Title: The biological and clinical implications of emerging SARSCoV-2 variant

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is continuing to evolve worldwide, emerging novel variants with spike protein mutations that are affecting the epidemiological and clinical aspects of the COVID-19 pandemic. Although most mutations identified in the SARS-CoV-2 genome are neutral or mildly deleterious, a small number of mutations can affect virus phenotype that confers a fitness advantage. These mutations can increase rates of virus transmission, increase the risk of reinfection and reduce the protection afforded by neutralizing monoclonal antibodies and vaccination. Since December 2020, the SARS-CoV-2 has generated four rapidly expanding strains, designated variants of concern (VOCs), including the Alpha variant (B.1.1.7), the Beta variant (B.1.351), the Gamma variant (P.1) and the Delta variant (B.1.617.2). These variants have multiple mutations in the immunodominant spike protein that facilities viral cell entry via the angiotensin-converting enzyme -2 (ACE2). Mutations in the receptor binding domain (RBD) on the spike protein are of great concern for their potential for immune escape. The B.1.1.7 variant emerged in the UK in the second half of 2020 that has spread globally and acquired the E484K mutation in the UK and the US. The Beta and Gamma variants emerged in South Africa and Brazil, respectively that have additional mutations in the RBD at positions E484 and K417. SARSCoV-2 variants containing the combination of N501Y, E484K, and K417N/T mutations have significantly reduced sensitivity to vaccine induced and convalescent sera. The Gamma variant may cause more severe disease even in persons who have been previously infected.The Delta variant emerged in India in December 2020 and has further spread to many countries including the United States and the United Kingdom. The delta variant has 8 mutations in the spike protein, including T19R, D157-158, L452R, T478K, D614G, P681R, and D950N. Several of these mutations may affect immune responses to the key antigenic regions of receptor binding protein (452 and 478) and deletion of part of the N-terminal domain. The spike protein mutations and other non-structurel mutations in the VOCs can cause escape approved vaccination in certain extend. Unfortunately, with the emergence of novel variants of SARS-CoV-2, early optimism regarding the development of COVID-19 vaccines has been tempered. This review highlights the biological and clinical effects of emerging novel SARS-CoV-2 variants and their impact on vaccine-elicited and monoclonal antibody-mediated neutralization.