Broad and potent neutralizing antibodies are elicited in vaccinated individuals following Delta/BA.1 breakthrough infection

Jeffrey Seow; Zayed A. Shalim; Carl Graham; Simon Kimuda; Aswin Pillai; Thomas Lechmere; Ashwini Kurshan; Atika M. Khimji; Luke B. Snell; Gaia Nebbia; Christine Mant; Anele Waters; Julie Fox; Michael H. Malim; Katie J. Doores

doi:10.1128/mbio.01206-23

Broad and potent neutralizing antibodies are elicited in vaccinated individuals following Delta/BA.1 breakthrough infection

Jeffrey Seow, Zayed A. Shalim, Carl Graham, Simon Kimuda, Aswin Pillai, Thomas Lechmere, Ashwini Kurshan, Atika M. Khimji, Luke B. Snell, Gaia Nebbia, Christine Mant, Anele Waters, Julie Fox, Michael H. Malim, Katie J. Doores

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

5 Citations (Scopus)

Abstract

Despite the success of COVID-19 vaccines in preventing infection and/or severe disease, there has been an increase in SARS-CoV-2 infections in vaccinated individuals owing to the waning vaccine-derived immunity, and the emergence of new variants which encode escape mutations in Spike. Following breakthrough infection in vaccinated individuals, an increase in neutralization breadth has been observed in sera/plasma. However, how exposure to a heterologous Spike broadens the neutralizing response at the monoclonal antibody (mAb) level is not fully understood. Through isolation of 119 mAbs from three individuals receiving two doses of BNT162b2 vaccine before becoming Delta or Omicron/BA.1 infected, we show that serum breadth occurs due to the presence of somatically mutated mAbs with broad neutralization activity indicative of re-activation and maturation of B cells generated through previous COVID-19 vaccination. Isolated mAbs frequently show reduced neutralization of current circulating variants including BA.2.75.2, XBB, XBB.1.5, and BQ.1.1 confirming continuous selective pressure on Spike to evolve and evade neutralization. However, isolation of mAbs that display effective cross-neutralization against all variants indicates the presence of conserved epitopes on the receptor binding domain and a lesser extent the N-terminal domain. These findings have implications for the selection of Spike antigens for next-generation COVID-19 vaccines. IMPORTANCE With the emergence of SARS-CoV-2 viral variants, there has been an increase in infections in vaccinated individuals. Here, we isolated monoclonal antibodies (mAbs) from individuals experiencing a breakthrough infection (Delta or BA.1) to determine how exposure to a heterologous Spike broadens the neutralizing antibody response at the monoclonal level. All mAbs isolated had reactivity to the Spike of the vaccine and infection variant. While many mAbs showed reduced neutralization of current circulating variants, we identified mAbs with broad and potent neutralization of BA.2.75.2, XBB, XBB.1.5, and BQ.1.1 indicating the presence of conserved epitopes on Spike. These results indicate that variant-based vaccine boosters have the potential to broaden the vaccine response.

Original language	English
Journal	Mbio
Volume	14
Issue number	5
DOIs	https://doi.org/10.1128/mbio.01206-23
Publication status	Published - 25 Sept 2023

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Seow, J., Shalim, Z. A., Graham, C., Kimuda, S., Pillai, A., Lechmere, T., Kurshan, A., Khimji, A. M., Snell, L. B., Nebbia, G., Mant, C., Waters, A., Fox, J., Malim, M. H., & Doores, K. J. (2023). Broad and potent neutralizing antibodies are elicited in vaccinated individuals following Delta/BA.1 breakthrough infection. Mbio, 14(5). https://doi.org/10.1128/mbio.01206-23

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title = "Broad and potent neutralizing antibodies are elicited in vaccinated individuals following Delta/BA.1 breakthrough infection",

abstract = "Despite the success of COVID-19 vaccines in preventing infection and/or severe disease, there has been an increase in SARS-CoV-2 infections in vaccinated individuals owing to the waning vaccine-derived immunity, and the emergence of new variants which encode escape mutations in Spike. Following breakthrough infection in vaccinated individuals, an increase in neutralization breadth has been observed in sera/plasma. However, how exposure to a heterologous Spike broadens the neutralizing response at the monoclonal antibody (mAb) level is not fully understood. Through isolation of 119 mAbs from three individuals receiving two doses of BNT162b2 vaccine before becoming Delta or Omicron/BA.1 infected, we show that serum breadth occurs due to the presence of somatically mutated mAbs with broad neutralization activity indicative of re-activation and maturation of B cells generated through previous COVID-19 vaccination. Isolated mAbs frequently show reduced neutralization of current circulating variants including BA.2.75.2, XBB, XBB.1.5, and BQ.1.1 confirming continuous selective pressure on Spike to evolve and evade neutralization. However, isolation of mAbs that display effective cross-neutralization against all variants indicates the presence of conserved epitopes on the receptor binding domain and a lesser extent the N-terminal domain. These findings have implications for the selection of Spike antigens for next-generation COVID-19 vaccines. IMPORTANCE With the emergence of SARS-CoV-2 viral variants, there has been an increase in infections in vaccinated individuals. Here, we isolated monoclonal antibodies (mAbs) from individuals experiencing a breakthrough infection (Delta or BA.1) to determine how exposure to a heterologous Spike broadens the neutralizing antibody response at the monoclonal level. All mAbs isolated had reactivity to the Spike of the vaccine and infection variant. While many mAbs showed reduced neutralization of current circulating variants, we identified mAbs with broad and potent neutralization of BA.2.75.2, XBB, XBB.1.5, and BQ.1.1 indicating the presence of conserved epitopes on Spike. These results indicate that variant-based vaccine boosters have the potential to broaden the vaccine response.",

author = "Jeffrey Seow and Shalim, {Zayed A.} and Carl Graham and Simon Kimuda and Aswin Pillai and Thomas Lechmere and Ashwini Kurshan and Khimji, {Atika M.} and Snell, {Luke B.} and Gaia Nebbia and Christine Mant and Anele Waters and Julie Fox and Malim, {Michael H.} and Doores, {Katie J.}",

note = "Funding Information: This work was funded by Huo Family Foundation Award to M.H.M. and K.J.D., MRC Genotype-to-Phenotype UK National Virology Consortium [(MR/W005611/1) to M.H.M. and K.J.D.], Fondation Dormeur, Vaduz for funding equipment to K.J.D., Wellcome Trust Investigator Award (222433/Z/21/Z) to M.H.M., and Wellcome Trust Multi-User Equipment Grant (208354/Z/17/Z) to M.H.M. and K.J.D. K.J.D. is supported by the Medical Research Foundation Emerging Leaders Prize 2021 (MRF-160-0016-ELP-DOOR-C0908). C.G. was supported by the MRC-KCL Doctoral Training Partnership in Biomedical Sciences (MR/N013700/1). This work and the Infectious Diseases Biobank (C.M.) were supported by the Department of Health via a National Institute for Health Research comprehensive Biomedical Research Centre award to Guy{\textquoteright}s and St Thomas{\textquoteright} NHS Foundation Trust in partnership with King{\textquoteright}s College London and King{\textquoteright}s College Hospital NHS Foundation Trust. This study is part of the EDCTP2 programme supported by the European Union (grant number RIA2020EF-3008 COVAB) (K.J.D., J.F., and M.H.M.). The views and opinions of authors expressed herein do not necessarily state or those of EDCTP. This project is supported by a joint initiative between the Botnar Research Centre for Child Health and the European & Developing Countries Clinical Trials Partnership (K.J.D. and J.F.). Publisher Copyright: Copyright {\textcopyright} 2023 Seow et al.",

year = "2023",

month = sep,

day = "25",

doi = "10.1128/mbio.01206-23",

language = "English",

volume = "14",

journal = "Mbio",

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publisher = "American Society for Microbiology",

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TY - JOUR

T1 - Broad and potent neutralizing antibodies are elicited in vaccinated individuals following Delta/BA.1 breakthrough infection

AU - Seow, Jeffrey

AU - Shalim, Zayed A.

AU - Graham, Carl

AU - Kimuda, Simon

AU - Pillai, Aswin

AU - Lechmere, Thomas

AU - Kurshan, Ashwini

AU - Khimji, Atika M.

AU - Snell, Luke B.

AU - Nebbia, Gaia

AU - Mant, Christine

AU - Waters, Anele

AU - Fox, Julie

AU - Malim, Michael H.

AU - Doores, Katie J.

N1 - Funding Information: This work was funded by Huo Family Foundation Award to M.H.M. and K.J.D., MRC Genotype-to-Phenotype UK National Virology Consortium [(MR/W005611/1) to M.H.M. and K.J.D.], Fondation Dormeur, Vaduz for funding equipment to K.J.D., Wellcome Trust Investigator Award (222433/Z/21/Z) to M.H.M., and Wellcome Trust Multi-User Equipment Grant (208354/Z/17/Z) to M.H.M. and K.J.D. K.J.D. is supported by the Medical Research Foundation Emerging Leaders Prize 2021 (MRF-160-0016-ELP-DOOR-C0908). C.G. was supported by the MRC-KCL Doctoral Training Partnership in Biomedical Sciences (MR/N013700/1). This work and the Infectious Diseases Biobank (C.M.) were supported by the Department of Health via a National Institute for Health Research comprehensive Biomedical Research Centre award to Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust. This study is part of the EDCTP2 programme supported by the European Union (grant number RIA2020EF-3008 COVAB) (K.J.D., J.F., and M.H.M.). The views and opinions of authors expressed herein do not necessarily state or those of EDCTP. This project is supported by a joint initiative between the Botnar Research Centre for Child Health and the European & Developing Countries Clinical Trials Partnership (K.J.D. and J.F.). Publisher Copyright: Copyright © 2023 Seow et al.

PY - 2023/9/25

Y1 - 2023/9/25

N2 - Despite the success of COVID-19 vaccines in preventing infection and/or severe disease, there has been an increase in SARS-CoV-2 infections in vaccinated individuals owing to the waning vaccine-derived immunity, and the emergence of new variants which encode escape mutations in Spike. Following breakthrough infection in vaccinated individuals, an increase in neutralization breadth has been observed in sera/plasma. However, how exposure to a heterologous Spike broadens the neutralizing response at the monoclonal antibody (mAb) level is not fully understood. Through isolation of 119 mAbs from three individuals receiving two doses of BNT162b2 vaccine before becoming Delta or Omicron/BA.1 infected, we show that serum breadth occurs due to the presence of somatically mutated mAbs with broad neutralization activity indicative of re-activation and maturation of B cells generated through previous COVID-19 vaccination. Isolated mAbs frequently show reduced neutralization of current circulating variants including BA.2.75.2, XBB, XBB.1.5, and BQ.1.1 confirming continuous selective pressure on Spike to evolve and evade neutralization. However, isolation of mAbs that display effective cross-neutralization against all variants indicates the presence of conserved epitopes on the receptor binding domain and a lesser extent the N-terminal domain. These findings have implications for the selection of Spike antigens for next-generation COVID-19 vaccines. IMPORTANCE With the emergence of SARS-CoV-2 viral variants, there has been an increase in infections in vaccinated individuals. Here, we isolated monoclonal antibodies (mAbs) from individuals experiencing a breakthrough infection (Delta or BA.1) to determine how exposure to a heterologous Spike broadens the neutralizing antibody response at the monoclonal level. All mAbs isolated had reactivity to the Spike of the vaccine and infection variant. While many mAbs showed reduced neutralization of current circulating variants, we identified mAbs with broad and potent neutralization of BA.2.75.2, XBB, XBB.1.5, and BQ.1.1 indicating the presence of conserved epitopes on Spike. These results indicate that variant-based vaccine boosters have the potential to broaden the vaccine response.

AB - Despite the success of COVID-19 vaccines in preventing infection and/or severe disease, there has been an increase in SARS-CoV-2 infections in vaccinated individuals owing to the waning vaccine-derived immunity, and the emergence of new variants which encode escape mutations in Spike. Following breakthrough infection in vaccinated individuals, an increase in neutralization breadth has been observed in sera/plasma. However, how exposure to a heterologous Spike broadens the neutralizing response at the monoclonal antibody (mAb) level is not fully understood. Through isolation of 119 mAbs from three individuals receiving two doses of BNT162b2 vaccine before becoming Delta or Omicron/BA.1 infected, we show that serum breadth occurs due to the presence of somatically mutated mAbs with broad neutralization activity indicative of re-activation and maturation of B cells generated through previous COVID-19 vaccination. Isolated mAbs frequently show reduced neutralization of current circulating variants including BA.2.75.2, XBB, XBB.1.5, and BQ.1.1 confirming continuous selective pressure on Spike to evolve and evade neutralization. However, isolation of mAbs that display effective cross-neutralization against all variants indicates the presence of conserved epitopes on the receptor binding domain and a lesser extent the N-terminal domain. These findings have implications for the selection of Spike antigens for next-generation COVID-19 vaccines. IMPORTANCE With the emergence of SARS-CoV-2 viral variants, there has been an increase in infections in vaccinated individuals. Here, we isolated monoclonal antibodies (mAbs) from individuals experiencing a breakthrough infection (Delta or BA.1) to determine how exposure to a heterologous Spike broadens the neutralizing antibody response at the monoclonal level. All mAbs isolated had reactivity to the Spike of the vaccine and infection variant. While many mAbs showed reduced neutralization of current circulating variants, we identified mAbs with broad and potent neutralization of BA.2.75.2, XBB, XBB.1.5, and BQ.1.1 indicating the presence of conserved epitopes on Spike. These results indicate that variant-based vaccine boosters have the potential to broaden the vaccine response.

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U2 - 10.1128/mbio.01206-23

DO - 10.1128/mbio.01206-23

M3 - Article

SN - 2150-7511

VL - 14

JO - Mbio

JF - Mbio

IS - 5

ER -

Broad and potent neutralizing antibodies are elicited in vaccinated individuals following Delta/BA.1 breakthrough infection

Abstract

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