Resistance of SARS-CoV-2 variants to neutralization by monoclonal and serum-derived polyclonal antibodies

Abstract

evere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the global COVID-19 pandemic infecting more than 111 million people and causing 2.4 million deaths. Clinical disease in humans ranges from asymptomatic infection to pneumonia, severe respiratory compromise, multi-organ failure and systemic inflammatory syndromes. The rapid expansion and prolonged nature of the COVID-19 pandemic and its accompanying morbidity, mortality and destabilizing socioeconomic effects have made the development of SARS-CoV-2 therapeutics and vaccines an urgent global health priority 1. Indeed, the emergency use authorization and rapid deployment of antibody-based countermeasures, including mAbs, immune plasma therapy and messenger RNA, and inactivated and viral-vectored vaccines has provided hope for curtailing disease and ending the pandemic. The spike protein of the SARS-CoV-2 virion binds the cell-surface receptor angiotensin-converting enzyme 2 (ACE2) to promote entry into human cells 2. Because the spike protein is critical for viral entry, it has been targeted for vaccine development and therapeutic antibody interventions. SARS-CoV-2 S proteins are cleaved to yield S1 and S2 fragments. The S1 protein includes the N-terminal (NTD) and receptor-binding (RBD) domains, whereas the S2 protein promotes membrane fusion. The RBD is recognized by many potently neutralizing monoclonal antibodies 3-7 , protein-based inhibitors 8 and serum antibodies 9. The current suite of antibody therapeutics and vaccines was designed with a spike protein based on strains circulating during the early phases of the pandemic in 2020. More recently, variants with enhanced transmissibility have emerged in the United Kingdom (B.1.1.7), South Africa (B.1.351), Brazil (B.1.1.248) and elsewhere with multiple substitutions in the spike protein, including in the NTD and the receptor-binding motif (RBM) of the RBD. Preliminary studies with pseudoviruses suggest that neutralization by some antibodies and immune sera may be diminished against variants expressing mutations in the spike gene 10-13. Given these

A public vaccine-induced human antibody protects against SARS-CoV-2 and emerging variants

“…To assess the protective capacity of 2C08 in vivo , we utilized a hamster model of SARS-CoV-2 infection ( 32 ). We evaluated the prophylactic efficacy of 2C08 against the D614G strain and against a fully infectious recombinant SARS-CoV-2 with B.1.351 spike gene (Wash SA-B.1.351; D80A, 242-244 deletion, R246I, K417N, E484K, N501Y, D614G and A701V) ( 16 ) in 4–6-week-old male Syrian hamsters. Animals treated with 2C08 and challenged with either virus did not lose weight during the experiment and started to gain weight (relative to starting weight) on 3 dpi.…”

SARS-CoV-2 mRNA vaccines induce a robust germinal centre reaction in humans

“…1d). The functional quality of serum antibody titers was measured using high-throughput focus reduction neutralization tests (FRNTs) 15 on Vero-TMPRSS2 cells against three authentic infectious SARS-CoV-2 strains with sequence variations in the S gene 16,17 The BNT162b2 vaccine is injected into the deltoid muscle, which drains primarily to the lateral axillary lymph nodes. Ultrasound was used to identify and guide FNA of accessible axillary nodes on the side of immunization approximately weeks after primary immunization.…”

TMPRSS2 inhibitor discovery facilitated through anin silicoand biochemical screening platform

“…With new strains of SARS-CoV-2 emerging, and the significance of TMPRSS2 in viral entry for multiple coronaviruses, it is pivotal that we uncover novel strategies to inhibit TMPRSS2 protease activity. 50,51 However, TMPRSS2 provides obstacles in multiple areas of the discovery pipeline.…”