Biology subjects

Augustine, T.

Publications and source records attributed to Augustine, T..

3 recordsLinked to original sources

bioRxiv2025

Temporal Dynamics of Transcriptional Responses to Repeated mRNA Vaccination: Insights from Third Dose Profiling

mRNA vaccines have played a crucial role in combating the COVID-19 pandemic, but the long-term dynamics of immune responses to repeated vaccination remain poorly understood. In this study, we extend our previous work on first and second dose responses by characterizing the immune signatures elicited by a third dose of COVID-19 mRNA vaccines using high-resolution temporal profiling of blood transcriptomes collected daily for 9 days post-vaccination. We observed distinct patterns of gene expression related to interferon responses, inflammation, erythroid cell signatures, and plasmablast activity across the three doses. While the first dose elicited a modest response primarily characterized by interferon signaling, the second dose induced a robust, polyfunctional response. The third dose, administered approximately nine months later, maintained this polyfunctional character and matched the second dose in magnitude, though with distinct temporal dynamics. The interferon component peaked on day 2 (similar to the first dose) rather than day 1 (as seen in the second dose), while the erythroid signature showed a markedly different trajectory, with sustained elevation rather than decrease over the following week. Notably, we observed a progressive amplification of the plasmablast response across the three doses, with an earlier peak (day 4) compared to other vaccines, potentially a unique feature of mRNA vaccines. These findings demonstrate that the heightened, polyfunctional responsiveness induced by the second dose is robustly maintained even after a prolonged interval, suggesting effective immune memory. Our results contribute to understanding mRNA vaccine-induced immunity, with implications for optimizing booster strategies and developing next-generation vaccines.

immunology↗

bioRxiv2021

High temporal resolution transcriptomic profiling delineates distinct patterns of interferon response following Covid-19 mRNA vaccination and SARS-CoV2 infection

Knowledge of the mechanisms underpinning the development of protective immunity conferred by mRNA vaccines is fragmentary. Here we investigated responses to COVID-19 mRNA vaccination via ultra-low-volume sampling and high-temporal-resolution transcriptome profiling (23 subjects across 22 timepoints, and with 117 COVID-19 patients used as comparators). There were marked differences in the timing and amplitude of the responses to the priming and booster doses. Notably, we identified two distinct interferon signatures. The first signature (A28/S1) was robustly induced both post-prime and post-boost and in both cases correlated with the subsequent development of antibody responses. In contrast, the second interferon signature (A28/S2) was robustly induced only post-boost, where it coincided with a transient inflammation peak. In COVID19 patients, a distinct phenotype dominated by A28/S2 was associated with longer duration of intensive care. In summary, high-temporal-resolution transcriptomic permitted the identification of post- vaccination phenotypes that are determinants of the course of COVID-19 disease.

immunology↗

bioRxiv2021

Reovirus sensitizes microsatellite stable colorectal cancer to anti-PD-1 treatment via cross-talk in innate and adaptive immune systems

BackgroundMicrosatellite stable (MSS) colorectal cancer (CRC) represents ~85% of all CRCs. These tumors are poorly immunogenic and largely resistant to immunotherapy, necessitating a need to develop new immune enhancing strategies. Oncolytic reovirus has a high propensity to replicate in KRAS mutant tumors which account for ~50% of MSS CRCs. Current study explores the ability of reovirus to potentiate the effect of immune checkpoint inhibition in MSS CRC. MethodsEffectiveness of reovirus infection was quantified through MTT assay for cell viability, and expression of immune-response genes by flow cytometry, RT-qPCR, and microarray. Computational analysis of differentially expressed genes was performed by TAC, DAVID and STRING. Combinatorial approach using anti-PD-1 monoclonal antibody was assessed in ex vivo and in vivo models. Live-cell imaging, tumor volume and survival were measured for quantification of anti-tumor activity. Expression of pattern recognition receptors (PRRs), cell surface and activation markers of immune cells, and PD-1/PD-L1 axis were studied using multi-color flow cytometry, immunoblotting, immunohistochemistry, and immunofluorescence. ResultsReovirus infection exerted growth arrest and expression of immune-response genes in CRCs cell lines in a KRAS-dependent manner. However, microsatellite instability, rather than KRAS status determined immune-repose pathways, functionalities and biological processes post-reovirus infection. Furthermore, reovirus significantly enhanced the anti-tumor activity of anti-human PD-1 [nivolumab] treatment in MSS CRC cell lines ex vivo. Similarly, reovirus increased the activity of anti-mouse PD-1 treatment in the CT26 [MSS, KRASMut], but not the MC38 [MSI, KRASWt] syngeneic mouse model of CRC. Combinatorial treatment has reduced the proliferative index, increased apoptosis and differentially altered PD-L1/PD-1 signaling among CT26 and MC38 tumors. Activation of innate immune system and expression of PRRs and antigen presentation markers were observed under reovirus and anti-PD-1 treatment that additionally reduced immunosuppressive macrophages. This led to an increase in T cell subsets, increase in effector T cell activation, and decrease in exhaustion markers specifically within CT26 microenvironment. ConclusionThe current study systematically evaluates immune characteristics and immune microenvironment of CRC under reovirus/anti-PD-1 combination treatment that proves increased effectiveness among MSS compared to MSI CRCs. This is a promising regimen warranting translation into clinical trials. One Sentence SummaryOncolytic reovirus alters innate and adaptive immune system and potentiates MSS type colorectal cancer to checkpoint inhibition therapy.

cancer biology↗