SARS-CoV-2 variants: Human antibody-mediated immunity or Harry Houdini?-技术资讯

Breaking News | Feb 01, 2021

Antibody neutralisation

The pandemic

COVID-19 has caused over 2 million deaths globally with the numbers increasing at an alarming rate. A monumental worldwide vaccination program is being rolled out with several companies including AstraZeneca/Oxford University, Pfizer/BioNTech and Moderna leading the way and offering real hope of slowing the pandemic. Upon SARS-CoV-2 infection, the human immune system responds with CD4⁺ cells and CD8⁺ T cells concomitant with neutralising antibodies that have been shown to persist for several months (1,2). These antibodies predominantly target the SARS-CoV-2 spike (S) protein in the receptor binding domain (RBD) (3). Given the emergence of SARS-CoV-2 variants and that human coronaviruses can undergo antigenic evolution that compromises neutralizing antibody immunity (4), it is essential to determine whether SARS-CoV-2 variants will confer immune avoidance.

Emerging SARS-CoV-2 variants

A D614G SARS-CoV-2 variant that exhibits enhanced transmission has led to this variant dominating the original strain (5) although the successful vaccine trials confirm this mutation unlikely impacts on antibody-mediated neutralisation. Two recent SARS-CoV-2 variants have received a lot of attention. B.1.1.7, designated Variant of Concern 202012/01 (VOC), possesses a N501Y mutation that increases ACE2 binding and infectivity (6,7). This, together with a P618H mutation, deletion of spike protein amino acids 69 and 70 (Δ69-70) and several additional mutations have yielded a phenotypic change that manifests in a higher rate of transmission. These mutations do not seem to offer a selective advantage for evading immune detection (8), however, very recent reports suggest this variant is more deadly (9). A SARS-CoV-2 variant originating in South Africa termed 501Y.V2 possesses 9 changes in the spike protein alone; both in the RBD domain (K417N, E484K and N501Y) and N-terminal domain (NTD; L18F, D80A, D215G, Δ242-244, and R246I) (10). This localised cluster of mutations and in particular E484K, also detected in a variant in Brazil (11), appear to increase the chances of avoiding antibody neutralisation (12).

In a recent publication by Wibner et al, the 501Y.V2 variant was assessed for its sensitivity to neutralisation by monoclonal antibodies using structural modelling, ELISA and lentivirus pseudotyping (13). By characterising the interaction between antibodies and the RBD of SARS-CoV-2, several antibodies with epitopes centred on amino acid changes found in the 501Y.V2 variant were assessed by ELISA. While the RBD of original SARS-CoV-2 bound to the antibodies, recombinant RBD protein containing mutations found in 501Y.V2 was unable to do so. Key residues identified that impaired antibody neutralisation included K417, E484, R102, R246 and Δ242-244. These findings were supported by neutralisation assays where lentivirus pseudotyped to express SARS-CoV-2 S protein was added to HEK293T cells expressing human ACE2 receptor. Neutralisation of viral transduction was assessed by the ability of monoclonal antibodies to inhibit viral transduction as measured by luciferase activity. To further evaluate mutations found in 501Y.V2 S protein, polyclonal plasma/serum from patients infected with severe COVID-19 were assayed for neutralisation activity. While plasma from these patients neutralised the SARS-CoV-2 D614G lineage, almost 50% of samples failed to neutralise the 501Y.V2 lineage. Psuedotyping lentivirus with just three of the known mutations; K417N, E484K and N501Y revealed a loss of activity further highlighting the importance of these residues.

The future

While considerably more studies are needed to fully evaluate new SARS-CoV-2 variants, particularly the efficacy of T cell responses, the role of non-neutralising antibodies and inter/intra-person heterogeneity, the data here suggest that new variants pose a significant risk of immune surveillance escape and re-infection. If so, the colossal R&D effort needs to continue to ensure we have a vaccine platform that can adapt and ultimately succeed.

VectorBuilder

VectorBuilderoffers a number of COVID-19 solutions including recombinant Coronavirus vectors for reconstitution of wild type and variant viruses, pseudotyped lentivirus and VSV with S protein from wild type, D614G, B.1.1.7 and 501Y.V2 and cell lines for isolation and propagation of virus. Contact us to find out more or help designing your custom vectors.