Biology subjects

Chappell, J. G.

Publications and source records attributed to Chappell, J. G..

3 recordsLinked to original sources

bioRxiv2025

Pre-Omicron Immunity Generates IgG⁺ but Not IgA⁺ Memory B Cells Reactive to Omicron Spike Protein

The emergence of the Omicron variant marked a major antigenic shift from previous SARS-CoV-2 variants. While the emergence of new variants of concern was associated with loss of protection from infection, protection from serious disease was maintained. What was less clear was whether this protection was associated with expansion, affinity maturation of pre-existing cross-reactive B cells, or de novo generation of variant-specific B cells. To define the cross-reactivity of memory B cell populations generated through infection and/or vaccination with pre-Omicron variant spike, we utilised archived samples from healthcare workers enrolled in the extensively monitored Panther study cohort. Using samples collected from Omicron-naive individuals approximately three months (106 days) after a third BNT162b2 vaccine dose, we analyzed the spike-specific B cell repertoire via multiparameter flow cytometry and B cell receptor (BCR) sequencing. Reactivity to both Lineage A and Omicron spike proteins was higher for serum IgG than IgA, and serum neutralisation potency was significantly reduced against pseudoviruses bearing the Omicron spike compared to those with Lineage A spike. The frequency of Omicron-reactive IgA+ B cells was markedly lower than that of Lineage A-reactive cells, whereas Omicron-reactive IgG+ memory B cells were more frequent. These responses were predominantly localized to classical memory and double-negative (DN) B cell subsets. BCR sequencing of donors unexposed to Omicron confirmed that Omicron-binding clones were class-switched and somatically mutated, indicating they originated from pre-existing memory B cells primed by vaccination or infection. Our findings demonstrate that memory B cells generated through infection and/or immunisation with pre-Omicron variants were primed for broad antigenic recognition despite Omicrons extensive genetic divergence. However, the diminished IgA+ B cell frequency suggests a weakened mucosal antibody defence, potentially explaining the continued susceptibility to infection despite preserved protection from severe disease.

immunology↗

bioRxiv2025

An ultra-long heavy chain bovine antibody neutralizes SARS-CoV-2 and reacts broadly with sarbecoviruses.

The ongoing threat of new SARS-CoV-2 variants and other sarbecoviruses has driven efforts to develop broadly neutralizing monoclonal antibodies (mAbs). This study used immunized cattle, known for producing antibodies with ultra-long CDRH3 domains, to generate 33 mAbs, ten of which had ultra-long CDRH3s (>50 amino acids). Of these, mAbs P7 and 99, demonstrated broad and potent neutralization. Notably, mAb P7 neutralized all tested variants, including SARS-CoV-1, with IC50 values between 0.05 and 9.2 {micro}g/mL, and showed cross-reactivity with RBDs from various sarbecoviruses. Structural analysis revealed that mAb 99 binds the spike proteins RBD at the ACE2 binding site. Although the exact binding of P7 wasnt resolved, evidence suggests it targets a hidden epitope, promoting spike trimer dissociation via its extended CDRH3. In Syrian hamsters, both mAbs significantly reduced lung viral loads. These results support the potential of bovine-derived mAbs, particularly those with ultra-long CDRH3s, for future antiviral therapies.

immunology↗

bioRxiv2019

Retrieval of the Complete Coding Sequence of the UK-Endemic Tatenale Orthohantavirus Reveals Extensive Strain Variation and Supports its Classification as a Novel Species

Hantaviruses are a diverse group of single-stranded, negative-sensed RNA viruses, known to cause sporadic outbreaks of potentially fatal human disease. To date, only two Orthohantavirus species have been detected in the UK - Seoul virus and Tatenale. Whilst Seoul is known to be pathogenic in humans, only partial fragments of Tatenale have been recovered, precluding any accurate analysis of its phylogeny or potential pathogenicity. To overcome this shortfall we used a degenerate primer PCR method to identify Tatenale-infection in rodents living in two separate locations in the UK. PCR positive samples were then subjected to either unbiased high-throughput sequencing or overlapping PCR product sequencing to recover the complete coding sequence of the Tatenale virus. This analysis provided in-depth insight into the evolutionary origins of this recently identified UK Orthohantavirus and unequivocally showed that Tatenale virus meets the established criteria for classification as a novel species. Crucially, our data will facilitate in vitro investigation into the zoonotic potential of Tatenale virus.

microbiology↗