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Virus-specific cellular and humoral responses are major determinants for protection from critical illness after SARS-CoV-2 infection. However, the magnitude of the contribution of each of the components to viral clearance remains unclear. Here, we studied the timing of viral clearance in relation to 122 immune parameters in 102 hospitalised patients with moderate and severe COVID-19 in a longitudinal design. Delayed viral clearance was associated with more severe disease and was associated with higher levels of SARS-CoV-2-specific (neutralising) antibodies over time, increased numbers of neutrophils, monocytes, basophils, and a range of pro-inflammatory cyto-/chemokines illustrating ongoing, partially Th2 dominating, immune activation. In contrast, early viral clearance and less critical illness correlated with the peak of neutralising antibodies, higher levels of CD4 T cells, and in particular naïve CD4+ T cells, suggesting their role in early control of SARS-CoV-2 possibly by proving appropriate B cell help. Higher counts of naïve CD4+ T cells also correlated with lower levels of MIF, IL-9, and TNF-beta, suggesting an indirect role in averting prolonged virus-induced tissue damage. Collectively, our data show that naïve CD4+ T cell play a critical role in rapid viral T cell control, obviating aberrant antibody and cytokine profiles and disease deterioration. These data may help in guiding risk stratification for severe COVID-19.

Metagenomics enables the detection of all the genetic material of organisms present in a sample, making it a pathogen-agnostic approach for detecting common and rare or novel pathogens that are not included in conventional testing⁠. Beforehand, a clinician does not need to have a hypothesis of what pathogen is expected, unlike traditional polymerase chain reaction (PCR) testing⁠.This thesis is focusing on diagnostic yield, clinical findings, and enhancing technical opportunities in viral metagenomics⁠. The identification, typing, and quantification of viruses by means of viral metagenomics as a diagnostic tool are evaluated⁠. Technical aspects are appraised for improved sensitivity and specificity of the wet and dry (bioinformatic) lab components of viral metagenomics⁠. The use of a metagenomic protocol for virus discovery directly in a patient sample is assessed, and the best methods and approaches for performing genetic analysis of the SARS-CoV-2 virus are investigated⁠.Viral metagenomic testing results in the identification of more viruses, therefore it is a valuable addition to current diagnostic test protocols⁠. Additionally, it is a useful test for virus discovery and monitoring during infectious disease outbreaks caused by novel viruses⁠.