Hybrid B- and T-Cell Immunity Associates With Protection Against Breakthrough Infection After Severe Acute Respiratory Syndrome Coronavirus 2 Vaccination in Avon Longitudinal Study of Parents and Children (ALSPAC) Participants

Holly E Baum; Marianna Santopaolo; Ore Francis; Emily J Milodowski; Katrina Entwistle; Elizabeth H Oliver; Benjamin E Hitchings; Divya Diamond; Amy Thomas; Ruth E Mitchell; Milla M Kibble; Kapil Gupta; Natalie D Di Bartolo; Paul Klenerman; Anthony Brown; M B Morales-Aza; Jennifer L Oliver; Imre Berger; Ash M Toye; Adam H R Finn; Anu Goenka; Andrew D Davidson; Susan M Ring; Lynn C Molloy; Melanie Lewcock; Kate Northstone; Firona Roth; Nicholas John  Timpson; Linda Wooldridge; Alice Halliday; Laura Rivino

doi:10.1093/infdis/jiaf246

Hybrid B- and T-Cell Immunity Associates With Protection Against Breakthrough Infection After Severe Acute Respiratory Syndrome Coronavirus 2 Vaccination in Avon Longitudinal Study of Parents and Children (ALSPAC) Participants

Holly E Baum, Marianna Santopaolo, Ore Francis, Emily J Milodowski, Katrina Entwistle, Elizabeth H Oliver, Benjamin E Hitchings, Divya Diamond, Amy Thomas, Ruth E Mitchell, Milla M Kibble, Kapil Gupta, Natalie D Di Bartolo, Paul Klenerman, Anthony Brown, M B Morales-Aza, Jennifer L Oliver, Imre Berger, Ash M Toye, Adam H R FinnAnu Goenka, Andrew D Davidson, Susan M Ring, Lynn C Molloy, Melanie Lewcock, Kate Northstone, Firona Roth, Nicholas John Timpson, Linda Wooldridge, Alice Halliday, Laura Rivino^*

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

Abstract

Background
Immunological memory to vaccination and viral infection involves the coordinated action of B and T cells; thus, integrated analysis of these 2 components is critical for understanding their respective contributions to protection against breakthrough infections (BIs) after vaccination.

Methods
We investigated cellular and humoral immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and/or vaccination in 300 adult participants from the Avon Longitudinal Study of Parents and Children (ALSPAC). Participants were grouped by those with (cases) and without (controls) a history of SARS-CoV-2 infection. To provide a quantitative correlate for protection against BI in the 8-month period after the study, Youden index thresholds were calculated for all immune measures analyzed.

Results
The magnitude of antibody and T-cell responses following the second vaccine dose was associated with protection against BI in participants with a history of SARS-CoV-2 infection (cases), but not in infection-naive controls. Over 8 months of follow-up, 2 threshold combinations provided the best performance for protection against BI in cases: (i) anti-spike immunoglobulin G (IgG) (≥666.4 binding antibody units [BAU]/mL) combined with anti-nucleocapsid pan-immunoglobulin (pan-Ig) (≥0.1332 BAU/mL) and (ii) spike 1–specific T cells (≥195.6 spot-forming units/106 peripheral blood mononuclear cells) combined with anti-N pan-Ig (≥0.1332 BAU/mL). Both combinations offered 100% specificity for detecting cases without BI, with sensitivities of 83.3% and 72.2%, respectively.

Conclusions
Collectively, these results suggest that hybrid B- and T-cell immunity offers superior protection from BI after coronavirus disease 2019 (COVID-19) vaccination, and this finding has implications for designing next-generation COVID-19 vaccines that are capable of eliciting immunity to a broader repertoire of SARS-CoV-2 proteins.

Original language	English
Article number	jiaf246
Number of pages	14
Journal	Journal of Infectious Diseases
Early online date	20 May 2025
DOIs	https://doi.org/10.1093/infdis/jiaf246
Publication status	E-pub ahead of print - 20 May 2025

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1093/infdis/jiaf246Licence: CC BY

Handle.net

Persistent link

Fingerprint

Dive into the research topics of 'Hybrid B- and T-Cell Immunity Associates With Protection Against Breakthrough Infection After Severe Acute Respiratory Syndrome Coronavirus 2 Vaccination in Avon Longitudinal Study of Parents and Children (ALSPAC) Participants'. Together they form a unique fingerprint.

Cite this

Baum, H. E., Santopaolo, M., Francis, O., Milodowski, E. J., Entwistle, K., Oliver, E. H., Hitchings, B. E., Diamond, D., Thomas, A., Mitchell, R. E., Kibble, M. M., Gupta, K., Di Bartolo, N. D., Klenerman, P., Brown, A., Morales-Aza, M. B., Oliver, J. L., Berger, I., Toye, A. M., ... Rivino, L. (2025). Hybrid B- and T-Cell Immunity Associates With Protection Against Breakthrough Infection After Severe Acute Respiratory Syndrome Coronavirus 2 Vaccination in Avon Longitudinal Study of Parents and Children (ALSPAC) Participants. Journal of Infectious Diseases, Article jiaf246. Advance online publication. https://doi.org/10.1093/infdis/jiaf246

@article{7b331346a2474e80bc29855336dd1589,

title = "Hybrid B- and T-Cell Immunity Associates With Protection Against Breakthrough Infection After Severe Acute Respiratory Syndrome Coronavirus 2 Vaccination in Avon Longitudinal Study of Parents and Children (ALSPAC) Participants",

abstract = "BackgroundImmunological memory to vaccination and viral infection involves the coordinated action of B and T cells; thus, integrated analysis of these 2 components is critical for understanding their respective contributions to protection against breakthrough infections (BIs) after vaccination.MethodsWe investigated cellular and humoral immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and/or vaccination in 300 adult participants from the Avon Longitudinal Study of Parents and Children (ALSPAC). Participants were grouped by those with (cases) and without (controls) a history of SARS-CoV-2 infection. To provide a quantitative correlate for protection against BI in the 8-month period after the study, Youden index thresholds were calculated for all immune measures analyzed.ResultsThe magnitude of antibody and T-cell responses following the second vaccine dose was associated with protection against BI in participants with a history of SARS-CoV-2 infection (cases), but not in infection-naive controls. Over 8 months of follow-up, 2 threshold combinations provided the best performance for protection against BI in cases: (i) anti-spike immunoglobulin G (IgG) (≥666.4 binding antibody units [BAU]/mL) combined with anti-nucleocapsid pan-immunoglobulin (pan-Ig) (≥0.1332 BAU/mL) and (ii) spike 1–specific T cells (≥195.6 spot-forming units/106 peripheral blood mononuclear cells) combined with anti-N pan-Ig (≥0.1332 BAU/mL). Both combinations offered 100% specificity for detecting cases without BI, with sensitivities of 83.3% and 72.2%, respectively.ConclusionsCollectively, these results suggest that hybrid B- and T-cell immunity offers superior protection from BI after coronavirus disease 2019 (COVID-19) vaccination, and this finding has implications for designing next-generation COVID-19 vaccines that are capable of eliciting immunity to a broader repertoire of SARS-CoV-2 proteins.",

author = "Baum, {Holly E} and Marianna Santopaolo and Ore Francis and Milodowski, {Emily J} and Katrina Entwistle and Oliver, {Elizabeth H} and Hitchings, {Benjamin E} and Divya Diamond and Amy Thomas and Mitchell, {Ruth E} and Kibble, {Milla M} and Kapil Gupta and {Di Bartolo}, {Natalie D} and Paul Klenerman and Anthony Brown and Morales-Aza, {M B} and Oliver, {Jennifer L} and Imre Berger and Toye, {Ash M} and Finn, {Adam H R} and Anu Goenka and Davidson, {Andrew D} and Ring, {Susan M} and Molloy, {Lynn C} and Melanie Lewcock and Kate Northstone and Firona Roth and Timpson, {Nicholas John} and Linda Wooldridge and Alice Halliday and Laura Rivino",

year = "2025",

month = may,

day = "20",

doi = "10.1093/infdis/jiaf246",

language = "English",

journal = "Journal of Infectious Diseases",

issn = "0022-1899",

publisher = "Oxford University Press",

}

Baum, HE, Santopaolo, M, Francis, O, Milodowski, EJ, Entwistle, K, Oliver, EH, Hitchings, BE, Diamond, D, Thomas, A, Mitchell, RE, Kibble, MM, Gupta, K, Di Bartolo, ND, Klenerman, P, Brown, A, Morales-Aza, MB, Oliver, JL, Berger, I , Toye, AM , Finn, AHR , Goenka, A , Davidson, AD , Ring, SM, Molloy, LC, Lewcock, M, Northstone, K, Roth, F, Timpson, NJ , Wooldridge, L , Halliday, A & Rivino, L 2025, 'Hybrid B- and T-Cell Immunity Associates With Protection Against Breakthrough Infection After Severe Acute Respiratory Syndrome Coronavirus 2 Vaccination in Avon Longitudinal Study of Parents and Children (ALSPAC) Participants', Journal of Infectious Diseases. https://doi.org/10.1093/infdis/jiaf246

Hybrid B- and T-Cell Immunity Associates With Protection Against Breakthrough Infection After Severe Acute Respiratory Syndrome Coronavirus 2 Vaccination in Avon Longitudinal Study of Parents and Children (ALSPAC) Participants. / Baum, Holly E; Santopaolo, Marianna; Francis, Ore et al.
In: Journal of Infectious Diseases, 20.05.2025.

Research output: Contribution to journal › Article (Academic Journal) › peer-review

TY - JOUR

T1 - Hybrid B- and T-Cell Immunity Associates With Protection Against Breakthrough Infection After Severe Acute Respiratory Syndrome Coronavirus 2 Vaccination in Avon Longitudinal Study of Parents and Children (ALSPAC) Participants

AU - Baum, Holly E

AU - Santopaolo, Marianna

AU - Francis, Ore

AU - Milodowski, Emily J

AU - Entwistle, Katrina

AU - Oliver, Elizabeth H

AU - Hitchings, Benjamin E

AU - Diamond, Divya

AU - Thomas, Amy

AU - Mitchell, Ruth E

AU - Kibble, Milla M

AU - Gupta, Kapil

AU - Di Bartolo, Natalie D

AU - Klenerman, Paul

AU - Brown, Anthony

AU - Morales-Aza, M B

AU - Oliver, Jennifer L

AU - Berger, Imre

AU - Toye, Ash M

AU - Finn, Adam H R

AU - Goenka, Anu

AU - Davidson, Andrew D

AU - Ring, Susan M

AU - Molloy, Lynn C

AU - Lewcock, Melanie

AU - Northstone, Kate

AU - Roth, Firona

AU - Timpson, Nicholas John

AU - Wooldridge, Linda

AU - Halliday, Alice

AU - Rivino, Laura

PY - 2025/5/20

Y1 - 2025/5/20

N2 - BackgroundImmunological memory to vaccination and viral infection involves the coordinated action of B and T cells; thus, integrated analysis of these 2 components is critical for understanding their respective contributions to protection against breakthrough infections (BIs) after vaccination.MethodsWe investigated cellular and humoral immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and/or vaccination in 300 adult participants from the Avon Longitudinal Study of Parents and Children (ALSPAC). Participants were grouped by those with (cases) and without (controls) a history of SARS-CoV-2 infection. To provide a quantitative correlate for protection against BI in the 8-month period after the study, Youden index thresholds were calculated for all immune measures analyzed.ResultsThe magnitude of antibody and T-cell responses following the second vaccine dose was associated with protection against BI in participants with a history of SARS-CoV-2 infection (cases), but not in infection-naive controls. Over 8 months of follow-up, 2 threshold combinations provided the best performance for protection against BI in cases: (i) anti-spike immunoglobulin G (IgG) (≥666.4 binding antibody units [BAU]/mL) combined with anti-nucleocapsid pan-immunoglobulin (pan-Ig) (≥0.1332 BAU/mL) and (ii) spike 1–specific T cells (≥195.6 spot-forming units/106 peripheral blood mononuclear cells) combined with anti-N pan-Ig (≥0.1332 BAU/mL). Both combinations offered 100% specificity for detecting cases without BI, with sensitivities of 83.3% and 72.2%, respectively.ConclusionsCollectively, these results suggest that hybrid B- and T-cell immunity offers superior protection from BI after coronavirus disease 2019 (COVID-19) vaccination, and this finding has implications for designing next-generation COVID-19 vaccines that are capable of eliciting immunity to a broader repertoire of SARS-CoV-2 proteins.

AB - BackgroundImmunological memory to vaccination and viral infection involves the coordinated action of B and T cells; thus, integrated analysis of these 2 components is critical for understanding their respective contributions to protection against breakthrough infections (BIs) after vaccination.MethodsWe investigated cellular and humoral immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and/or vaccination in 300 adult participants from the Avon Longitudinal Study of Parents and Children (ALSPAC). Participants were grouped by those with (cases) and without (controls) a history of SARS-CoV-2 infection. To provide a quantitative correlate for protection against BI in the 8-month period after the study, Youden index thresholds were calculated for all immune measures analyzed.ResultsThe magnitude of antibody and T-cell responses following the second vaccine dose was associated with protection against BI in participants with a history of SARS-CoV-2 infection (cases), but not in infection-naive controls. Over 8 months of follow-up, 2 threshold combinations provided the best performance for protection against BI in cases: (i) anti-spike immunoglobulin G (IgG) (≥666.4 binding antibody units [BAU]/mL) combined with anti-nucleocapsid pan-immunoglobulin (pan-Ig) (≥0.1332 BAU/mL) and (ii) spike 1–specific T cells (≥195.6 spot-forming units/106 peripheral blood mononuclear cells) combined with anti-N pan-Ig (≥0.1332 BAU/mL). Both combinations offered 100% specificity for detecting cases without BI, with sensitivities of 83.3% and 72.2%, respectively.ConclusionsCollectively, these results suggest that hybrid B- and T-cell immunity offers superior protection from BI after coronavirus disease 2019 (COVID-19) vaccination, and this finding has implications for designing next-generation COVID-19 vaccines that are capable of eliciting immunity to a broader repertoire of SARS-CoV-2 proteins.

U2 - 10.1093/infdis/jiaf246

DO - 10.1093/infdis/jiaf246

M3 - Article (Academic Journal)

C2 - 40392230

SN - 0022-1899

JO - Journal of Infectious Diseases

JF - Journal of Infectious Diseases

M1 - jiaf246

ER -

Baum HE, Santopaolo M, Francis O, Milodowski EJ, Entwistle K, Oliver EH et al. Hybrid B- and T-Cell Immunity Associates With Protection Against Breakthrough Infection After Severe Acute Respiratory Syndrome Coronavirus 2 Vaccination in Avon Longitudinal Study of Parents and Children (ALSPAC) Participants. Journal of Infectious Diseases. 2025 May 20;jiaf246. Epub 2025 May 20. doi: 10.1093/infdis/jiaf246