Dataset Information

Blood transcriptome profiling reveals distinct gene networks induced by mRNA vaccination against COVID-19

ABSTRACT: Messenger RNA (mRNA) vaccines represent a new class of vaccines that has been shown to be highly effective during the COVID-19 pandemic and that holds great potential for other preventative and therapeutic applications. Understanding the underlying mechanisms of the immune responses induced by this novel vaccine type and their relation to vaccine responses might help to further refine and optimize future vaccine design. In this study, we conducted an in-depth analysis of the blood transcriptome before and 24h after second and third vaccination with licensed mRNA vaccines against COVID-19 in humans, following a prime vaccination with either mRNA or ChAdOx vaccines. Utilizing an unsupervised weighted gene correlation network analysis, we identified distinct gene networks of co-varying genes characterized by either an expressional up- or down-regulation in response to vaccination. Down-regulated networks were associated with cell metabolic processes and regulation of transcription factors, while up-regulated networks were associated with myeloid differentiation, antigen presentation, and antiviral, interferon-driven pathways. Within this interferon-associated network, we identified highly connected hub genes such as STAT2 and RIGI, potentially playing important regulatory roles in the vaccine-induced immune response. The expression profile of this network significantly correlated with S1-specific IgG levels at the follow-up visit in vaccinated individuals. Those findings could be corroborated in an independent cohort of mRNA vaccine recipients. Collectively, insights from this study might contribute to current research endeavors aimed at further enhancing/ or optimizing vaccine-induced immunity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE247401 | GEO | 2024/01/29

REPOSITORIES: GEO

ACCESS DATA

Similar Datasets

Project description:The COVID-19 pandemic has prompted vaccine development efforts on an unprecedented scale. Vaccines based on mRNA technology have emerged as particularly attractive due to their high efficacy and short development timelines. However, relatively little is known about the factors contributing to the development of protective immunity by this new class of vaccines. We employed a high-temporal-resolution transcriptome profiling approach to investigate responses to COVID-19 mRNA vaccination. A cohort of 23 subjects was recruited and changes in blood transcript abundance were measured daily for 9 days post-priming and post-booster vaccination via RNA sequencing. Antibody responses were measured on days 7 and 14 post-vaccination using a custom multiplex assay. Marked differences were observed between responses to the priming and booster doses, with the latter inducing widespread changes in blood transcript abundance consistent with those found in patients with acute viral respiratory infections. The delineation of interferon responses at a high-temporal frequency also suggested that the priming and booster doses elicited distinct types of responses that peaked on day 2 post-priming dose and day 1 post-booster dose. The booster dose also induced inflammation on day 1 and erythroid cell signatures as well as an atypical plasmablast signature on day 4. Notably, this plasmablast signature, together with the post-booster interferon response signature, correlated with the antibody response levels induced on day 14 after the booster dose. Taken together, this work provides a detailed map of the antibody and transcriptional responses to the first and second doses of a new class of vaccine and yields important insights into the mechanisms underlying their immunogenicity. Furthermore, our results suggest that implementing high-temporal-frequency immune profiling protocols may provide an opportunity to better resolve the immune responses elicited by the growing number of available COVID-19 vaccines.

Project description:Since December 2019, the novel human Coronavirus SARS-CoV-2 has spread globally, causing millions of deaths. Unprecedented efforts have enabled development and authorization of a range of vaccines, which reduce transmission rates and confer protection against the associated disease COVID-19. These vaccines are conceptually diverse, including e.g. classical adjuvanted whole-inactivated virus, viral vectors, and mRNA vaccines. We have analysed two prototypic model vaccines, the strongly TH1-biased measles vaccine-derived candidate MeVvac2-SARS2-S(H) and a TH2-biased Alum-adjuvanted, non-stabilized Spike protein side-by-side, for their ability to protect Syrian hamsters upon challenge with a low-passage SARS-CoV-2 patient isolate. The MeVvac2-SARS2-S(H) vaccine protected the hamsters from severe disease. In contrast, the protein vaccine induced vaccine-associated enhanced respiratory disease (VAERD) with massive infiltration of eosinophils into the lungs. Global RNA-Seq analysis of hamster lungs revealed reduced viral RNA and less host dysregulation in MeVvac2-SARS2-S(H) vaccinated animals, while S protein vaccination triggered enhanced host gene dysregulation when compared to unvaccinated control animals. Of note, mRNAs encoding the major eosinophil attractant CCL-11, the TH2 response-driving cytokine IL-19, as well as TH2-cytokines IL-4, IL-5, and IL-13 were exclusively up-regulated in the lungs of S protein vaccinated animals, consistent with previously described VAERD induced by RSV vaccine candidates. IL-4, IL-5, and IL-13 were also up-regulated in S-specific splenocytes after protein vaccination. Using scRNA-Seq, T cells and innate lymphoid cells were identified as the source of these cytokines, while CCL11 and IL-19 mRNAs was found in interstitial macrophages displaying an activated phenotype. Interestingly, the amount of viral reads in this macrophage population correlated with the abundance of Fc-receptor reads. These findings suggest that VAERD is triggered by induction of TH2-type helper cells secreting IL-4, IL-5, and IL-13, together with stimulation of macrophages dependent on Fc-receptor mediated uptake of virus complexed with non-neutralizing antibodies. Via this mechanism, uncontrolled eosinophil recruitment to the infected tissue occurs, a hallmark of VAERD immunopathogenesis. These effects could effectively be treated using dexamethasone and were not observed in animals vaccinated with MeVvac2-SARS2-S(H). Taken together, our data validate the potential for, and identify the transcriptional mediators that underlie VAERD and their cellular origins, in the context of protein-based TH2-biased COVID-19 vaccines. Dexamethasone, which is already in use for treatment of severe COVID-19, may alleviate such VAERD, but in-depth scrutiny of any next-generation protein-based vaccine candidates is required, prior and after their regulatory approval.

Dataset Information

Blood transcriptome profiling reveals distinct gene networks induced by mRNA vaccination against COVID-19

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure