Vir Biotechnology Publishes New Research Characterizing Variation in the SARS-CoV-2 Spike Protein and Virulence of a Prevalent Immune Evasion Variant, N439K
“This study shows that the receptor binding motif of SARS-CoV-2, a major target of neutralizing antibodies, is evolving at a higher rate than the rest of the receptor binding domain and spike, and is resilient to change,” said Herbert “Skip” Virgin, M.D., Ph.D., chief scientific officer of Vir. “It is reminiscent of our experience with influenza A, where the mutability of the region targeted by the most potent neutralizing antibodies results in ineffective immunity year-over-year. Our demonstration of a virulent SARS-CoV-2 immune evasion mutant provides a cautionary tale for how we address this pandemic, and indicates the importance of ongoing surveillance for immune evasion mutations in the development of antibodies and vaccines.”
Data analyzed from approximately 130,000 SARS-CoV-2 genomic sequences, alongside evaluation of a published deep mutational scanning of the receptor binding domain (RBD), demonstrated that the RBM has a high degree of structural plasticity that permits significant changes in the amino acid sequence of the RBM, including N439K, while maintaining hACE2 binding.
Researchers also sought to define the clinical and epidemiologic impact, molecular features and immune response to the RBM variant, N439K. The goal was to determine if variants emerging in the pandemic have immune evasion potential. This variant, which was first identified in
Based on a review of sequenced viral isolates from 1,918 Scottish patients and clinical outcomes for 1,591 of these patients, N439K demonstrated similar clinical virulence to the wild-type 439N strain, full replication in the upper respiratory tract, the capacity to replicate in cultured cells, and the ability to effectively compete in in vitro growth assays with the wild-type virus. These data demonstrate that the virus exhibits fitness despite a mutation in the RBM.
To understand whether and how the N439K mutation might evade immunity, researchers noted that the binding of polyclonal sera to SARS-CoV-2 spike was reduced by the mutation in a sizeable fraction of the 445 samples obtained from recovered individuals. Additionally, out of 144 human neutralizing mAbs isolated from individuals who recovered from SARS-CoV-2 infection early in the pandemic, a significant number failed to efficiently recognize N439K. When tested across four clinical-stage antibodies – S309 (the precursor of VIR-7831), LY-CoV555, REGN10933 and REGN10987 – S309, which targets a non-RBM epitope, LY-CoV555 and REGN10933 were capable of neutralizing the N439K variant.
“These data provide critical evidence that more immune-evasive SARS-CoV-2 variants are likely to emerge, necessitating the updating of vaccines and the development of monoclonal antibodies that are highly resistant to viral escape,” said
This study was conducted in collaboration with Professors
As part of Vir’s ongoing commitment to addressing the COVID-19 pandemic, Vir scientists continue to publish new research designed to enhance the scientific understanding of SARS-CoV-2 and COVID-19. The Company’s most recent publications highlight:
- The mechanisms and risk for antibody-mediated enhancement of disease (Nature, October 2020);
- The identification and characterization of ultra-potent anti-COVID neutralizing mAbs (Science September 2020);
- The nature and half-life of human anti-SARS-CoV-2 antibodies in recovered individuals (Cell,
September 2020). This research also showed that the part of the SARS-CoV-2 spike that contains the N439K mutation is a dominant target of the antibody response in many individuals;
- A mAb, S309 (the parent of VIR-7831 and VIR-7832), that covers both SARS-CoV-1 and SARS-CoV-2, which may be useful for the current and future pandemics (Nature,
May 2020); and
- How to engineer mAbs with significantly increased efficacy in the treatment and prophylaxis of respiratory viral infections (Nature, April 2020).
VIR-7831 is a monoclonal antibody that has shown the ability to neutralize SARS-CoV-2 live virus in vitro and in vivo. The antibody binds to an epitope on SARS-CoV-2 that is shared with SARS-CoV-1 (also known as SARS), indicating that the epitope is highly conserved, which may make it more difficult for resistance to develop. VIR-7831 has been engineered with the potential to enhance lung bioavailability and have an extended half-life.
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Source: Vir Biotechnology, Inc.