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PreprintCited by 216SARS-CoV-2 and COVID-19 Researchvaccines and immunoinformatics approachesImmune responses and vaccinations

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Two doses of SARS-CoV-2 vaccination induce more robust immune responses to emerging SARS-CoV-2 variants of concern than does natural infection.

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Skelly, Donal T., Harding, Adam C., Gilbert-Jaramillo, Javier, Knight, Michael L., Longet, Stephanie, Anthony Brown, Adele, Sandra, Adland, Emily, Brown, Helen, Team, Medawar Laboratory, Tom Tipton, Stafford, Lizzie, Johnson, Síle A., Amini, Ali, Group, OPTIC Clinical, Kit Tan, Tiong, Schimanski, Lisa, Huang, Kuan-Ying A., Rijal, Pramila, Group, PITCH Study, Group, CMORE/PHOSP-C, Frater, John, Goulder, Philip, Conlon, Christopher P., Jeffery, Katie, Dold, Christina, Pollard, Andrew J., Sigal, Alex, de Oliveira, Tulio, Townsend, Alain R., Klenerman, Paul, Dunachie, Susanna J ., Barnes, Eleanor, Carroll, Miles W., James, William S.·2021·Nature Communications
DOI 10.21203/rs.3.rs-226857/v2PMC PMC8371089

Preprint — published as 10.1038/s41467-021-25167-5

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Abstract

Both natural infection with SARS-CoV-2 and immunization with vaccines induce protective immunity. However, the extent to which such immune responses protect against emerging variants is of increasing importance. Such variants of concern (VOC) include isolates of lineage B.1.1.7, first identified in the UK, and B.1.351, first identified in South Africa. Our data confirm that VOC, particularly those with substitutions at residues 484 and 417, escape neutralization by antibodies directed to the ACE2-binding Class 1 and the adjacent Class 2 epitopes but are susceptible to neutralization by the generally less potent antibodies directed to Class 3 and 4 epitopes on the flanks of the receptor-binding domain. To address the potential threat posed by VOC, we sampled a SARS-CoV-2 uninfected UK cohort recently vaccinated with BNT162b2 (Pfizer-BioNTech, two doses delivered 18-28 days apart), alongside a cohort sampled in the early convalescent stages after natural infection in the first wave of the pandemic in Spring 2020. We tested antibody and T cell responses against a reference isolate of the original circulating lineage, B, and the impact of sequence variation in the B.1.1.7 and B.1.351 VOC. Neutralization of the VOC compared to B isolate was reduced, and this was most evident for the B.1.351 isolate. This reduction in antibody neutralization was less marked in post-boost vaccine-induced responses compared to naturally induced immune responses and could be largely explained by the potency of the homotypic antibody response. After a single vaccination, which induced only modestly neutralizing homotypic antibody titres, neutralization against the VOC was completely abrogated in the majority of vaccinees. Importantly, high magnitude T cell responses were generated after two vaccine doses, with the majority of the T cell response directed against epitopes that are conserved between the prototype isolate B and the VOC. These data indicate that VOC may evade protective neutralizing responses induced by prior infection, and to a lesser extent by immunization, particularly after a single vaccine dose, but the impact of the VOC on T cell responses appears less marked. The results emphasize the need to generate high potency immune responses through vaccination in order to provide protection against these and other emergent variants.

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Figures

Fig. 1 Sequence variation in spike glycoprotein. The open reading frame encoding spike (S) is illustrated, with the position of key features of processing and function indicated to approximate scale (residue number indicated above). During co-translational translocation to the endoplasmic reticulum (ER), the short leader peptide (LP) is proteolytically removed. Following folding, trimer assembly and glycosylation in the ER and Golgi, the trans-Golgi localized protease, furin, cleaves the boundary between the S1 and S2 polypeptides. Following binding of the receptor-binding domain (RBD, cyan) to ACE2 on host cells, cell-surface TMPRSS2 proteolytically cleaves the S2’ site, facilitating conformational changes to spike that result in fusion of the virus envelope with the plasma membrane. Variant residue positions are indicated below, and their approximate location on the S polypeptide is indicated. Residue identities are shown at each of these positions for a prototype lineage B isolate, and at each position in four lineages of interest, B.1.1.7 (α—Alpha), B.1.351 (β—Beta), P.1 (γ—Gamma) and B.1.617 (δ—Delta), at which the respective lineage differs from prototype. Δ indicates deletion of one or more residues. Note, there are lineage-defining substitutions outside RBD, in the N-terminal domain (NTD) and C-terminal domain (CTD) of S1 (dark blue), and in S2 (tan). These may include changes that directly or indirectly affect antibody-mediated neutralization or cellular immunity, by loss or altered dynamics of epitope, respectively.
Fig. 1 Sequence variation in spike glycoprotein. The open reading frame encoding spike (S) is illustrated, with the position of key features of processing and function indicated to approximate scale (residue number indicated above). During co-translational translocation to the endoplasmic reticulum (ER), the short leader peptide (LP) is proteolytically removed. Following folding, trimer assembly and glycosylation in the ER and Golgi, the trans-Golgi localized protease, furin, cleaves the boundary between the S1 and S2 polypeptides. Following binding of the receptor-binding domain (RBD, cyan) to ACE2 on host cells, cell-surface TMPRSS2 proteolytically cleaves the S2’ site, facilitating conformational changes to spike that result in fusion of the virus envelope with the plasma membrane. Variant residue positions are indicated below, and their approximate location on the S polypeptide is indicated. Residue identities are shown at each of these positions for a prototype lineage B isolate, and at each position in four lineages of interest, B.1.1.7 (α—Alpha), B.1.351 (β—Beta), P.1 (γ—Gamma) and B.1.617 (δ—Delta), at which the respective lineage differs from prototype. Δ indicates deletion of one or more residues. Note, there are lineage-defining substitutions outside RBD, in the N-terminal domain (NTD) and C-terminal domain (CTD) of S1 (dark blue), and in S2 (tan). These may include changes that directly or indirectly affect antibody-mediated neutralization or cellular immunity, by loss or altered dynamics of epitope, respectively.CC BY · PubMed Central
Fig. 2 Binding assays. IgG antibodies specific to; a–c SARS-CoV-2 (spike [S], receptor-binding domain [RBD], nucleocapsid [N]), d, e SARS-CoV-1 S, MERS-CoV S, f–i HCoV-OC43 S, HCoV-HKU1 S, HCoV-229E S, HCoV-NL63 S, were measured using an MSD technology platform customised array. Sera analysed were from vaccinees (post-prime and post-boost), asymptomatic (mean 27 days post-PCR positive test, range 22–33 days) and mild COVID-19 convalescent sera (mean 29 days post-symptom onset, range 18–40 days) and a cohort of prepandemic sera collected between 2014 and 2018 negative for SARS-CoV-2 (negatives). Data are displayed as calculated concentrations which use an MSD standard reference curve to interpret arbitrary units (AU). Statistical difference between the groups was performed using a two-tailed Kruskal–Wallis one-way ANOVA with Dunn’s post-test for multiple comparisons made to compare all groups (significant adjusted P values are displayed). Vaccinees post-prime n = 11; vaccinees post-boost n = 25; negatives n = 103; asymptomatic COVID-19 convalescents n = 11; mild COVID-19 convalescents n = 62. The dashed lines in a–c show the cut-offs determined as the mean of negatives +3 SD. Samples were run in monoplicate (convalescent samples) or duplicates (vaccine samples). j Inhibition analysis between ACE2 and recombinant spike from the designated homotypic and heterotypic lineages. Sera derived from individuals receiving prime or boost vaccination: post-prime n = 11, post-boost n = 18–25 dependent on spike variant. Differences between B and other variants in post-prime and post samples were tested using a Friedman statistical test with Dunn’s multiple comparison test (significant P values are displayed on lines linking B to variant). A two-tailed Mann–Whitney U test was used to compare post-prime and post boost groups for each variant. P values are displayed on the boost panel, immediately above each variant and are italicized. Plots show median with error bars indicating ± intraquartile range) (IQR). ACE2 inhibition assay samples were run in monoplicate.
Fig. 2 Binding assays. IgG antibodies specific to; a–c SARS-CoV-2 (spike [S], receptor-binding domain [RBD], nucleocapsid [N]), d, e SARS-CoV-1 S, MERS-CoV S, f–i HCoV-OC43 S, HCoV-HKU1 S, HCoV-229E S, HCoV-NL63 S, were measured using an MSD technology platform customised array. Sera analysed were from vaccinees (post-prime and post-boost), asymptomatic (mean 27 days post-PCR positive test, range 22–33 days) and mild COVID-19 convalescent sera (mean 29 days post-symptom onset, range 18–40 days) and a cohort of prepandemic sera collected between 2014 and 2018 negative for SARS-CoV-2 (negatives). Data are displayed as calculated concentrations which use an MSD standard reference curve to interpret arbitrary units (AU). Statistical difference between the groups was performed using a two-tailed Kruskal–Wallis one-way ANOVA with Dunn’s post-test for multiple comparisons made to compare all groups (significant adjusted P values are displayed). Vaccinees post-prime n = 11; vaccinees post-boost n = 25; negatives n = 103; asymptomatic COVID-19 convalescents n = 11; mild COVID-19 convalescents n = 62. The dashed lines in a–c show the cut-offs determined as the mean of negatives +3 SD. Samples were run in monoplicate (convalescent samples) or duplicates (vaccine samples). j Inhibition analysis between ACE2 and recombinant spike from the designated homotypic and heterotypic lineages. Sera derived from individuals receiving prime or boost vaccination: post-prime n = 11, post-boost n = 18–25 dependent on spike variant. Differences between B and other variants in post-prime and post samples were tested using a Friedman statistical test with Dunn’s multiple comparison test (significant P values are displayed on lines linking B to variant). A two-tailed Mann–Whitney U test was used to compare post-prime and post boost groups for each variant. P values are displayed on the boost panel, immediately above each variant and are italicized. Plots show median with error bars indicating ± intraquartile range) (IQR). ACE2 inhibition assay samples were run in monoplicate.CC BY · PubMed Central
Fig. 3 Homotypic and heterotypic neutralization of key SARS-CoV-2 lineages by antibody. The potency of neutralization was determined by a focus-forming unit microneutralization assay against authentic virus of prototype B lineage and isolates of B.1.1.7 and B.1.351. a A cartoon of a ‘squirrel’ illustrating the receptor-binding domain (RBD). Markings on the squirrel show the epitopes of the RBD antibodies used in this study (classes 1–447). Neutralization by the panel of monoclonal antibodies binding to four distinct epitopes of RBD (upper left). A space-filling model of prototype RBD (PDB 6YZ5) created in PyMOL, shows the residue of the mutations present in the B.1.1.7 and B.1.351 lineages in blue (upper middle and upper right; same aspect and reverse aspect as the space-filling model, respectively). b Neutralization by the international reference plasma NIBSC 20/13038, nominally NT50 = 1/1000. The mean number of foci ± SD relative to a no-antibody control is plotted against the reciprocal of the respective serum dilution. Data were fitted by non-linear regression in GraphPad Prism 9 to the Hill Equation, with TOP and BOTTOM constrained to 100 and 0%, respectively. Where a significant fit was obtained, it is represented by a trend line on the respective plot, and NT50 values used in Supplementary Fig. 1 and main results. NT50 against B established in our assay indicated by the vertical dashed line with grey bars indicating the 95% confidence interval. c Neutralization by convalescent sera from asymptomatic participants (left) and those with mild symptoms (right) against B, B.1.1.7 and B.1.351 isolates. A Tukey’s multiple comparison test was performed for each serum group, comparing mean NT50 response to each virus isolate. P values of all comparisons are displayed in the figures. d Neutralization by sera from recipients of a single dose (left) and both prime and boost doses (right) of BNT162b2 vaccine. e Homotypic and heterotypic neutralization potencies of the three sources of antibody against the three isolates, shown by individual (dots) and sub-population mean and SD of NT50 values shown with error bars (upper panel). For each isolate, pairwise comparisons of average NT50 estimates were made between groups of serum using the Kolmogorov–Smirnov non-parametric test. P values for the r statistic are shown (lower panel), both numerically and symbolically. P > 0.05 in green and ‘ns’. No results for 0.05 > P > 0.01. 0.01 > P > 0.001 in yellow and **P < 0.001 in red and ****. Vaccinees post-prime n = 11; vaccinees post-boost n = 25; asymptomatic COVID-19 convalescents n = 12; mild COVID-19 convalescents n = 13. MNA tests were performed in quadruplicate for all samples. Each plate contained serum-free controls for normalization of results.
Fig. 3 Homotypic and heterotypic neutralization of key SARS-CoV-2 lineages by antibody. The potency of neutralization was determined by a focus-forming unit microneutralization assay against authentic virus of prototype B lineage and isolates of B.1.1.7 and B.1.351. a A cartoon of a ‘squirrel’ illustrating the receptor-binding domain (RBD). Markings on the squirrel show the epitopes of the RBD antibodies used in this study (classes 1–447). Neutralization by the panel of monoclonal antibodies binding to four distinct epitopes of RBD (upper left). A space-filling model of prototype RBD (PDB 6YZ5) created in PyMOL, shows the residue of the mutations present in the B.1.1.7 and B.1.351 lineages in blue (upper middle and upper right; same aspect and reverse aspect as the space-filling model, respectively). b Neutralization by the international reference plasma NIBSC 20/13038, nominally NT50 = 1/1000. The mean number of foci ± SD relative to a no-antibody control is plotted against the reciprocal of the respective serum dilution. Data were fitted by non-linear regression in GraphPad Prism 9 to the Hill Equation, with TOP and BOTTOM constrained to 100 and 0%, respectively. Where a significant fit was obtained, it is represented by a trend line on the respective plot, and NT50 values used in Supplementary Fig. 1 and main results. NT50 against B established in our assay indicated by the vertical dashed line with grey bars indicating the 95% confidence interval. c Neutralization by convalescent sera from asymptomatic participants (left) and those with mild symptoms (right) against B, B.1.1.7 and B.1.351 isolates. A Tukey’s multiple comparison test was performed for each serum group, comparing mean NT50 response to each virus isolate. P values of all comparisons are displayed in the figures. d Neutralization by sera from recipients of a single dose (left) and both prime and boost doses (right) of BNT162b2 vaccine. e Homotypic and heterotypic neutralization potencies of the three sources of antibody against the three isolates, shown by individual (dots) and sub-population mean and SD of NT50 values shown with error bars (upper panel). For each isolate, pairwise comparisons of average NT50 estimates were made between groups of serum using the Kolmogorov–Smirnov non-parametric test. P values for the r statistic are shown (lower panel), both numerically and symbolically. P > 0.05 in green and ‘ns’. No results for 0.05 > P > 0.01. 0.01 > P > 0.001 in yellow and **P < 0.001 in red and ****. Vaccinees post-prime n = 11; vaccinees post-boost n = 25; asymptomatic COVID-19 convalescents n = 12; mild COVID-19 convalescents n = 13. MNA tests were performed in quadruplicate for all samples. Each plate contained serum-free controls for normalization of results.CC BY · PubMed Central
Fig. 4 ELISpot responses to prototype, B.1.1.7, B.1.351 and P.1. T cell responses were measured using IFN-γ ELISpot assays in 24 healthy volunteers, 7–17 days after receiving the 2nd dose of BNT162b2. a T cell responses to 15–18-mer peptides in B strain overlapping by 10 amino-acids and spanning the entire spike region. b Summed T cell responses to peptides from B strain that mapped to sites with mutations in B.1.1.7 (n = 17 peptides), B.1.351 (n = 21 peptides) and P.1 (n = 22 peptides). c Percentage contribution T cells (using B peptides) that target mutational regions within B.1.1.7, B.1.351 and P.1, relative to the total T cell spike response in each of the 24 volunteers. d T cell responses to 22 individual peptides in B strain that have corresponding mutations in B.1.1.7, B.1.351 and P.1 variants. Standardised ELISpot assays were run in triplicate for background and spike peptides and duplicates for all others to allow cell preservation. DMSO control with matching percent DMSO was also used in all assays to account for DMSO content in peptide pools. Each bar represents one volunteer with a positive response (defined as a response to the peptide minus the background that was greater than twice the background). SFC/106 PBMC = spot forming cells per million peripheral blood mononuclear cells, with background subtracted.
Fig. 4 ELISpot responses to prototype, B.1.1.7, B.1.351 and P.1. T cell responses were measured using IFN-γ ELISpot assays in 24 healthy volunteers, 7–17 days after receiving the 2nd dose of BNT162b2. a T cell responses to 15–18-mer peptides in B strain overlapping by 10 amino-acids and spanning the entire spike region. b Summed T cell responses to peptides from B strain that mapped to sites with mutations in B.1.1.7 (n = 17 peptides), B.1.351 (n = 21 peptides) and P.1 (n = 22 peptides). c Percentage contribution T cells (using B peptides) that target mutational regions within B.1.1.7, B.1.351 and P.1, relative to the total T cell spike response in each of the 24 volunteers. d T cell responses to 22 individual peptides in B strain that have corresponding mutations in B.1.1.7, B.1.351 and P.1 variants. Standardised ELISpot assays were run in triplicate for background and spike peptides and duplicates for all others to allow cell preservation. DMSO control with matching percent DMSO was also used in all assays to account for DMSO content in peptide pools. Each bar represents one volunteer with a positive response (defined as a response to the peptide minus the background that was greater than twice the background). SFC/106 PBMC = spot forming cells per million peripheral blood mononuclear cells, with background subtracted.CC BY · PubMed Central
Fig. 5 Cross-correlation of immune parameters. For each serum, pairwise Spearman correlation analyses were undertaken between the value of binding of serum antibody to coronavirus antigens, the ACE2-spike binding-inhibition potency (see Fig. 2), and the homotypic and heterotypic neutralizing titre of the same sera (see Fig. 3). a Heatmap of two-tailed Spearman’s r parameter for each comparison in which spike binding data was available across samples drawn from participants after 1 dose (n = 11, mean 27 days after the 1st dose) and 2 doses of BNT162b2 vaccine (n = 25, mean 8 days after receiving the 2nd dose), and previous infection (n = 20, 11:9 asymptomatic to symptomatic, mean 28 days since PCR test for asymptomatics or symptoms onset). Colour mapping is dual gradient from Blue (r = 1.0) through White (r = 0.5) to Red (r = 0). Values outside this range are Black. b Heatmap Spearman’s r parameter for each comparison in which ACE2-spike binding-inhibition data were available (n = 35:11 after the 1st dose and 24 after the 2nd vaccine dose). Colour mapping as in (a).
Fig. 5 Cross-correlation of immune parameters. For each serum, pairwise Spearman correlation analyses were undertaken between the value of binding of serum antibody to coronavirus antigens, the ACE2-spike binding-inhibition potency (see Fig. 2), and the homotypic and heterotypic neutralizing titre of the same sera (see Fig. 3). a Heatmap of two-tailed Spearman’s r parameter for each comparison in which spike binding data was available across samples drawn from participants after 1 dose (n = 11, mean 27 days after the 1st dose) and 2 doses of BNT162b2 vaccine (n = 25, mean 8 days after receiving the 2nd dose), and previous infection (n = 20, 11:9 asymptomatic to symptomatic, mean 28 days since PCR test for asymptomatics or symptoms onset). Colour mapping is dual gradient from Blue (r = 1.0) through White (r = 0.5) to Red (r = 0). Values outside this range are Black. b Heatmap Spearman’s r parameter for each comparison in which ACE2-spike binding-inhibition data were available (n = 35:11 after the 1st dose and 24 after the 2nd vaccine dose). Colour mapping as in (a).CC BY · PubMed Central

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Authors
Skelly, D. T., Harding, A. C., Gilbert-Jaramillo, J., Knight, M. L., Longet, S., Brown, A., Adele, S., Adland, E., Brown, H., Team, M. L., Tipton, T., Stafford, L., Johnson, S. A., Amini, A., Group, O. C., Kit Tan, T., Schimanski, L., Huang, K.-Y. A., Rijal, P., Group, P. S., Group, C.-C., Frater, J., Goulder, P., Conlon, C. P., Jeffery, K., Dold, C., Pollard, A. J., Sigal, A., de Oliveira, T., Townsend, A. R., Klenerman, P., Dunachie, S. J., Barnes, E., Carroll, M. W., & James, W. S.
Affiliations
  • University of Oxford (GB)
  • Sir William Dunn School of Pathology, University of Oxford, Oxford, UK
  • Public Health England, Porton Down, UK
  • Centre for Human Genetics (GB)
  • MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, UK
  • Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
  • Tao Yuan General Hospital (TW)
  • KwaZulu-Natal Research Innovation and Sequencing Platform, Durban, South Africa, 4001
Corresponding author
James, William S.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2021-03-29
Volume
12
Issue
1
Pages
5061-5061
ISSN
2041-1723 (ISSN-L)
DOI
10.21203/rs.3.rs-226857/v2
PMC
PMC8371089
OpenAlex
W3193567675
Cited by
216
References
50
Citations by year
2026: 4 · 2025: 12 · 2024: 21 · 2023: 49 · 2022: 75 · 2021: 55
FWCI
15.84
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Greater South Information System
Funders
  • Meso Scale Diagnostics
  • Wellcome Trust (216417/Z/19/Z, 204721/Z/16/Z, WT 109965MA, 110,110z/15/Z, 211153/Z/18/Z, 109965/Z/15/Z)
  • UK Research and Innovation (NIHR200907, MR/V027859/1)
  • National Institute for Health Research Health Protection Research Unit (NIHR200907)
  • National Institute for Health and Care Research (NIHR-INF-0067, CL-2018-13-007, NIHR-INF-1867, 10980107, U19 I082360, ACF-2019-13-003, DHCS/04/G121/68, COVID-19, ACF-2018-13-005, NIHR300791, MR/V027859/1, WT109965MA, COV19-RECPLA, NF-SI-0515-10005, CL-2020-13-002, NIHR200907, CL-2013-13-003, NF-SI-0617-10139)
  • British Heart Foundation (RE/18/3/34214)
  • Department of Health and Social Care (COVID-19)
  • University of Oxford (RE/18/3/34214, NIHR200907)
  • University of New South Wales
  • Public Health England
  • Huo Family Foundation
  • Hamilton Health Sciences Foundation
  • UK Coronavirus Immunology Consortium
  • National Institutes of Health (WT109965MA, U19 I082360, COVID-19)
  • Medical Research Council (MR/V027859/1, 75F40120C00085, MR/L006588/1, COVID-19)
  • Biotechnology and Biological Sciences Research Council
  • NIHR Oxford Biomedical Research Centre
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
  • Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
Keywords
SARS-CoV-2, COVID-19 vaccines, variants of concern, Beta variant, Alpha variant, neutralizing antibodies, T cell response, booster vaccination, natural infection, conserved epitopes, vaccine efficacy
MeSH terms
Angiotensin-Converting Enzyme 2, COVID-19, SARS-CoV-2, COVID-19 Vaccines, Animals, Antibodies, Monoclonal, Antibodies, Viral, Epitopes, Carrier Proteins, Humans, Immunity, T-Lymphocytes, Antibodies, Neutralizing

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