The spike protein of #SARS-CoV-2 variant A.30 is heavily #mutated and evades vaccine-induced antibodies with high efficiency

The COVID-19 pandemic, caused by SARS-CoV-2, continues to rage in many countries, straining health systems and economies. Vaccines protect against severe disease and death and are considered central to ending the pandemic. COVID-19 vaccines (and SARS-CoV-2 infection) elicit antibodies that are directed against the viral spike (S) protein and neutralize the virus. However, the emergence of SARS-CoV-2 variants with S protein mutations that confer resistance to neutralization might compromise vaccine efficacy [1]. Furthermore, emerging viral variants with enhanced transmissibility, likely due to altered virus-host cell interactions, might rapidly spread globally. Therefore, it is important to investigate whether emerging SARS-CoV-2 variants exhibit altered host cell interactions and resistance against antibody-mediated neutralization.

We investigated host cell entry and antibody-mediated neutralization of the variant A.30 (also termed A.VOI.V2), which was detected in several patients in Angola and Sweden in spring 2021 and likely originated in Tanzania [2]. For comparison, we analyzed the Beta (B.1.351) and Eta (B.1.525) variants. These two variants were first detected in Africa, and the Beta variant, which is considered a variant of concern (VOC), shows the highest level of neutralization resistance among SARS-CoV-2 VOCs [3, 4]. Compared to the S protein of SARS-CoV-2 B.1, which circulated in the early phase of the pandemic, the S protein of the A.30 variant contains 10 amino acid substitutions and five deletions (Fig. 1a and Supplementary information, Fig. S1a). All deletions along with four substitutions are found in the N-terminal domain of the surface unit S1, which harbors an antigenic supersite that is targeted by most neutralizing antibodies not directed against the receptor-binding domain (RBD) [5].

In addition, three mutations are located inside the RBD, which binds to the cellular receptor ACE2 and constitutes the main target of neutralizing antibodies (Fig. 1a). Two of these mutations, T478R and E484K, are located close to the ACE2 binding site (Supplementary information, Fig. S1a), and E484K is known to reduce susceptibility to antibody-mediated neutralization. Finally, two mutations are located close to the S1/S2 cleavage site, and one mutation is found in the transmembrane unit S2, which facilitates fusion of the viral envelope with cellular membranes..