Gideon Schreiber Lab

SARS-CoV-2 has the capacity to evolve mutations that escape vaccine- and infection-acquired immunity and antiviral drugs. A variant-agnostic therapeutic agent that protects against severe disease without putting selective pressure on the virus would thus be a valuable biomedical tool that would maintain its efficacy despite the ongoing emergence of new variants. Here, we challenge male rhesus macaques with SARS-CoV-2 Delta\u2014the most pathogenic variant in a highly susceptible animal model. At the time of challenge, we also treat the macaques with aerosolized RBD-62, a protein developed through multiple rounds of in vitro evolution of SARS-CoV-2 RBD to acquire 1000-fold enhanced ACE2 binding affinity. RBD-62 treatment equivalently suppresses virus replication in both upper and lower airways, a phenomenon not previously observed with clinically approved vaccines. Importantly, RBD-62 does not block the development of virus-specific T- and B-cell responses and does not elicit anti-drug immunity. These data provide proof-of-concept that RBD-62 can prevent severe disease from a highly virulent variant.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has substantially diversified during the pandemic, resulting in the successive emergence of variants characterized by various mutations. It has been observed that several epidemic variants, including those classified as variants of concern, share mutations at four key residues (L452R, T478K, E484K, and N501Y) within the receptor binding motif (RBM) region of the spike protein. However, the processes through which these four specific RBM mutations were acquired during the evolution of SARS-CoV-2, as well as the degree to which they enhance viral fitness, remain unclear. Moreover, the effect of these mutations on the properties of the spike protein is not yet fully understood. In this study, we performed a comprehensive phylogenetic analysis and showed that the four RBM mutations have been convergently acquired across various lineages throughout the evolutionary history of SARS-CoV-2. We also found a specific pattern in the order of acquisition for some of these mutations. Additionally, our epidemic dynamic modeling demonstrated that acquiring these mutations leads to an increase in the effective reproduction number of the virus. Furthermore, we engineered mutant spike proteins with all feasible combinations of the four mutations, and examined their properties to uncover the influence that these mutations have on viral characteristics. Our results provide insights into the roles these four mutations play in shaping the viral characteristics, epidemic proliferation, and evolutionary pathway of SARS-CoV-2.

In late 2022, SARS-CoV-2 Omicron subvariants have become highly diversified, and XBB is spreading rapidly around the world. Our phylogenetic analyses suggested that XBB emerged through the recombination of two cocirculating BA.2 lineages, BJ.1 and BM.1.1.1 (a progeny of BA.2.75), during the summer of 2022. XBB.1 is the variant most profoundly resistant to BA.2/5 breakthrough infection sera to date and is more fusogenic than BA.2.75. The recombination breakpoint is located in the receptor-binding domain of spike, and each region of the recombinant spike confers immune evasion and increases fusogenicity. We further provide the structural basis for the interaction between XBB.1 spike and human ACE2. Finally, the intrinsic pathogenicity of XBB.1 in male hamsters is comparable to or even lower than that of BA.2.75. Our multiscale investigation provides evidence suggesting that XBB is the first observed SARS-CoV-2 variant to increase its fitness through recombination rather than substitutions.