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 Oliver; Benjamin Hitchings; Divya Diamond; Amy C. Thomas; Ruth E. Mitchell; Milla Kibble; Kapil Gupta; Natalie Di Bartolo; Paul Klenerman; Anthony Brown; Begonia Morales-Aza; Jennifer Oliver; Imre Berger; Ash M. Toye; Adam Finn; Anu Goenka; Andrew D. Davidson; Susan Ring; Lynn Molloy; Melanie Lewcock; Kate Northstone; Firona Roth; Nicholas J. 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 Oliver
, Benjamin Hitchings
, Divya Diamond
, Amy C. Thomas
, Ruth E. Mitchell
, Milla Kibble
, Kapil Gupta
, Natalie Di Bartolo
, Paul Klenerman
, Anthony Brown
, Begonia Morales-Aza
, Jennifer Oliver
, Imre Berger
, Ash M. Toye
, Adam Finn

Anu Goenka, Andrew D. Davidson, Susan Ring, Lynn Molloy, Melanie Lewcock, Kate Northstone, Firona Roth, Nicholas J. Timpson, Linda Wooldridge, Alice Halliday, Laura Rivino

University of Bristol
University of Cambridge
King's College London
University of Oxford
University Hospitals Bristol and Weston NHS Foundation Trust

Research output: Contribution to journal › Article › peer-review

3 Citations (Scopus)

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
Pages (from-to)	e327-e340
Journal	Journal of Infectious Diseases
Volume	232
Issue number	2
Early online date	20 May 2025
DOIs	https://doi.org/10.1093/infdis/jiaf246
Publication status	Published - 15 Aug 2025
Externally published	Yes

UN SDGs

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

SDG 3 Good Health and Well-being

Keywords

ALSPAC
breakthrough infection
hybrid immunity
SARS-CoV-2
vaccination

Access to Document

10.1093/infdis/jiaf246

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Baum, H. E., Santopaolo, M., Francis, O., Milodowski, E. J., Entwistle, K., Oliver, E., Hitchings, B., Diamond, D., Thomas, A. C., Mitchell, R. E., Kibble, M., Gupta, K., Di Bartolo, N., Klenerman, P., Brown, A., Morales-Aza, B., Oliver, J., 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, 232(2), e327-e340. https://doi.org/10.1093/infdis/jiaf246

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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 = "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.",

keywords = "ALSPAC, breakthrough infection, hybrid immunity, SARS-CoV-2, vaccination",

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

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doi = "10.1093/infdis/jiaf246",

language = "English",

volume = "232",

pages = "e327--e340",

journal = "Journal of Infectious Diseases",

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publisher = "Oxford University Press",

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Baum, HE, Santopaolo, M, Francis, O, Milodowski, EJ, Entwistle, K, Oliver, E, Hitchings, B, Diamond, D, Thomas, AC, Mitchell, RE, Kibble, M, Gupta, K, Di Bartolo, N, Klenerman, P, Brown, A, Morales-Aza, B, Oliver, J, Berger, I, Toye, AM, Finn, A, Goenka, A, Davidson, AD, Ring, S, Molloy, L, 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, vol. 232, no. 2, pp. e327-e340. 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, Vol. 232, No. 2, 15.08.2025, p. e327-e340.

Research output: Contribution to journal › Article › 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

AU - Hitchings, Benjamin

AU - Diamond, Divya

AU - Thomas, Amy C.

AU - Mitchell, Ruth E.

AU - Kibble, Milla

AU - Gupta, Kapil

AU - Di Bartolo, Natalie

AU - Klenerman, Paul

AU - Brown, Anthony

AU - Morales-Aza, Begonia

AU - Oliver, Jennifer

AU - Berger, Imre

AU - Toye, Ash M.

AU - Finn, Adam

AU - Goenka, Anu

AU - Davidson, Andrew D.

AU - Ring, Susan

AU - Molloy, Lynn

AU - Lewcock, Melanie

AU - Northstone, Kate

AU - Roth, Firona

AU - Timpson, Nicholas J.

AU - Wooldridge, Linda

AU - Halliday, Alice

AU - Rivino, Laura

PY - 2025/8/15

Y1 - 2025/8/15

N2 - 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.

AB - 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.

KW - ALSPAC

KW - breakthrough infection

KW - hybrid immunity

KW - SARS-CoV-2

KW - vaccination

U2 - 10.1093/infdis/jiaf246

DO - 10.1093/infdis/jiaf246

M3 - Article

C2 - 40392230

AN - SCOPUS:105013234246

SN - 0022-1899

VL - 232

SP - e327-e340

JO - Journal of Infectious Diseases

JF - Journal of Infectious Diseases

IS - 2

ER -

Baum HE, Santopaolo M, Francis O, Milodowski EJ, Entwistle K, Oliver E 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 Aug 15;232(2):e327-e340. Epub 2025 May 20. doi: 10.1093/infdis/jiaf246