Biology subjects

Sievers, B. L.

Publications and source records attributed to Sievers, B. L..

4 recordsLinked to original sources

bioRxiv2025

COVID-19 vaccination induces cross-neutralisation of sarbecoviruses related to SARS-CoV-2

Close relatives of SARS-CoV-1 and SARS-CoV-2 continue to circulate in wildlife, posing an ongoing threat of zoonotic spillover. While vaccination played a key role in controlling the COVID-19 pandemic, variants of concern (VOC) with immune evasive substitutions emerged on multiple occasions, causing widespread breakthrough infections. The combined threats of zoonosis and newly emerging VOCs, coupled with the potential for recombination, underscore the need to assess the breadth of existing vaccine-mediated protection. Here, we investigate a cohort of older individuals (median age 68.5 years) for the potential of cross-neutralisation against Omicron lineage VOC and animal sarbecoviruses induced by four COVID-19 vaccine doses. Despite the recent use of a bivalent mRNA vaccine dose (encoding spike from Wu-1 and omicron), we observed that neutralisation of Omicron lineage VOCs such as BA.1 and BA.2 were reduced compared to SARS-CoV-2 Wu-1, suggesting an imprinted immune response from pre-Omicron lineage viruses. Similarly, both SARS-CoV-1 and a SARS-CoV-1-related bat CoV were neutralised less efficiently than SARS-CoV-2 Wu-1. Unexpectedly, however, we observed that two animal SARS-CoV-2-related viruses, BANAL-20-52 (from bats) and a pangolin-CoV, were more sensitive to serum neutralising antibodies than SARS-CoV-2 Wu-1 itself. These surprising findings suggest that vaccine-mediated adaptive immunity may provide efficient cross-protection against certain animal sarbecoviruses.

microbiology↗

bioRxiv2024

Nasopharyngeal specific selection and emergence of SARS-CoV-2 spike fusion peptide mutation P812S during chronic infection

Omicron emergence represented a seismic event in the COVID-19 pandemic, demonstrating what was essentially antigenic shift in a virus that cannot reassort its genome as influenza can. Understanding the success of Omicron is essential, and yet we have little understanding of the biological underpinnings of its ability to accommodate diverse mutations and bring together deleterious mutations to generate a highly successful new serotype. Persistent SARS-CoV-2 infections are a likely source of new variants and may provide valuable insight into past and future evolutionary trajectories, in particular those involving allosteric interactions that defy genotype to phenotype prediction. Here we observe upper airway specific evolution of SARS-CoV-2 demonstrating fusion peptide (FP) domain mutation S:P812S adjacent to the S2 cleavage site that emerged during a chronic infection in an immunocompromised individual. Indeed, this mutation had previously emerged in an ancestral B lineage as well as the delta variant lineage and transmitted successfully in populations globally, though remains uncharacterised. P812S in spike pseudotyped virus particles did not impact entry efficiency across cell lines expressing endogenous ACE2 and TMPRSS2. However, efficiency of spike cleavage at S1/S2 was reduced and molecular dynamics simulation demonstrated altered S1/S2 loop conformations that possibly impacted furin mediated cleavage. Consistent with impaired S1/S2 cleavage, and reminiscent of Omicron BA.1, cell-cell fusogenicity was severely impaired by introduction of P812S. The mutation also introduced significant perturbations to the FP region and also affected protomer-protomer packing. P812S conferred evasion of a neutralising monoclonal antibody targeting the fusion peptide, consistent with significant structural rearrangements in the FP region. Finally, P812S bearing viruses showed evasion of polyclonal neutralising antibodies in sera from vaccinated individuals at 32{degrees}C (simulating upper respiratory tract) and to a lesser extent at 37{degrees}C. Thus we report a novel mutational adaptation to the upper airway allowing enhanced immune evasion to fusion peptide targeting neutralising antibodies that also incurs a defect in ability to induce syncytia. These data shed light on the balance between upper airway adaptation/immune evasion by SARS-CoV-2, ability to induce syncytia formation, and disease severity given the established link between syncytia and severe COVID-19.

immunology↗

bioRxiv2022

Immune and Clotting Dysfunction Detected in Saliva and Blood Plasma after COVID-19.

A growing number of studies indicate that coronavirus disease 2019 (COVID-19) is associated with inflammatory sequelae, but molecular signatures governing the normal vs. pathologic convalescence process have not been well-delineated. We characterized global immune and proteome responses in matched plasma and saliva samples obtained from COVID-19 patients collected between 4-6 weeks after initial clinical symptoms resolved. Convalescent subjects showed robust IgA and IgG responses and positive antibody correlations between matched saliva and plasma samples. However, global shotgun proteomics revealed persistent inflammatory patterns in convalescent samples including dysfunction of salivary innate immune cells and clotting factors in plasma (e.g., fibrinogen and antithrombin), with positive correlations to acute COVID-19 disease severity. Saliva samples were characterized by higher concentrations of IgA, and proteomics showed altered pathways that correlated positively with IgA levels. Our study positions saliva as a viable fluid to monitor immunity beyond plasma to document COVID-19 immune, inflammatory, and coagulation-related sequelae.

immunology↗

bioRxiv2021

Divergent early antibody responses define COVID-19 disease trajectories

A damaging inflammatory response is strongly implicated in the pathogenesis of severe COVID-19 but mechanisms contributing to this response are unclear. In two prospective cohorts, early non-neutralizing, afucosylated, anti-SARS-CoV-2 IgG predicted progression from mild, to more severe COVID-19. In contrast to the antibody structures that predicted disease progression, antibodies that were elicited by mRNA SARS-CoV-2 vaccines were low in Fc afucosylation and enriched in sialylation, both modifications that reduce the inflammatory potential of IgG. To study the biology afucosylated IgG immune complexes, we developed an in vivo model which revealed that human IgG-Fc{gamma}R interactions can regulate inflammation in the lung. Afucosylated IgG immune complexes induced inflammatory cytokine production and robust infiltration of the lung by immune cells. By contrast, vaccine elicited IgG did not promote an inflammatory lung response. Here, we show that IgG-Fc{gamma}R interactions can regulate inflammation in the lung and define distinct lung activities associated with the IgG that predict severe COVID-19 and protection against SARS-CoV-2. One Sentence SummaryDivergent early antibody responses predict COVID-19 disease trajectory and mRNA vaccine response and are functionally distinct in vivo.

immunology↗