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Augmenting SARS-CoV-2 vaccine induced spike protein-specific CD4+ T cell responses through IL-1β and its receptors.

ABSTRACT: Immunity to SARS-CoV-2 infection provided by COVID-19 mRNA vaccines decline over time. Thus, there is a need for interventions to augment and sustain such immunity. To address this, we characterized S protein-specific CD4+ T cells in healthy individuals who received COVID-19 mRNA vaccines utilizing high-dimensional single cell RNA-seq and mass cytometry. S protein-specific CD4+ T cells highly expressed IL-1 receptor (R) 1 and its decoy receptor IL-1R2. IL-1b promoted IFN-g expression by S protein-stimulated CD4+ T cells, which was furthered by adding anti-IL-1R2-blocking antibodies, supporting the functional implications of IL-1R1 and IL-1R2. Following the 2nd dose of a COVID-19 mRNA vaccine, IL-1R1 expression increased while IL-1R2 expression decreased in S protein-specific CD4+ T cells. Our findings provide novel insight into augmenting COVID-19 mRNA vaccine-induced CD4+ T cell immunity by modulating IL-1β and its receptor system, which could foster a more effective and prolonged immune response.

ORGANISM(S): Homo sapiens

PROVIDER: GSE206134 | GEO | 2023/03/01

REPOSITORIES: GEO

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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.

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Augmenting SARS-CoV-2 vaccine induced spike protein-specific CD4+ T cell responses through IL-1β and its receptors.

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