Biology subjects

Riddell, S.

Publications and source records attributed to Riddell, S..

5 recordsLinked to original sources

bioRxiv2026

Myeloma and therapy reshape the bone marrow niche to durably constrain immune reconstitution and vaccine responsiveness

Infections are the most common cause of non-relapse mortality in multiple myeloma (MM), but the basis of persistent immune dysfunction is obscured by patient heterogeneity and complex treatment regimens, including autologous stem cell transplant (ASCT). We performed longitudinal multi-omic profiling of matched bone marrow and peripheral blood from MM patients across diagnosis, induction, ASCT, and recovery. We found the tumor imposes a compartment-specific immune program where the marrow exhibits metabolic and inflammatory changes that bias hematopoiesis and alter cytotoxic effector programs not mirrored in blood. Adaptive immune reconstitution is impaired up to two years post-ASCT. Half of patients fail to mount IgG responses to high-dose non-adjuvanted influenza vaccine, a defect overcome by the lipid nanoparticle (LNP) adjuvanted COVID mRNA vaccine, which elicited responses in all patients, supporting adjuvanted influenza vaccine strategies in MM. Together these findings define how myeloma and its treatment durably reshape immunity from the marrow outward. HighlightsO_LIMultiple Myeloma marrow and blood show opposing metabolic and inflammatory states C_LIO_LIInduction therapy selects durable myeloma plasma-cell transcriptional states C_LIO_LIB cell and follicular helper T deficits blunt antigen responses after transplant C_LIO_LICOVID-19 vaccination builds immune memory with variable responses to flu vaccination C_LI eTOCMultiple myeloma and its treatment leave a lasting imprint on the bone marrow niche. By profiling bone marrow and blood longitudinally at diagnosis, through induction, autologous transplant, and recovery, we show that marrow-local metabolic and inflammatory constraints persist and help explain why influenza vaccination often fails while mRNA vaccination succeeds.

cancer biology↗

bioRxiv2025

Precise engineering of chimeric antigen receptor expression levels defines T cell identity and function

Chimeric Antigen Receptor (CAR) T therapy is a potent treatment for haematological malignancies, but T cell exhaustion reduces its efficacy in many patients. Although high CAR transgene levels appear to drive T cell exhaustion, the relationship between CAR expression levels, T cell function, and transcriptional identity is yet to be mapped at high resolution. Here, we harness a high-resolution microRNA-based control system to precisely modulate CAR transgene expression levels and assess the impact on T cell activation, gene expression and function. By post-transcriptionally modulating CAR abundance, we show that differential CAR levels significantly impact T cell proliferation, cytokine production and tonic signalling. T cells with high CAR expression become strongly activated even at low target antigen densities, while those with low CAR expression are triggered only by high concentrations of their target. Single-cell RNA sequencing of primary T cells expressing a broad range of CAR transcript levels revealed global transcriptional programmes that become dysfunctional with increased CAR abundance, expanding our understanding of T cell exhaustion. Notably, we identified a narrow CAR expression range where the exhaustion transcriptional state is not triggered, demonstrating that T cell exhaustion can be controlled by fine-tuning CAR levels. This work demonstrates that CAR expression levels are key determinants of T cell transcriptional identity and function and introduces a tractable method to precisely tune CAR expression and T cell activity.

synthetic biology↗

bioRxiv2024

Use of Stem Cell-Derived Cardiomyocyte and Nasal Epithelium Models to Establish a Multi-Tissue Model Platform to Validate Repurposed Drugs Against SARS-CoV-2 Infection

The novel coronavirus disease (COVID-19) and any future coronavirus outbreaks will require more affordable, effective and safe treatment options to complement current ones such as Paxlovid. Drug repurposing can be a promising approach if we are able to find a rapid, robust and reliable way to down-select and screen candidates using in silico and in vitro approaches. With repurposed drugs, ex vivo models could offer a rigorous route to human clinical trials with less time invested into nonclinical animal (in vivo) studies. We have previously shown the value of commercially available ex vivo/3D airway and alveolar tissue models, and this paper takes this further by developing and validating human nasal epithelial model and embryonic stem cells derived cardiomyocyte model. Five shortlisted candidates (fluvoxamine, everolimus, pyrimethamine, aprepitant and sirolimus) were successfully compared with three control drugs (remdesivir, molnupiravir, nirmatrelvir) when tested against key variants of the SARS-CoV-2 virus including Delta and Omicron, and we were able to reconfirm our earlier finding that fluvoxamine can induce antiviral efficacy in combination with other drugs. Scalability of this high-throughput screening approach has been demonstrated using a liquid handling robotic platform for future Disease-X outbreaks.

microbiology↗

bioRxiv2022

Highly Thermotolerant SARS-CoV-2 Vaccine Elicits Neutralising Antibodies Against Delta and Omicron in Mice

As existing vaccines fail to completely prevent COVID-19 infections or community transmission, there is an unmet need for vaccines that can better combat SARS-CoV-2 variants of concern (VOC). We have previously developed highly thermo-tolerant monomeric and trimeric receptor binding domain derivatives that can withstand 100{degrees}C for 90 minutes and 37{degrees}C for four weeks, and help eliminate cold chain requirements. We show that mice immunised with these vaccine formulations elicit high titres of antibodies that neutralise SARS-CoV-2 variants VIC31 (with Spike: D614G mutation), Delta and Omicron (BA.1.1) VOC. Compared to VIC31, there was an average 14.4-fold reduction in neutralisation against BA.1.1 for the three monomeric antigen-adjuvant combinations, and 16.5-fold reduction for the three trimeric antigen-adjuvant combinations; the corresponding values against Delta were 2.5 and 3.0. Our findings suggest that monomeric formulations are suitable for the upcoming Phase I human clinical trials, and that there is potential for increasing efficacy with vaccine matching to improve responses against emerging variants. These findings are consistent with in silico modelling and AlphaFold predictions which show that while oligomeric presentation can be generally beneficial, it can make important epitopes inaccessible, and also carries the risk of eliciting unwanted antibodies against the oligomerisation domain.

immunology↗

bioRxiv2021

Live virus neutralisation of the 501Y.V1 and 501Y.V2 SARS-CoV-2 variants following INO-4800 vaccination of ferrets

The ongoing COVID-19 pandemic has resulted in significant global morbidity and mortality on a scale similar to the influenza pandemic of 1918. Over the course of the last few months, a number of SARS-CoV-2 variants have been identified against which vaccine-induced immune responses may be less effective. These "variants-of-concern" have garnered significant attention in the media, with discussion around their impact on the future of the pandemic and the ability of leading COVID-19 vaccines to protect against them effectively. To address concerns about emerging SARS-CoV-2 variants affecting vaccine-induced immunity, we investigated the neutralisation of representative G614, 501Y.V1 and 501Y.V2 virus isolates using sera from ferrets that had received prime-boost doses of the DNA vaccine, INO-4800. Neutralisation titres against G614 and 501Y.V1 were comparable, but titres against the 501Y.V2 variant were approximately 4-fold lower, similar to results reported with other nucleic acid vaccines and supported by in silico biomolecular modelling. The results confirm that the vaccine-induced neutralising antibodies generated by INO-4800 remain effective against current variants-of-concern, albeit with lower neutralisation titres against 501Y.V2 similar to other leading nucleic acid-based vaccines.

immunology↗