Project description:Since SARS-CoV-2 Omicron variant emerged, it is constantly evolving into multiple sub-variants, including BF.7, BQ.1, BQ.1.1, XBB, XBB.1.5 and recently-emerging BA.2.86 and JN.1. Receptor binding and immune evasion are recognized as two major drivers for evolution of receptor binding domain (RBD) of the spike(S) protein. However, the underlying mechanism of interplay between two factors remains elusive. Herein, we determined the structures of human ACE2 complexed with BF.7, BQ.1, BQ.1.1, XBB and XBB.1.5 RBDs. From the ACE2/RBD structures of these sub-variants, in comparison with the known complex structures as well, we found that R493 but not Q493 was regulated by R346T substitution through long-range conformation alterations. Furthermore, we found that R493Q and F486V exert a balanced impact and immune evasion was somewhat compromised to achieve an optimal receptor binding, and proposed a "two-steps-forward and one-step-backward" model to describe such a compromise between the two factors. These results enhance our comprehension of the balance between receptor binding and immune evasion of Omicron sub-variants.
Project description:The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant has become the dominant infective strain. We report the structures of the Omicron spike trimer on its own and in complex with angiotensin-converting enzyme 2 (ACE2) or an anti-Omicron antibody. Most Omicron mutations are located on the surface of the spike protein and change binding epitopes to many current antibodies. In the ACE2-binding site, compensating mutations strengthen receptor binding domain (RBD) binding to ACE2. Both the RBD and the apo form of the Omicron spike trimer are thermodynamically unstable. An unusual RBD-RBD interaction in the ACE2-spike complex supports the open conformation and further reinforces ACE2 binding to the spike trimer. A broad-spectrum therapeutic antibody, JMB2002, which has completed a phase 1 clinical trial, maintains neutralizing activity against Omicron. JMB2002 binds to RBD differently from other characterized antibodies and inhibits ACE2 binding.
Project description:By December 2021, about 80% of people over the age of 12 had been vaccinated in Japan, and almost all people were vaccinated with the mRNA vaccine. We investigated here the anti-spike protein antibody titer at the time of breakthrough infection of SARS-CoV-2 omicron. A total of 32 SARS-CoV2 omicron breakthrough infection was included in the study. The median antibody titer at breakthrough infection was 776 AU/mL overall, of which the median antibody titer of BNT162b2 vaccinated was 633 AU/mL and that of mRNA-1273 vaccinated was 9416 AU/mL. This result suggests that low levels of antibody titers 6 months after vaccination do not provide sufficient antibodies to prevent the omicron variant breakthrough infection, which may occur with a higher anti-spike antibody titer after vaccination with mRNA-1273. However, antibody titers in some patients were comparable to those immediately after the second vaccination with either mRNA vaccine.