IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-57947-8.html
   My bibliography  Save this article

Complement-mediated enhancement of SARS-CoV-2 antibody neutralisation potency in vaccinated individuals

Author

Listed:
  • Jack Mellors

    (University of Oxford)

  • Raman Dhaliwal

    (University of Oxford)

  • Stephanie Longet

    (Inserm)

  • Tom Tipton

    (University of Oxford)

  • Eleanor Barnes

    (Oxford University Hospitals NHS Foundation Trust
    University of Oxford)

  • Susanna J. Dunachie

    (Oxford University Hospitals NHS Foundation Trust
    University of Oxford)

  • Paul Klenerman

    (Oxford University Hospitals NHS Foundation Trust
    University of Oxford)

  • Julian Hiscox

    (University of Liverpool)

  • Miles Carroll

    (University of Oxford)

Abstract

With the continued emergence of SARS-CoV-2 variants and concerns of waning immunity, there is a need for better defined correlates of protection to aid future vaccine and therapeutic developments. Whilst neutralising antibody titres are associated with protection, these are typically determined in the absence of the complement system, which has the potential to enhance neutralisation titres and strengthen correlates with protection in vivo. Here we show that replenishment of the complement system in neutralisation assays can significantly enhance neutralisation titres, with up to an ~83-fold increase in neutralisation of the BA.1.1.529 strain using cross-reactive sera from vaccination against the ancestral strain. The magnitude of enhancement significantly varies between individuals, viral strains (wild-type/VIC01 and Omicron/BA.1), and cell lines (Vero E6 and Calu-3), and is abrogated following heat-inactivation of the complement source. Utilising ACE2 competition assays, we show that the mechanism of action is partially mediated by reducing ACE2-spike interactions. Through the addition of compstatin (a C3 inhibitor) to live virus neutralisation assays, the complement protein C3 is shown to be required for maximum efficiency. These findings further our understanding of SARS-CoV-2 immunity and neutralisation, with implications for protection against emerging variants and assessing future vaccine and therapeutic developments.

Suggested Citation

  • Jack Mellors & Raman Dhaliwal & Stephanie Longet & Tom Tipton & Eleanor Barnes & Susanna J. Dunachie & Paul Klenerman & Julian Hiscox & Miles Carroll, 2025. "Complement-mediated enhancement of SARS-CoV-2 antibody neutralisation potency in vaccinated individuals," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57947-8
    DOI: 10.1038/s41467-025-57947-8
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-57947-8
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-025-57947-8?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Adriana Tomic & Donal T. Skelly & Ane Ogbe & Daniel O’Connor & Matthew Pace & Emily Adland & Frances Alexander & Mohammad Ali & Kirk Allott & M. Azim Ansari & Sandra Belij-Rammerstorfer & Sagida Bibi , 2022. "Divergent trajectories of antiviral memory after SARS-CoV-2 infection," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    2. Bo Meng & Adam Abdullahi & Isabella A. T. M. Ferreira & Niluka Goonawardane & Akatsuki Saito & Izumi Kimura & Daichi Yamasoba & Pehuén Pereyra Gerber & Saman Fatihi & Surabhi Rathore & Samantha K. Zep, 2022. "Altered TMPRSS2 usage by SARS-CoV-2 Omicron impacts infectivity and fusogenicity," Nature, Nature, vol. 603(7902), pages 706-714, March.
    3. Donal T. Skelly & Adam C. Harding & Javier Gilbert-Jaramillo & Michael L. Knight & Stephanie Longet & Anthony Brown & Sandra Adele & Emily Adland & Helen Brown & Tom Tipton & Lizzie Stafford & Alexand, 2021. "Two doses of SARS-CoV-2 vaccination induce robust immune responses to emerging SARS-CoV-2 variants of concern," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Taha Y. Taha & Irene P. Chen & Jennifer M. Hayashi & Takako Tabata & Keith Walcott & Gabriella R. Kimmerly & Abdullah M. Syed & Alison Ciling & Rahul K. Suryawanshi & Hannah S. Martin & Bryan H. Bach , 2023. "Rapid assembly of SARS-CoV-2 genomes reveals attenuation of the Omicron BA.1 variant through NSP6," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Guoli Shi & Tiansheng Li & Kin Kui Lai & Reed F. Johnson & Jonathan W. Yewdell & Alex A. Compton, 2024. "Omicron Spike confers enhanced infectivity and interferon resistance to SARS-CoV-2 in human nasal tissue," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    3. Delphine Planas & Timothée Bruel & Isabelle Staropoli & Florence Guivel-Benhassine & Françoise Porrot & Piet Maes & Ludivine Grzelak & Matthieu Prot & Said Mougari & Cyril Planchais & Julien Puech & M, 2023. "Resistance of Omicron subvariants BA.2.75.2, BA.4.6, and BQ.1.1 to neutralizing antibodies," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    4. Nikhil Kumar Tulsian & Raghuvamsi Venkata Palur & Xinlei Qian & Yue Gu & Bhuvaneshwari D/O Shunmuganathan & Firdaus Samsudin & Yee Hwa Wong & Jianqing Lin & Kiren Purushotorman & Mary McQueen Kozma & , 2023. "Defining neutralization and allostery by antibodies against COVID-19 variants," Nature Communications, Nature, vol. 14(1), pages 1-23, December.
    5. Meriem Bekliz & Kenneth Adea & Pauline Vetter & Christiane S. Eberhardt & Krisztina Hosszu-Fellous & Diem-Lan Vu & Olha Puhach & Manel Essaidi-Laziosi & Sophie Waldvogel-Abramowski & Caroline Stephan , 2022. "Neutralization capacity of antibodies elicited through homologous or heterologous infection or vaccination against SARS-CoV-2 VOCs," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    6. Kaiyuan Sun & Stefano Tempia & Jackie Kleynhans & Anne Gottberg & Meredith L. McMorrow & Nicole Wolter & Jinal N. Bhiman & Jocelyn Moyes & Maimuna Carrim & Neil A. Martinson & Kathleen Kahn & Limakats, 2023. "Rapidly shifting immunologic landscape and severity of SARS-CoV-2 in the Omicron era in South Africa," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    7. Haofeng Wang & Qi Yang & Xiaoce Liu & Zili Xu & Maolin Shao & Dongxu Li & Yinkai Duan & Jielin Tang & Xianqiang Yu & Yumin Zhang & Aihua Hao & Yajie Wang & Jie Chen & Chenghao Zhu & Luke Guddat & Hong, 2023. "Structure-based discovery of dual pathway inhibitors for SARS-CoV-2 entry," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    8. Denis Mongin & Nils Bürgisser & Gustavo Laurie & Guillaume Schimmel & Diem-Lan Vu & Stephane Cullati & Delphine Sophie Courvoisier, 2023. "Effect of SARS-CoV-2 prior infection and mRNA vaccination on contagiousness and susceptibility to infection," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    9. Delphine Planas & Isabelle Staropoli & Vincent Michel & Frederic Lemoine & Flora Donati & Matthieu Prot & Francoise Porrot & Florence Guivel-Benhassine & Banujaa Jeyarajah & Angela Brisebarre & Océane, 2024. "Distinct evolution of SARS-CoV-2 Omicron XBB and BA.2.86/JN.1 lineages combining increased fitness and antibody evasion," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    10. Yuanchen Liu & Xiaoyu Zhao & Jialu Shi & Yajie Wang & Huan Liu & Ye-Fan Hu & Bingjie Hu & Huiping Shuai & Terrence Tsz-Tai Yuen & Yue Chai & Feifei Liu & Hua-Rui Gong & Jiayan Li & Xun Wang & Shujun J, 2024. "Lineage-specific pathogenicity, immune evasion, and virological features of SARS-CoV-2 BA.2.86/JN.1 and EG.5.1/HK.3," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    11. Matthias Reinscheid & Hendrik Luxenburger & Vivien Karl & Anne Graeser & Sebastian Giese & Kevin Ciminski & David B. Reeg & Valerie Oberhardt & Natascha Roehlen & Julia Lang-Meli & Kathrin Heim & Nina, 2022. "COVID-19 mRNA booster vaccine induces transient CD8+ T effector cell responses while conserving the memory pool for subsequent reactivation," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    12. Daan K. J. Pieren & Sebastián G. Kuguel & Joel Rosado & Alba G. Robles & Joan Rey-Cano & Cristina Mancebo & Juliana Esperalba & Vicenç Falcó & María J. Buzón & Meritxell Genescà, 2023. "Limited induction of polyfunctional lung-resident memory T cells against SARS-CoV-2 by mRNA vaccination compared to infection," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    13. Anna Huhn & Daniel Nissley & Daniel B. Wilson & Mikhail A. Kutuzov & Robert Donat & Tiong Kit Tan & Ying Zhang & Michael I. Barton & Chang Liu & Wanwisa Dejnirattisai & Piyada Supasa & Juthathip Mongk, 2025. "The molecular reach of antibodies crucially underpins their viral neutralisation capacity," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    14. Hidetoshi Igari & Seiichiro Sakao & Takayuki Ishige & Kengo Saito & Shota Murata & Misuzu Yahaba & Toshibumi Taniguchi & Akiko Suganami & Kazuyuki Matsushita & Yutaka Tamura & Takuji Suzuki & Eiji Ido, 2024. "Dynamic diversity of SARS-CoV-2 genetic mutations in a lung transplantation patient with persistent COVID-19," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    15. Ryuta Uraki & Shun Iida & Peter J. Halfmann & Seiya Yamayoshi & Yuichiro Hirata & Kiyoko Iwatsuki-Horimoto & Maki Kiso & Mutsumi Ito & Yuri Furusawa & Hiroshi Ueki & Yuko Sakai-Tagawa & Makoto Kuroda , 2023. "Characterization of SARS-CoV-2 Omicron BA.2.75 clinical isolates," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    16. Markus Hoffmann & Lok-Yin Roy Wong & Prerna Arora & Lu Zhang & Cheila Rocha & Abby Odle & Inga Nehlmeier & Amy Kempf & Anja Richter & Nico Joel Halwe & Jacob Schön & Lorenz Ulrich & Donata Hoffmann & , 2023. "Omicron subvariant BA.5 efficiently infects lung cells," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    17. Hannah Klim & Timothy William & Jack Mellors & Caolann Brady & Giri S. Rajahram & Tock H. Chua & Helena Brazal Monzó & Jecelyn Leslie John & Kelly Costa & Mohammad Saffree Jeffree & Nigel J. Temperton, 2024. "Serological analysis in humans in Malaysian Borneo suggests prior exposure to H5 avian influenza near migratory shorebird habitats," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    18. Yuki Furuse, 2022. "Properties of the Omicron Variant of SARS-CoV-2 Affect Public Health Measure Effectiveness in the COVID-19 Epidemic," IJERPH, MDPI, vol. 19(9), pages 1-8, April.
    19. Juan Liu & Fengfeng Mao & Jianhe Chen & Shuaiyao Lu & Yonghe Qi & Yinyan Sun & Linqiang Fang & Man Lung Yeung & Chunmei Liu & Guimei Yu & Guangyu Li & Ximing Liu & Yuansheng Yao & Panpan Huang & Dongx, 2023. "An IgM-like inhalable ACE2 fusion protein broadly neutralizes SARS-CoV-2 variants," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    20. Raffaele Palladino & Michelangelo Mercogliano & Claudio Fiorilla & Alessandro Frangiosa & Sabrina Iodice & Stefano Sanduzzi Zamparelli & Emma Montella & Maria Triassi & Alessandro Sanduzzi Zamparelli, 2022. "Association between COVID-19 and Sick Leave for Healthcare Workers in a Large Academic Hospital in Southern Italy: An Observational Study," IJERPH, MDPI, vol. 19(15), pages 1-8, August.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57947-8. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.