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MRNA vaccine efficacy in a severe COVID-19 model: attenuated activation of pulmonary immune cells after the challenge

ABSTRACT: mRNA-1273, an mRNA-based vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is efficacious in mouse and non-human primate models of mild COVID-19. Hamsters exhibit more severe clinical disease from SARS-CoV-2, making it an important model to evaluate vaccine efficacy. Here we show that mock-vaccine treated hamsters infected with SARS-CoV-2 show weight loss and pulmonary infection with pathological changes and increased activated interstitial macrophages and other immune cell types. Prime-boost administration of mRNA-1273 elicited dose-independent robust binding and neutralizing antibodies, ameliorated weight loss and suppressed virus replication in the upper and lower airways. Vaccination largely prevented pulmonary pathological changes, antiviral immune cell activation and changes in cell type composition although increases in some immune cell types and activation of regulatory pathways were found and coincided with an anamnestic antibody response. The results characterize unexpected pulmonary cellular responses to SARS-CoV-2 in vaccinated animals that were shared but greatly attenuated, when compared to mock-vaccinated animals. The efficacy of mRNA-1273 is demonstrated as a two-dose vaccination schedule in a model of severe COVID-19.

ORGANISM(S): Mesocricetus auratus

PROVIDER: GSE163838 | GEO | 2021/12/01

REPOSITORIES: GEO

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Project description:In the last two years, the coronavirus disease 19 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been a scientific and social challenge worldwide. Vaccines have been the most effective intervention for reducing virus transmission and disease severity. However, virus genetic variants are still circulating among vaccinated individuals with different symptomatology disease cases. Understanding the protective or disease associated mechanisms in vaccinated individuals is relevant to advance in vaccine development and implementation. To address this objective, serum protein profiles were characterized by quantitative proteomics and data analysis algorithms in four cohorts of vaccinated individuals uninfected and SARS-CoV-2 infected with asymptomatic, nonsevere and severe disease symptomatology. The results showed that immunoglobulins were the most overrepresented proteins in infected cohorts when compared to PCR-negative individuals. The immunoglobulin profile varied between different infected cohorts and correlated with protective or disease associated capacity. Overrepresented immunoglobulins in PCR-positive individuals correlated with protective response against SARS-CoV-2, other viruses, and thrombosis in asymptomatic cases. In nonsevere cases, correlates of protection against SARS-CoV-2 and HBV together with risk of myasthenia gravis and allergy and autoantibodies were observed. Patients with severe symptoms presented risk for allergy, chronic idiopathic thrombocytopenic purpura, and autoantibodies. The analysis of underrepresented immunoglobulins in PCR-positive compared to PCR-negative individuals identified vaccine-induced protective epitopes in various coronavirus proteins including the Spike receptor-binding domain RBD. Non-immunoglobulin proteins were associated with COVID-19 symptoms and biological processes. These results evidence host-associated differences in response to vaccination and the possibility of improving vaccine efficacy against SARS-CoV-2.

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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MRNA vaccine efficacy in a severe COVID-19 model: attenuated activation of pulmonary immune cells after the challenge

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