Antibody escape drives emergence of diverse spike haplotypes resembling variants of concern in persistent SARS-CoV-2 infections

Luke Blagdon Snell; Suzy Pickering; Adela Alcolea-Medina; Helena Winstone; Jeffrey Seow; Carl Graham; Lorcan O'Connell; Rahul Batra; Michael Malim; Katherine Doores; Gaia Nebbia; Jonathan Edgeworth; Stuart Neil; Rui Pedro Ribeiro Galao

Antibody escape drives emergence of diverse spike haplotypes resembling variants of concern in persistent SARS-CoV-2 infections

^*Corresponding author for this work

St Thomas' Hospital
Guy's and St Thomas' NHS Foundation Trust

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

Abstract

Evolution of SARS-CoV-2 in long-term persistent infections is hypothesised to be a
major source of variants of concern (VOC). However, linking intra-host variants into
haplotypes that reflect viral subpopulations is limited by commonly used genomic
sequencing techniques. We develop sequencing and analysis methods for identifying
full-length spike haplotypes and analyse their diversification during persistent infections in individuals with inherited or acquired immunodeficiencies. This reveals accelerated evolutionary rates, with mutations frequently emerging at VOC-associated sites that confer escape from neutralising antibodies, often undergoing strong positive selection. In a single infection lasting over 500 days from the first wave of the pandemic, we detail the evolution of spike as it acquires mechanisms to evade both autologous and heterologous neutralising antibodies, redolent of Omicron variants. This evidence reinforces the argument for persistent infections being the source of immune-evasive variants, underscoring their impact on the evolutionary trajectory of SARS-CoV-2.

Original language	English
Journal	Cell Reports Medicine
Publication status	Accepted/In press - 27 Nov 2025

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

SDG 3 Good Health and Well-being

The G2P2 virology consortium: keeping pace with SARS-CoV-2 variants, providing evidence to vaccine policy, and building agility for the next pandemic
Malim, M. (Primary Investigator), Doores, K. (Co-Investigator), Neil, S. (Co-Investigator) & Ribeiro Galao, R. P. (Co-Investigator)
MRC Medical Research Council
1/10/2023 → 30/09/2027
Project: Research

Cite this

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title = "Antibody escape drives emergence of diverse spike haplotypes resembling variants of concern in persistent SARS-CoV-2 infections",

abstract = "Evolution of SARS-CoV-2 in long-term persistent infections is hypothesised to be a major source of variants of concern (VOC). However, linking intra-host variants into haplotypes that reflect viral subpopulations is limited by commonly used genomic sequencing techniques. We develop sequencing and analysis methods for identifying full-length spike haplotypes and analyse their diversification during persistent infections in individuals with inherited or acquired immunodeficiencies. This reveals accelerated evolutionary rates, with mutations frequently emerging at VOC-associated sites that confer escape from neutralising antibodies, often undergoing strong positive selection. In a single infection lasting over 500 days from the first wave of the pandemic, we detail the evolution of spike as it acquires mechanisms to evade both autologous and heterologous neutralising antibodies, redolent of Omicron variants. This evidence reinforces the argument for persistent infections being the source of immune-evasive variants, underscoring their impact on the evolutionary trajectory of SARS-CoV-2.",

author = "Snell, \{Luke Blagdon\} and Suzy Pickering and Adela Alcolea-Medina and Helena Winstone and Jeffrey Seow and Carl Graham and Lorcan O'Connell and Rahul Batra and Michael Malim and Katherine Doores and Gaia Nebbia and Jonathan Edgeworth and Stuart Neil and \{Ribeiro Galao\}, \{Rui Pedro\}",

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day = "27",

language = "English",

journal = "Cell Reports Medicine",

issn = "2666-3791",

publisher = "Cell Press",

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TY - JOUR

T1 - Antibody escape drives emergence of diverse spike haplotypes resembling variants of concern in persistent SARS-CoV-2 infections

AU - Snell, Luke Blagdon

AU - Pickering, Suzy

AU - Alcolea-Medina, Adela

AU - Winstone, Helena

AU - Seow, Jeffrey

AU - Graham, Carl

AU - O'Connell, Lorcan

AU - Batra, Rahul

AU - Malim, Michael

AU - Doores, Katherine

AU - Nebbia, Gaia

AU - Edgeworth, Jonathan

AU - Neil, Stuart

AU - Ribeiro Galao, Rui Pedro

PY - 2025/11/27

Y1 - 2025/11/27

N2 - Evolution of SARS-CoV-2 in long-term persistent infections is hypothesised to be a major source of variants of concern (VOC). However, linking intra-host variants into haplotypes that reflect viral subpopulations is limited by commonly used genomic sequencing techniques. We develop sequencing and analysis methods for identifying full-length spike haplotypes and analyse their diversification during persistent infections in individuals with inherited or acquired immunodeficiencies. This reveals accelerated evolutionary rates, with mutations frequently emerging at VOC-associated sites that confer escape from neutralising antibodies, often undergoing strong positive selection. In a single infection lasting over 500 days from the first wave of the pandemic, we detail the evolution of spike as it acquires mechanisms to evade both autologous and heterologous neutralising antibodies, redolent of Omicron variants. This evidence reinforces the argument for persistent infections being the source of immune-evasive variants, underscoring their impact on the evolutionary trajectory of SARS-CoV-2.

AB - Evolution of SARS-CoV-2 in long-term persistent infections is hypothesised to be a major source of variants of concern (VOC). However, linking intra-host variants into haplotypes that reflect viral subpopulations is limited by commonly used genomic sequencing techniques. We develop sequencing and analysis methods for identifying full-length spike haplotypes and analyse their diversification during persistent infections in individuals with inherited or acquired immunodeficiencies. This reveals accelerated evolutionary rates, with mutations frequently emerging at VOC-associated sites that confer escape from neutralising antibodies, often undergoing strong positive selection. In a single infection lasting over 500 days from the first wave of the pandemic, we detail the evolution of spike as it acquires mechanisms to evade both autologous and heterologous neutralising antibodies, redolent of Omicron variants. This evidence reinforces the argument for persistent infections being the source of immune-evasive variants, underscoring their impact on the evolutionary trajectory of SARS-CoV-2.

M3 - Article

SN - 2666-3791

JO - Cell Reports Medicine

JF - Cell Reports Medicine

ER -

Antibody escape drives emergence of diverse spike haplotypes resembling variants of concern in persistent SARS-CoV-2 infections

Abstract

UN SDGs

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The G2P2 virology consortium: keeping pace with SARS-CoV-2 variants, providing evidence to vaccine policy, and building agility for the next pandemic

Cite this