David GoldblattProfessor of Vaccinology and ImmunologyUniversity College London

David Goldblatt* 1,2, Andrew Fiore-Gartland3, Marina Johnson1, Adam Hunt1, Christopher Bengt1, Dace Zavadska4, Jeremy S Brown5, Lesley Workman6, Heather J Zar6, David Montefiori7, Xiaoying Shen7, Peter Dull8, Stanley Plotkin9, George Siber10, Donna Ambrosino11

Author Affiliation:1) Great Ormond Street Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1 EH, UK2) Great Ormond Street Children’s Hospital NHS Foundation Trust, Great Ormond Street, London, WC1N 3JH, UK3) Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA4) Children’s Clinical University Hospital, Vienibas gatve 45, Riga, LV-1004, Latvia5) UCL Respiratory, Division of Medicine, University College London, London WC1E 6JJ, UK6) Dept of Paediatrics & Child Health, Red Cross Children's Hospital, and SA-MRC unit on Child & Adolescent Health, University of Cape

Town, South Africa7) Department of Surgery, Duke University Medical Center, Durham, NC, USA8) Vaccine Development and Surveillance, Bill & Melinda Gates Foundation, Seattle, WA, USA9) Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA10) Independent Advisor, New York, NY, USA11) Independent Advisor, Stuart, FL, USA

https://doi.org/10.21203/rs.3.rs-832531/v1

David Goldblatt* 1,2, Andrew Fiore-Gartland3, Marina Johnson1, Adam Hunt1, Christopher Bengt1, Dace Zavadska4, Jeremy S Brown5, Lesley Workman6, Heather J Zar6, David Montefiori7, Xiaoying Shen7, Peter Dull8, Stanley Plotkin9, George Siber10, Donna Ambrosino11

Author Affiliation:1) Great Ormond Street Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1 EH, UK2) Great Ormond Street Children’s Hospital NHS Foundation Trust, Great Ormond Street, London, WC1N 3JH, UK3) Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA4) Children’s Clinical University Hospital, Vienibas gatve 45, Riga, LV-1004, Latvia5) UCL Respiratory, Division of Medicine, University College London, London WC1E 6JJ, UK6) Dept of Paediatrics & Child Health, Red Cross Children's Hospital, and SA-MRC unit on Child & Adolescent Health, University of Cape

Town, South Africa7) Department of Surgery, Duke University Medical Center, Durham, NC, USA8) Vaccine Development and Surveillance, Bill & Melinda Gates Foundation, Seattle, WA, USA9) Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA10) Independent Advisor, New York, NY, USA11) Independent Advisor, Stuart, FL, USA

https://doi.org/10.21203/rs.3.rs-832531/v1

• Evidence for antibody as a correlate of protection

• Comparative immunogenicity of 4 SARS-CoV-2 Vaccines

• Relationship of IgG spike titres to original and alpha strain efficacy

• Correlation of binding antibodies with function

• Background to population based thresholds of protection

• Derivation of Correlates of Protection for SARS-CoV-2 vaccines

17th March: https://www.medrxiv.org/content/10.1101/2021.03.17.20200246v1 and Vaccine 2021 May 24:S0264-410X(21)00658-7. PMID: 34210573

Conveneince sample of SARS-CoV-2 naïve subjects vaccinated as part of national rollouts donated blood samples for this evaluationVaccine Name Manufacturer Number of

SubjectsOne Dose /Two Dose

Gender Ratio Female/Male

Median Age Yrs(range)

Median Days Between Doses (range)

Median Days from First Dose to post dose 1 Bleed (range)

Median Days from Final Dose to Bleed (range)

mRNA 1273 Moderna 19/19 1.6 35 (20-55) 27(26-28) 27 (26-28) 7 (7-8)

BNT 162b2 Pfizer 36/51 1.8 43 (21-77) 21(20-60) 23 (7-54) 8 (7-29)

ChadOx1/AZ 1222

AstraZeneca 28/21 2.6 60 (23-70) 66 (33-79) 22 (19-31) 8 (7-10)

Ad26.COV2.S J&J 25/NA 1.2 48 (31-69) N/A N/A 34 (20-31)

S Orig

inal

S Alpha

S Orig

inal

S Alpha

S Orig

inal

S Alpha

S Orig

inal

S Alpha

1

10

100

1000

10000

100000

Spik

e Ig

G B

AU

/ml

mRNA-1273 ChadOx nCoV-19 Ad26.COV2.S

RBD Original RBD Alpha RBD Original RBD Alpha RBD Original RBD Alpha RBD Original RBD Alpha1

10

100

1000

10000

100000

RB

D Ig

G B

AU

/ml

mRNA-1273 ChadOx nCoV-19 Ad26.COV2.S

SPIKE (original and alpha) RBD (original and alpha)

IgG measured on the MesoScaleDiscovery platform, titres expressed in WHO standardized BAU/mlAssay qualification from the Goldblatt lab described in Johnson et al, J Clin Virol. 2020 Aug 2;130:104572. doi: 10.1016/j.jcv.2020.104572. PMID: 32769024

0 1 2 3 4 52.0

2.5

3.0

3.5

4.0

4.5

Log D614G ID50

Log

CoV

-2 S

r=0.8864, r2=0.7858

0 1 2 3 4 50

1

2

3

4

5

r=0.9027, r2=0.8149

Log D614G ID50

Log

CoV

-2 R

BD

0 1 2 3 4 50

1

2

3

4

r=0.7332, r2=0.5375

Log D614G ID50

Log

S in

hib

0 1 2 3 4 50

1

2

3

4

r=0.8119, r2=0.6953

Log D614G ID50

Log

RB

D in

hib

D614G

Correlation betweeen PseudoneutralisationID50 D614G titers (Montefiori laboratory) and Spike and RBD Titers measured on the MSD platform

Post 2 dose sera from naïve vaccinees (All correlations significant, p< 0.0001)

SPIKE

RBD

Population Based Approach to defining a CoP:Relate the observed distribution of antibodiesin a representative subset of the immunized population to the observed point estimates of vaccine efficacyagainst disease

After Bob Kohberger and Ih Chang

Siber et alVaccine 2007

Estimating the protectiveConcentrationof anti-pneumococcal capsular polysaccharideantibodies

Vaccine Efficacy (CI)To Original

Source of Data for Original

Efficacy/Effectiveness (CI)To Alpha

Source of Data for Alpha

ModernaOne DoseTwo Doses

81(64-90)94.1 (89.3-96.8)

MMWR1

Baden et al288.1 (83.7-91.5)100* (91.8-100*)

Chemaitelly et al7Chemaitelly et al7

PfizerOne DoseTwo Doses

81 (64-90)94.6 (89.9-97.3)

MMWR1

Polack et al347.5 (41.6-52.8)93.7 (91.6-95.3)

Lopez Bernal et al4Lopez Bernal et al4

AstraZenecaOne DoseTwo Doses (>12 weeks)

76 (59.3-85.9)80.7 (66.5-88.9)

Voysey et al5Voysey et al5

48.7 (45.2-51.9)74.5 (68.4-79.4)

Lopez Bernal et al4Lopez Bernal et al4

J&JOne Dose (US) 72 (58.2-81.7) Sadoff et al6

Threshold (BAU/ml)

Threshold (BAU/ml)

Head to Head: Licensed vaccine vs Comparator

Primary endpoint: Comparison of Proportions above a threshold

Secondary Endpoint (or Co-Primary): Comparison of Geometric Mean Titres

• How to apply to Variants of Concern?• Assay standardisation• Focus on quantitation of antibody to variants of concern