Pandemic's silver lining.

The intense international focus on the COVID-19 pandemic has provided a unique opportunity to use a wide array of novel tools to carry out scientific studies on the SARS-CoV-2 virus. The value of these comparative studies extends far beyond their consequences for SARS-CoV-2, providing broad implications for health-related science. Here we specifically discuss the impacts of these comparisons on advances in vaccines, the analysis of host humoral immunity, and antibody discovery. As an extension, we also discuss potential synergies between these areas.Abbreviations: CoVIC: The Coronavirus Immunotherapeutic Consortium; EUA: Emergency Use Authorization.

A pandemic-enabled comparison of discovery platforms demonstrates a naïve antibody library can match the best immune-sourced antibodies.

As a result of the SARS-CoV-2 pandemic numerous scientific groups have generated antibodies against a single target: the CoV-2 spike antigen. This has provided an unprecedented opportunity to compare the efficacy of different methods and the specificities and qualities of the antibodies generated by those methods. Generally, the most potent neutralizing antibodies have been generated from convalescent patients and immunized animals, with non-immune phage libraries usually yielding significantly less potent antibodies. Here, we show that it is possible to generate ultra-potent (IC50 < 2 ng/ml) human neutralizing antibodies directly from a unique semisynthetic naïve antibody library format with affinities, developability properties and neutralization activities comparable to the best from hyperimmune sources. This demonstrates that appropriately designed and constructed naïve antibody libraries can effectively compete with immunization to directly provide therapeutic antibodies against a viral pathogen, without the need for immune sources or downstream optimization.

SARS-COV2 antibody phenotype and immune gene expression in MIS-C

Introduction: Multisystem Inflammatory Syndrome in Children (MIS-C) is a severe disease that affects a small proportion of children exposed to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Differences in SARS-CoV-2 antibody responses and immune gene expression between SARS-CoV-2-infected children who develop MIS-C and those who do not may provide insight into the mechanism of MIS-C. Objectives: To determine the difference in SARS-CoV2 antibody responses and immune gene expression in children with MIS-C and healthy children with evidence of previous SARS-CoV2 infection. Methods: Healthy children presenting for elective surgery and those with MIS-C were recruited between 22 June 2020 and 5 November 2020 from a single paediatric hospital during the first wave of SARSCoV- 2 in the region. Clinical data, whole blood RNA and serum were collected. Titres of SARS-CoV-2 spike-specific antibody (SAb) and their capacity to perform neutralization, antibody-dependent cellular phagocytosis (ADCP) and antibody dependant cellular cytotoxicity (ADCC) were measured. Whole blood RNA gene expression was measured using multiplex Fluidigm quantitative Polymerase Chain Reaction (qPCR) with a panel of 84 immune genes. Principal component analysis was performed to assess for differences in gene expression. A linear regression model was developed with a forward stepwise model selection method to assess which genes associated with Creactive protein (CRP) in MIS-C after controlling for the neutrophil to lymphocyte ratio (NLR). Results: Twenty-three children with MIS-C and 25 healthy children were recruited. Nine healthy children had detectable SARS-CoV-2 serum antibodies (healthy exposed). No children had preceding clinical disease related to SARS-CoV-2 infection. Comparing children with MIS-C and healthy exposed children showed no difference in SAb binding responses (p=0.372) or ADCC (p=0.992). Increased neutralisation titre (p=0.084) and ADCP (p=0.086) in children with MIS-C was observed although was non-significant. Antibody function or titre did not change over time or with treatment in MIS-C. There was a clear distinction in immune gene expression between healthy children and those with MIS-C. Immune gene expression in MIS-C resolved to become indistinct from healthy children with time. Whole blood immune gene expression associated with an abundance of neutrophils in MIS-C. In a model that accounted for 66% of the variance in CRP (adjusted R2 = 0.66) the expression of IL27 accounted for 64% of the model effect (B=35;p<0.001) followed by NLR (15%, B=6.6, p=0.002) and the expression of MCP2 (11%, B=-14.59, p=0.008). Conclusion: Comparing children infected with SARS-COV-2 from the same time period and region with or without MIS-C provides unique mechanistic insight into the disease. A trend towards higher SAb titres and ADCP implies a distinct humoral immune response to SARSCOV- 2 in children with MIS-C, although further studies are required to validate this observation. The resolution of the abnormal immune gene expression in MIS-C implies a monophasic immune perturbation. The association of IL27 and MCP2 with CRP suggests that these may be important targets in future studies for possible pathogenicity and as potential biomarkers in MIS-C.