ADNKA overcomes SARS-CoV2-mediated NK cell inhibition through non-spike antibodies



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This research has not been peer-reviewed, and has been posted on pre-print repository bioRxiv. This is a preliminary report that should not be regarded as conclusive, guide clinical practice/health-related behaviour, or be reported in news media as established information.


The outcome of infection is dependent on the ability of viruses to manipulate the infected cell to evade immunity, and the ability of the immune response to overcome this evasion. Understanding this process is key to understanding pathogenesis, genetic risk factors, and both natural and vaccine-induced immunity. SARS-CoV-2 antagonises the innate interferon response, but whether it manipulates innate cellular immunity is unclear. An unbiased proteomic analysis determined how cell surface protein expression is altered on SARS-CoV-2-infected lung epithelial cells, showing downregulation of activating NK ligands B7-H6, MICA, ULBP2, and Nectin1, with minimal effects on MHC-I. This correlated with a reduction in NK cell activation, identifying a novel mechanism by which SARS-CoV2 antagonises innate immunity. Later in the disease process, strong antibody-dependent NK cell activation (ADNKA) developed. These responses were sustained for at least 6 months in most patients, and led to high levels of pro-inflammatory cytokine production. Depletion of spike-specific antibodies confirmed their dominant role in neutralisation, but these antibodies played only a minor role in ADNKA compared to antibodies to other proteins, including ORF3a, Membrane, and Nucleocapsid. In contrast, ADNKA induced following vaccination was focussed solely on spike, was weaker than ADNKA following natural infection, and was not boosted by the second dose. These insights have important implications for understanding disease progression, vaccine efficacy, and vaccine design.

Author list:


  1. Division of Infection and Immunity, School of Medicine, Cardiff University, CF14 4XN
  2. Cambridge Institute for Therapeutic Immunology & Infectious Disease, Jeffrey Cheah
  3. Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge
  4. CB2 0AW, UK
  5. Department of Infectious Diseases, School of Immunology & Microbial Sciences, King's
  6. College London, London, UK
  7. Department of Infectious Diseases, Guy’s and St Thomas’ NHS Foundation Trust, London
  8. MRC - University of Glasgow Centre for Virus Research, 464 Bearsden Road, Glasgow, G61
  9. 1QH



Fielding CA1, Sabberwal P1, Williamson JC2, Greenwood EJD2, Crozier TWM2, Zelek W1, Seow J3, Graham C3, Huettner I3, Edgeworth JD3,4, Price D1, Morgan BP1, Ladell K1, Eberl M1, Humphreys IR1, Merrick B3,4, Doores K3, Wilson SJ5, Lehner PJ2, Wang ECY1, Stanton RJ1*