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The coronavirus disease 2019 (COVID-19) is determined by SARS-CoV-2 replication and host immune response, but studies evaluating viral evasion of immune response are lacking. Here we employed unbiased screening to identify SARS-CoV-2 proteins that antagonize type-I interferon (IFN-I) response. Three proteins were found to antagonize IFN-I production via distinct mechanisms: nsp6 binds TBK1 to suppress IRF3 phosphorylation; nsp13 binds and blocks TBK1 phosphorylation; and ORF6 binds importin KPNA2 to inhibit IRF3 nuclear translocation. Two sets of viral proteins were identified to antagonize IFN-I signaling through blocking STAT1/STAT2 phosphorylation or nuclear translocation. Remarkably, SARS-CoV-2 nsp1 and nsp6 suppressed IFN-I signaling more efficiently than SARS-CoV and MERS-CoV. Thus, when treated with IFN-I, a SARS-CoV2 replicon replicated to a higher level than chimeric replicons containing nsp1 or nsp6 from SARS-CoV or MERS-CoV. Altogether, the study has provided insights on SARS-CoV-2 evasion of IFN-I response and its potential impact on viral transmission and pathogenesis.

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We engineered three severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viruses containing key spike mutations from the newly emerged United Kingdom (UK) and South African (SA) variants: N501Y from UK and SA; 69/70-deletion + N501Y + D614G from UK; and E484K + N501Y + D614G from SA. Neutralization geometric mean titers (GMTs) of 20 BTN162b2 vaccine-elicited human sera against the three mutant viruses were 0.81-to 1.46-fold of the GMTs against parental virus, indicating small effects of these mutations on neutralization by sera elicited by two BNT162b2 doses. We previously reported that BNT162b2, a nucleoside-modified RNA vaccine that encodes the SARS-CoV-2 full-length, prefusion-stabilized spike glycoprotein, elicited dose-dependent SARS-CoV-2-neutralizing GMTs that were similar to or higher than the GMT of a panel of SARS-CoV-2 convalescent human serum samples 1. We subsequently reported that, in a randomized, placebo-controlled trial of approximately 44,000 participants 16 years of age or older, a two-dose regimen of BNT162b2 conferred 95% protection against Coronavirus Disease 2019 (COVID-19) 2. Since the previously reported studies were conducted, rapidly spreading variants of SARS-CoV-2 have arisen in the UK, SA and other regions 3,4. These variants have multiple mutations in their spike glycoproteins, which are key targets of virus-neutralizing antibodies. The emerged spike mutations have raised concerns of vaccine efficacy against these new strains. The goal of this study was to examine the effect of several key spike mutations from the UK and SA strains on BNT162b2 vaccine-elicited neutralization. Using an infectious complementary DNA (cDNA) clone of SARS-CoV-2 (ref. 5), we engineered three spike mutant viruses on the genetic background of clinical strain USA-WA1/2020 (Supplementary Fig. 1). 1) Mutant N501Y virus contains the N501Y mutation that is shared by both the UK and SA variants. This mutation is located in the viral receptor-binding domain (RBD) for cell entry, increases binding to the angiotensin-converting enzyme 2 receptor and enables the virus to expand its host range to infect mice 5,6. 2) Mutant Δ69/70 + N501Y + D614G virus contains two additional changes present in the UK variants: amino acid 69 and 70 deletion (Δ69/70) and D614G substitution. Amino acids 69 and 70

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