Recently, a new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineage called B.1.1.7 (variant of concern: VOC 202012/01), which is reported to spread more efficiently and faster than ...other strains, emerged in the United Kingdom. This variant has an unusually large number of mutations, with 10 amino acid changes in the spike (S) protein, raising concerns that its recognition by neutralizing antibodies may be affected. In this study, we tested SARS-CoV-2-S pseudoviruses bearing either the Wuhan reference strain or the B.1.1.7 lineage spike protein with sera of 40 participants who were vaccinated in a previously reported trial with the messenger RNA-based COVID-19 vaccine BNT162b2. The immune sera had slightly reduced but overall largely preserved neutralizing titers against the B.1.1.7 lineage pseudovirus. These data indicate that the B.1.1.7 lineage will not escape BNT162b2-mediated protection.
The globally circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant of concern Omicron (B.1.1.529) has a large number of mutations, especially in the spike protein, ...indicating that recognition by neutralizing antibodies may be compromised. We tested Wuhan (Wuhan-Hu-1 reference strain), Beta (B.1.351), Delta (B.1.617.2), or Omicron pseudoviruses with sera of 51 participants who received two or three doses of the messenger RNA (mRNA)-based COVID-19 vaccine BNT162b2. After two doses, Omicron-neutralizing titers were reduced >22-fold compared with Wuhan-neutralizing titers. One month after the third vaccine dose, Omicron-neutralizing titers were increased 23-fold relative to their levels after two doses and were similar to levels of Wuhan-neutralizing titers after two doses. The requirement of a third vaccine dose to effectively neutralize Omicron was confirmed with sera from a subset of participants using live SARS-CoV-2. These data suggest that three doses of the mRNA vaccine BNT162b2 may protect against Omicron-mediated COVID-19.
BNT162b2-vaccinated individuals after Omicron BA.1 breakthrough infection have strong serum-neutralizing activity against Omicron BA.1, BA.2, and previous SARS-CoV-2 variants of concern (VOCs) yet ...less against the highly contagious Omicron sublineages BA.4 and BA.5 that have displaced previous variants. Because the latter sublineages are derived from Omicron BA.2, we characterized serum-neutralizing activity of COVID-19 mRNA vaccine triple-immunized individuals who experienced BA.2 breakthrough infection. We demonstrate that sera of these individuals have broadly neutralizing activity against previous VOCs and all tested Omicron sublineages, including BA.2-derived variants BA.2.12.1 and BA.4/BA.5. Furthermore, applying antibody depletion, we showed that neutralization of BA.2 and BA.4/BA.5 sublineages by BA.2 convalescent sera is driven to a considerable extent by antibodies targeting the N-terminal domain (NTD) of the spike glycoprotein. However, neutralization by Omicron BA.1 convalescent sera depends exclusively on antibodies targeting the receptor binding domain (RBD). These findings suggest that exposure to Omicron BA.2, in contrast to BA.1 spike glycoprotein, triggers substantial NTD-specific recall responses in vaccinated individuals and thereby enhances the neutralization of BA.4/BA.5 sublineages. Given the current epidemiology with a predominance of BA.2-derived sublineages such as BA.4/BA.5 and rapidly ongoing evolution, these findings helped to inform development of our Omicron BA.4/BA.5-adapted vaccine.
Abstract
Splicing is catalyzed by the spliceosome, a compositionally dynamic complex assembled stepwise on pre-mRNA. We reveal links between splicing machinery components and the intrinsically ...disordered ciliopathy protein SANS. Pathogenic mutations in SANS/USH1G lead to Usher syndrome—the most common cause of deaf-blindness. Previously, SANS was shown to function only in the cytosol and primary cilia. Here, we have uncovered molecular links between SANS and pre-mRNA splicing catalyzed by the spliceosome in the nucleus. We show that SANS is found in Cajal bodies and nuclear speckles, where it interacts with components of spliceosomal sub-complexes such as SF3B1 and the large splicing cofactor SON but also with PRPFs and snRNAs related to the tri-snRNP complex. SANS is required for the transfer of tri-snRNPs between Cajal bodies and nuclear speckles for spliceosome assembly and may also participate in snRNP recycling back to Cajal bodies. SANS depletion alters the kinetics of spliceosome assembly, leading to accumulation of complex A. SANS deficiency and USH1G pathogenic mutations affects splicing of genes related to cell proliferation and human Usher syndrome. Thus, we provide the first evidence that splicing dysregulation may participate in the pathophysiology of Usher syndrome.
Graphical Abstract
Graphical Abstract
SANS acts as a factor required for the release of tri-snRNPs from Cajal bodies following by recruitment of the tri-snRNP complex to nuclear speckles for spliceosome assembly. SANS may also participate in the snRNP recycling back to the Cajal bodies.
The SARS-CoV-2 Omicron variant and its sublineages show pronounced viral escape from neutralizing antibodies elicited by vaccination or prior SARS-CoV-2 variant infection owing to over 30-amino acid ...alterations within the spike (S) glycoprotein. Breakthrough infection of vaccinated individuals with Omicron sublineages BA.1 and BA.2 is associated with distinct patterns of cross-neutralizing activity against SARS-CoV-2 variants of concern (VOCs). In continuation of our previous work, we characterized the effect of Omicron BA.4/BA.5 S glycoprotein exposure on the neutralizing antibody response upon breakthrough infection in vaccinated individuals and upon variant-adapted booster vaccination in mice. We found that immune sera from triple mRNA-vaccinated individuals with subsequent breakthrough infection during the Omicron BA.4/BA.5 wave showed cross-neutralizing activity against previous Omicron variants BA.1, BA.2, BA.2.12.1, and BA.4/BA.5 itself. Administration of a prototypic BA.4/BA.5-adapted mRNA booster vaccine to mice after SARS-CoV-2 wild-type strain-based primary immunization is associated with broader cross-neutralizing activity than a BA.1-adapted booster. Whereas the Omicron BA.1-adapted mRNA vaccine in a bivalent format (wild-type + BA.1) broadens cross-neutralizing activity relative to the BA.1 monovalent booster, cross-neutralization of BA.2 and descendants is more effective in mice boosted with a bivalent wild-type + BA.4/BA.5 vaccine. In naïve mice, primary immunization with the bivalent wild-type + Omicron BA.4/BA.5 vaccine induces strong cross-neutralizing activity against Omicron VOCs and previous variants. These findings suggest that, when administered as boosters, mono- and bivalent Omicron BA.4/BA.5-adapted vaccines enhance neutralization breadth and that the bivalent version also has the potential to confer protection to individuals with no preexisting immunity against SARS-CoV-2.
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