The cellular immune response to COVID-19 deciphered by single cell multi-omics across three UK centres (preprint)

The COVID-19 pandemic, caused by SARS coronavirus 2 (SARS-CoV-2), has resulted in excess morbidity and mortality as well as economic decline. To characterise the systemic host immune response to SARS-CoV-2, we performed single-cell RNA-sequencing coupled with analysis of cell surface proteins, providing molecular profiling of over 800,000 peripheral blood mononuclear cells from a cohort of 130 patients with COVID-19. Our cohort, from three UK centres, spans the spectrum of clinical presentations and disease severities ranging from asymptomatic to critical. Three control groups were included: healthy volunteers, patients suffering from a non-COVID-19 severe respiratory illness and healthy individuals administered with intravenous lipopolysaccharide to model an acute inflammatory response. Full single cell transcriptomes coupled with quantification of 188 cell surface proteins, and T and B lymphocyte antigen receptor repertoires have provided several insights into COVID-19: 1. a new non-classical monocyte state that sequesters platelets and replenishes the alveolar macrophage pool; 2. platelet activation accompanied by early priming towards megakaryopoiesis in immature haematopoietic stem/progenitor cells and expansion of megakaryocyte-primed progenitors; 3. increased clonally expanded CD8+ effector:effector memory T cells, and proliferating CD4+ and CD8+ T cells in patients with more severe disease; and 4. relative increase of IgA plasmablasts in asymptomatic stages that switches to expansion of IgG plasmablasts and plasma cells, accompanied with higher incidence of BCR sharing, as disease severity increases. All data and analysis results are available for interrogation and data mining through an intuitive web portal. Together, these data detail the cellular processes present in peripheral blood during an acute immune response to COVID-19, and serve as a template for multi-omic single cell data integration across multiple centers to rapidly build powerful resources to help combat diseases such as COVID-19.

Nature Of, Immune Reaction to and Side Effects of COVID-19 Vaccines: Synthesis of Information Including Exclusions from Ten Phase II Trials for Planning Vaccination Programmes (preprint)

Background: Phase III clinical trials reporting the efficacy and safety of covid-19 vaccines are awaited with optimism about their ability to prevent infection, transmission and mortality/morbidity. Phase II trials results indicate what they might show.Methods: We identified published and pre-print results of phase II covid-19 vaccine trials synthesising data about the vaccines, trial designs, efficacy and safety. We extracted details on trial characteristics, participant details, immunogenicity and adverse effect outcomes focusing on the dose producing the largest immune response.Results: We found ten publications describing Covid-19 vaccine trials. Eight were randomised controlled trials. Vaccination was by intramuscular injection of either inactivated SARS-CoV-2, genetically engineered virus, genetically engineered RNA or protein. One trial used the meningococcal vaccine as a control. Trials recruited 20 to 1,077 participants, totaling 3983, the largest trial having 634 in the intervention arm. Participants were mostly aged between 18 and 60 years, and the (mean or median) age between 26.4 and 43.5-years with no participants under 18-years and few over 80-years. All vaccines produced neutralising antibodies and T-cell responses (when measured). Side effects included fatigue, localised pain, muscle-ache, fever and feeling feverish. These symptoms were more common in covid-19 vaccine recipients compared with controls. In the largest study, compared with meningococcal vaccine as control, 70% of participants reported post-vaccination fatigue (48% in controls), 68% headache (38%), 60% muscle ache (25%), 18% fever (<1% ) and 51% reported feeling feverish (8% ). Some of these were grade 3 adverse events (severe). Transient neutropenia was reported in 46% of a subgroup of 54participants in this trial. Transient lymphopenia was also reported in two further trials. There were five reports of serious adverse events, one deemed vaccine related. One vaccine-arm participant was hospitalised with fever.Discussion: People under 18-years and few over 80-years are not represented in these trials. The immune response is generally vigorous. Mild-moderate grade adverse effects mimicking covid-19 are common, with implications for the anticipated vaccination programmes, including distinguishing covid-19 and post-vaccine symptoms.

Population perspective comparing COVID-19 to all and common causes of death in seven European countries (preprint)

BackgroundMortality statistics on the COVID-19 pandemic have led to widespread concern and fear. To contextualise these data, we compared mortality related to COVID-19 with all and common causes of death, stratifying by age and sex. We also calculated deaths as a proportion of the population by age and sex. MethodsCOVID-19 related mortality and population statistics from seven European countries were extracted: England and Wales, Italy, Germany, Spain, France, Portugal and Netherlands. Available data spanned 14-16 weeks since the first recorded deaths in each country, except Spain, where only comparable stratified data over an 8-week time period was available. The Global Burden of Disease database provided data on all deaths and those from pneumonia, cardiovascular disease combining ischaemic heart disease and stroke, chronic obstructive pulmonary disease, cancer, road traffic accidents and dementia. FindingsDeaths related to COVID-19, while modest overall, varied considerably by age. Deaths as a percentage of all cause deaths during the time period under study ranged from <0.01% in children in Germany, Portugal and Netherlands, to as high as 41.65% for men aged over 80 years in England and Wales. The percentage of the population who died from COVID-19 was less than 0.2% in every age group under the age of 80. In each country, over the age of 80, these proportions were: England and Wales 1.27% males, 0.87% females; Italy 0.6% males, 0.38% females; Germany 0.13% males, 0.09% females; France 0.39% males, 0.2% females; Portugal 0.2% males, 0.15% females; and Netherlands 0.6% males, 0.4% females. InterpretationMortality rates from COVID-19 remains low including when compared to other common causes of death and will likely decline further while control measures are maintained. These data may help people contextualise their risk and policy makers in decision-making.