Project description:RNA was extracted from whole blood of subjects collected in Tempus tubes prior to COVID-19 mRNA booster vaccination. D01 and D21 correspond to samples collected at pre-dose 1 and pre-dose 2 respectively. RNA was also extracted from blood collected at indicated time points post-vaccination. DB1, DB2, DB4 and DB7 correspond to booster day 1 (pre-booster), booster day 2, booster day 4 and booster day 7 respectively. The case subject experienced cardiac complication following mRNA booster vaccination. We performed gene expression analysis of case versus controls over time.
Project description:Background and study aims
COVID-19 is a condition caused by the coronavirus (called SARS-CoV-2) that was first identified in late 2019. This virus can infect the respiratory (breathing) system. Some people do not have symptoms but can carry the virus and pass it on to others. People who have developed the condition may develop a fever and/or a continuous cough among other symptoms. This can develop into pneumonia. Pneumonia is a chest infection where the small air pockets of the lungs, called alveoli, fill with liquid and make it more difficult to breathe.
Nearly 32 million people in the UK have received two doses of the COVID-19 vaccine. Research shows that this prevents infection in over 90% of people. However, these vaccines were tested in healthy people. Recent research in individuals with chronic health problems or cancer suggests that 30% are generating low antibody or T-cells (a type of white blood cell which fights infection) levels after two doses of the Pfizer or AstraZeneca COVID-19 vaccines. This raises the question of the potential benefit of a third dose (re-boost) of the vaccine in these vulnerable patients. A re-boost strategy has been successfully used for other vaccines but the limited research performed to date for COVID-19 has given variable results, so additional research is needed. This study aims to find out whether a re-boost vaccine strategy can induce an immune response in clinically vulnerable patients who have not produced an adequate antibody response after two doses of the COVID-19 vaccine.
Who can participate?
Patients aged 18 and over who have not produced an adequate antibody response after two doses of COVID-19 vaccine and have one of the following diseases:
1. Breast or lung cancer
2. Certain types of blood cancer
3. Immune-mediated rheumatic diseases (e.g. rheumatoid arthritis)
4. Chronic kidney disease
5. Chronic liver disease
6. Inflammatory bowel disease on immune suppressive therapy
7. Stem cell transplant
8. Primary immunodeficiency (a group of disorders characterized by poor or absent immune function)
What does the study involve?
Participants will be randomly allocated to receive an additional dose of Pfizer or Moderna COVID-19 vaccine (the main study) or, for a sub-set of patients with blood cancer, the Pfizer or Moderna or Novavax vaccine. Blood samples will be collected before and 21 days after the re-boost vaccine and the level of antibodies and T-cells determined. Patients will be followed up for 3 months to see if they go on to develop COVID-19.
Project description:At this stage in the COVID-19 pandemic, most infections are 'breakthrough' infections that occur in individuals with prior immunity to SARS-CoV-2 through infection or vaccination. Understanding both innate and adaptive immune induction in the setting of breakthrough infection is critical to refining vaccine strategies to ensure long-term efficacy against emerging variants, yet existing studies have primarily focused on adaptive immune responses. Here, we performed single-cell transcriptomic, proteomic, and functional profiling of innate and adaptive immunity during primary and breakthrough COVID-19 infections by comparing immune responses between unvaccinated and vaccinated individuals during the SARS-CoV-2 Delta wave. Breakthrough infections were characterized by a significantly less activated transcriptomic profile in CD56dim NK cells and monocytes, with induction of pathways limiting NK cell proliferation and monocyte migratory potential. Furthermore, we observed a female-specific trend of increased transcriptomic activation of CD16+ monocytes and type-2 conventional dendritic cells (cDC2s) during breakthrough infections. Despite these differences, antibody-dependent cellular cytotoxicity responses were similar between breakthrough and primary infection groups. These insights suggest that prior vaccination prevents overactivation of innate immune responses during breakthrough infections with discernible sex-specific patterns and underscore the potential of harnessing vaccines in mitigating pathologic immune responses resulting from overactivation.
Project description:COVID-19, caused by SARS-CoV-2, is a virulent pneumonia, with >4,000,000 confirmed cases worldwide and >280,000 deaths as of May 13, 2020. It is critical to develop and evaluate vaccines and therapeutic interventions as rapidly as possible. Mice, the ideal animal for such studies, are resistant to SARS-CoV-2. Here, we overcome this difficulty by exogenous delivery of human ACE2 with a replication-deficient adenovirus (Ad5-hACE2). Ad5-hACE2-sensitized mice developed pneumonia characterized by weight loss, severe pulmonary pathology, and high-titer virus replication in lungs. Type I interferon, T cells and, most importantly, signal transducer and activator of transcription 1 (STAT1) are critical for virus clearance and diminished disease in these mice. Ad5-hACE2-transduced mice enabled rapid assessments of a vaccine candidate, of human convalescent plasma, and of two antiviral therapies (poly I:C and remdesivir). In summary, we describe a murine model of broad and immediate utility to investigate COVID-19 pathogenesis, and to evaluate new therapies and vaccines.
Project description:Acute viral infections can have durable functional impacts on the immune system long after recovery, but how they affect homeostatic immune states and responses to future perturbations remain poorly understood. Here we use systems immunology approaches, including longitudinal multimodal single cell analysis (surface proteins, transcriptome, and V(D)J sequences), to comparatively assess baseline immune statuses and responses to influenza vaccination in 33 healthy individuals after recovery from mild, non-hospitalized COVID-19 (mean: 151 days after diagnosis) and 40 age- and sex-matched controls who never had COVID-19. At baseline and independent of time since COVID-19, recoverees had elevated T-cell activation signatures and lower expression of innate immune genes in monocytes. COVID-19-recovered males had coordinately higher innate, influenza-specific plasmablast, and antibody responses after vaccination compared to healthy male and COVID-19-recovered females, partly because male recoverees had monocytes with higher IL-15 responses early after vaccination coupled with elevated pre-vaccination frequencies of "virtual memory" like CD8+ T-cells poised to produce more IFNg upon IL-15 stimulation. In addition, the expression of the repressed innate immune genes in monocytes increased by day 1 through day 28 post-vaccination in recoverees, thus moving towards the pre-vaccination baseline of healthy controls. In contrast, these genes decreased on day 1 and returned to the baseline by day 28 in controls. Our study reveals sex-dimorphic impacts of prior mild COVID-19 and suggests that viral infections in humans can establish new immunological set-points impacting future immune responses in an antigen-agnostic manner.