals (black) and breakthrough infection of vaccinated individuals
Koutsakos et al MedRxiv 2021. https://www.medrxiv.org/content/10.1101/2021.12.23.21268285v1
(red). (B) Ct values for SARS-CoV-2 N gene in serial nasopharyngeal swabs. (C-D)time unknown -30
COR038
#6
C
-40 -40 -40
-3 0 3 6 9 12 15 18 -50 -50
DoesDays
recall affect
after symptom onset outcome?
Days post onset 101 102 103
Neut IC50
Neutralization IC50
104 103 104
Spike IgG
Neut IC50
105
E Neutralization
NeutralisationIC50 SpikeSpike IgG
IgG Binding
10 2 1011 1022
10 101
COMET-ICE study
Fold Δ from baseline
Fold Δ from peak
Viral load (2^Ct)
Antibody levels
10 0
10 1011
0
101 10 100
• 0.5g Sotrovimab < 5 days POS
100 10-1-1
10 1000
10 10-1
10
• 85% protection from hospitalization / death
10 -2 10-1
https://www.nejm.org/doi/full/10.1056/NEJMoa2107934
10
0 5 10 15 20 0 5 10 15 20
Days after exposure Days after exposure
Figure 4. of
Recall Immune recall
antibody and viral
response loadaround
occurs kinetics in SARS-CoV-2
5 days POS breakthrough
(8 days post-exposure)
infections. (A) Comparative kinetics of immune recall following vaccination of
seropositive individuals (black) and breakthrough infection of vaccinated individuals
Koutsakos et al MedRxiv 2021. https://www.medrxiv.org/content/10.1101/2021.12.23.21268285v1
(red). (B) Ct values for SARS-CoV-2 N gene in serial nasopharyngeal swabs. (C-D)time unknown -30
COR038
#6
C
-40 -40 -40
-3 0 3 6 9 12 15 18 -50 -50
DoesDays
recall affect
after symptom onset outcome?
Days post onset 101 102 103
Neut IC50
Neutralization IC50
104 103 104
Spike IgG
Neut IC50
105
E Neutralization
NeutralisationIC50 SpikeSpike IgG
IgG Binding
10 2 1011 1022
10 101
COMET-ICE study
Fold Δ from baseline
Fold Δ from peak
Viral load (2^Ct)
Antibody levels
10 0
10 1011
0
101 10 100
• 0.5g Sotrovimab < 5 days POS
100 10-1-1
10 1000
10 10-1
10
• 85% protection from hospitalization / death
10 -2 10-1
https://www.nejm.org/doi/full/10.1056/NEJMoa2107934
10
0 5 10 15 20 0 5 10 15 20
Days after exposure Days after exposure
Figure 4. Immune recall and viral load kinetics in SARS-CoV-2 breakthrough
Antibodies
infections. (A) Comparative affect
kinetics of outcome of following
immune recall severevaccination
disease!of
seropositive individuals (black) and breakthrough infection of vaccinated individuals
Koutsakos et al MedRxiv 2021. https://www.medrxiv.org/content/10.1101/2021.12.23.21268285v1
(red). (B) Ct values for SARS-CoV-2 N gene in serial nasopharyngeal swabs. (C-D)University of Melbourne
Acknowledgements Stephen Kent
Infection Analytics (UNSW)
Jen Juno
David Khoury
Adam Wheatley
Deborah Cromer
Marios Koutsakos
Arnold Reynaldi
Tim Schlub
Sydney University WHO Flu Centre (Melbourne)
Jamie Triccas Kanta Subbarao
Megan Steain Fred Hutchinson
Peter Gilbert
Funding:
NHMRC (Australia)
MRFF
42Antibody responses to natural
infection and vaccines
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