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1.
Cell Rep ; 39(5): 110757, 2022 05 03.
Article in English | MEDLINE | ID: covidwho-1850799

ABSTRACT

Although the antibody response to COVID-19 vaccination has been studied extensively at the polyclonal level using immune sera, little has been reported on the antibody response at the monoclonal level. Here, we isolate a panel of 44 anti-SARS-CoV-2 monoclonal antibodies (mAbs) from an individual who received two doses of the ChAdOx1 nCoV-19 (AZD1222) vaccine at a 12-week interval. We show that, despite a relatively low serum neutralization titer, Spike-reactive IgG+ B cells are still detectable 9 months post-boost. Furthermore, mAbs with potent neutralizing activity against the current SARS-CoV-2 variants of concern (Alpha, Gamma, Beta, Delta, and Omicron) are present. The vaccine-elicited neutralizing mAbs form eight distinct competition groups and bind epitopes overlapping with neutralizing mAbs elicited following SARS-CoV-2 infection. AZD1222-elicited mAbs are more mutated than mAbs isolated from convalescent donors 1-2 months post-infection. These findings provide molecular insights into the AZD1222 vaccine-elicited antibody response.


Subject(s)
COVID-19 , SARS-CoV-2 , Antibodies, Monoclonal , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines , Humans , Vaccination
2.
Cell Calcium ; 105: 102605, 2022 07.
Article in English | MEDLINE | ID: covidwho-1850778

ABSTRACT

Gain-of-function mutations on STIM1 and ORAI1 genes are responsible for an increased store-operated calcium entry, and underlie the characteristic symptoms of three overlapping ultra-rare genetic disorders (i.e tubular aggregate myopathy, Stormorken syndrome, York platelet syndrome) that can be grouped as tubular aggregate myopathies. These mutations lead to a wide spectrum of defects, which usually include muscle weakness and cramps. Negative modulators of store-operated Ca2+-entry targeting wild-type STIM1 and ORAI1 have entered clinical trials for a different array of disorders, including pancreatitis, COVID-19, cancer, and autoimmune disorders and, while efficacy data is awaited, safety data indicates tolerability of this STIM1/ORAI1 mutations are amenable to pharmacological intervention. If this were so, given that there are no approved treatments or clinical trials ongoing for these rare disorders, it could be envisaged that these agents could also rehabilitate tubular aggregate myopathy patients. In the present contribution we characterized the Ca2+-entry patterns induced by eleven STIM1 and three ORAI1 mutations in heterologous systems or in patient-derived cells, i.e. fibroblasts and myotubes, and evaluated the effect of CIC-37 and CIC-39, two novel store-operated calcium entry modulators. Our data show that all STIM1 and ORAI1 gain-of-function mutations tested, with the possible exception of the R304Q STIM1 mutation, are amenable to inhibition, albeit with slightly different sensitivities, paving the way to the development of SOCE modulators in tubular aggregate myopathies.


Subject(s)
COVID-19 , Myopathies, Structural, Congenital , Blood Platelet Disorders , Calcium/metabolism , Dyslexia , Erythrocytes, Abnormal , Humans , Ichthyosis , Migraine Disorders , Miosis , Muscle Fatigue , Mutation/genetics , Myopathies, Structural, Congenital/genetics , Neoplasm Proteins/genetics , ORAI1 Protein/genetics , Spleen/abnormalities , Stromal Interaction Molecule 1/genetics
3.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-296734

ABSTRACT

The recent emergence of the omicron variant of the SARS-CoV-2 virus with large numbers of mutations has raised concern about a potential new surge in infections. Here we use molecular dynamics to study the biophysics of the interface of the omicron spike protein binding to (i) the ACE2 receptor protein, (ii) antibodies from all known binding regions, and (iii) the furin binding domain. Our simulations suggest that while there is significant reduction of antibody binding strength corresponding to escape, the omicron spike pays a cost in terms of weaker receptor binding. The furin cleavage domain is the same or weaker binding than the alpha variant, suggesting less viral load and disease intensity than the extant delta variant.

4.
Nat Microbiol ; 6(11): 1433-1442, 2021 11.
Article in English | MEDLINE | ID: covidwho-1469971

ABSTRACT

COVID-19 vaccine design and vaccination rollout need to take into account a detailed understanding of antibody durability and cross-neutralizing potential against SARS-CoV-2 and emerging variants of concern (VOCs). Analyses of convalescent sera provide unique insights into antibody longevity and cross-neutralizing activity induced by variant spike proteins, which are putative vaccine candidates. Using sera from 38 individuals infected in wave 1, we show that cross-neutralizing activity can be detected up to 305 days pos onset of symptoms, although sera were less potent against B.1.1.7 (Alpha) and B1.351 (Beta). Over time, despite a reduction in overall neutralization activity, differences in sera neutralization potency against SARS-CoV-2 and the Alpha and Beta variants decreased, which suggests that continued antibody maturation improves tolerance to spike mutations. We also compared the cross-neutralizing activity of wave 1 sera with sera from individuals infected with the Alpha, the Beta or the B.1.617.2 (Delta) variants up to 79 days post onset of symptoms. While these sera neutralize the infecting VOC and parental virus to similar levels, cross-neutralization of different SARS-CoV-2 VOC lineages is reduced. These findings will inform the optimization of vaccines to protect against SARS-CoV-2 variants.


Subject(s)
Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , COVID-19/immunology , SARS-CoV-2/immunology , Adult , Aged , Aged, 80 and over , Antibodies, Viral/immunology , COVID-19/therapy , COVID-19/virology , COVID-19 Vaccines , Female , Humans , Immunization, Passive , Immunoglobulin G , Immunoglobulin M , Male , Middle Aged , Mutation , Neutralization Tests , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Vaccination , Young Adult
5.
Head Neck ; 42(7): 1392-1396, 2020 Jul.
Article in English | MEDLINE | ID: covidwho-1384168

ABSTRACT

The severe acute respiratory syndrome (SARS)-CoV-2 pandemic continues to produce a large number of patients with chronic respiratory failure and ventilator dependence. As such, surgeons will be called upon to perform tracheotomy for a subset of these chronically intubated patients. As seen during the SARS and the SARS-CoV-2 outbreaks, aerosol-generating procedures (AGP) have been associated with higher rates of infection of medical personnel and potential acceleration of viral dissemination throughout the medical center. Therefore, a thoughtful approach to tracheotomy (and other AGPs) is imperative and maintaining traditional management norms may be unsuitable or even potentially harmful. We sought to review the existing evidence informing best practices and then develop straightforward guidelines for tracheotomy during the SARS-CoV-2 pandemic. This communication is the product of those efforts and is based on national and international experience with the current SARS-CoV-2 pandemic and the SARS epidemic of 2002/2003.


Subject(s)
Clinical Decision-Making , Coronavirus Infections/epidemiology , Hospital Mortality/trends , Pandemics/statistics & numerical data , Pneumonia, Viral/epidemiology , Severe Acute Respiratory Syndrome/therapy , Tracheotomy/methods , COVID-19 , Coronavirus Infections/prevention & control , Critical Care/methods , Elective Surgical Procedures/methods , Elective Surgical Procedures/statistics & numerical data , Emergencies , Female , Follow-Up Studies , Humans , Intensive Care Units/statistics & numerical data , Internationality , Intubation, Intratracheal , Male , Occupational Health , Pandemics/prevention & control , Patient Safety , Pneumonia, Viral/prevention & control , Respiration, Artificial/methods , Risk Assessment , SARS Virus/pathogenicity , Survival Rate , Time Factors , Treatment Outcome , United States/epidemiology , Ventilator Weaning/methods
6.
ANZ J Surg ; 91(11): 2263-2268, 2021 11.
Article in English | MEDLINE | ID: covidwho-1183143

ABSTRACT

BACKGROUND: In Australia, ethics committees across different states vary in application, requirement and process for the ethical review and approval for clinical research. This may lead to confusion and delays in the enablement of multicentre research projects. This study explores the effect of differing processes for Ethics and Governance in the establishment of the CovidSurg-Cancer study during the global COVID-19 pandemic. METHODS: An anonymous, structured web-based questionnaire was designed using the Research Electronic Data Capture application (REDCap) platform to capture consultant surgeons, fellows, and trainees experience in the ethics application process. 'CovidSurg-Cancer' was an international multicentre collaborative study to assess the impact of COVID-19 on the outcomes of patients undergoing cancer surgery. The ethics process to set up this observational study was used as to explore the differing processes applied across Australia. RESULTS: The CovidSurg-Cancer study was successfully set up in 14 hospitals. Four hospitals approved the study directly as an audit. Of the remaining sites, 10 ethics applications underwent Human Research Ethics Committee review following which two (14%) were subsequently approved as an audit activity and eight hospitals (57%) were given formal ethical approval with waiver of consent. Ethics application acceptance from another Australian Human Research Ethics Committee was provided with six applications; however, only three were reciprocated without the requirement for further agreements. A third of (30%) respondents suggested that the details of the application pathway, process and documentation were unclear. CONCLUSION: Ethics processes are varied across Australia with considerable repetition. A centralized, harmonized application process would enhance collaborative research.


Subject(s)
COVID-19 , Ethics Committees, Research , Australia , Humans , Pandemics , SARS-CoV-2
7.
People Nat (Hoboken) ; 3(3): 518-527, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1171131

ABSTRACT

The coronavirus (COVID-19) pandemic and the global response have dramatically changed people's lifestyles in much of the world. These major changes, as well as the associated changes in impacts on the environment, can alter the dynamics of the direct interactions between humans and nature (hereafter human-nature interactions) far beyond those concerned with animals as sources of novel human coronavirus infections. There may be a variety of consequences for both people and nature.Here, we suggest a conceptual framework for understanding how the COVID-19 pandemic might affect the dynamics of human-nature interactions. This highlights three different, but not mutually exclusive, pathways: changes in (a) opportunity, (b) capability and (c) motivation.Through this framework, we also suggest that there are several feedback loops by which changes in human-nature interactions induced by the COVID-19 pandemic can lead to further changes in these interactions such that the impacts of the pandemic could persist over the long term, including after it has ended.The COVID-19 pandemic, which has had the most tragic consequences, can also be viewed as a 'global natural experiment' in human-nature interactions that can provide unprecedented mechanistic insights into the complex processes and dynamics of these interactions and into possible strategies to manage them to best effect. A free Plain Language Summary can be found within the Supporting Information of this article.

8.
J Trauma Acute Care Surg ; 89(4): 698-702, 2020 10.
Article in English | MEDLINE | ID: covidwho-630310

ABSTRACT

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic presents a threat to health care systems worldwide. Trauma centers may be uniquely impacted, given the need for rapid invasive interventions in severely injured and the growing incidence of community infection. We discuss the impact that SARS-CoV-2 has had in our trauma center and our steps to limit the potential exposures. METHODS: We performed a retrospective evaluation of the trauma service, from March 16 to 30, following the appearance of SARS-CoV-2 in our state. We recorded the daily number of trauma patients diagnosed with SARS-CoV-2 infection, the presence of clinical symptoms or radiological signs of COVID-19, and the results of verbal symptom screen (for new admissions). The number of trauma activations, admissions, and census, as well as staff exposures and infections, was recorded daily. RESULTS: Over the 14-day evaluation period, we tested 85 trauma patients for SARS-CoV-2 infection, and 21 (25%) were found to be positive. Sixty percent of the patients in the trauma/burn intensive care unit were infected with SARS-CoV-2. Positive verbal screen results, presence of ground glass opacities on admission chest CT, and presence of clinical symptoms were not significantly different in patients with or without SARS-CoV-2 infection (p > 0.05). Many infected patients were without clinical symptoms (9/21, 43%) or radiological signs on admission (18/21, 86%) of COVID-19. CONCLUSION: Forty-five percent of trauma patients are asymptomatic at the time of SARS-CoV-2 diagnosis. Respiratory symptoms, as well as verbal screening (recent fevers, shortness of breath, cough, international travel, and close contact with known SARS-CoV-2 carriers), are inaccurate in the trauma population. These findings demonstrate the need for comprehensive rapid testing of all trauma patients upon presentation to the trauma bay. LEVEL OF EVIDENCE: Diagnostic tests or criteria, level III, Therapeutic/care management, level IV.


Subject(s)
Asymptomatic Infections/epidemiology , Clinical Laboratory Techniques/standards , Coronavirus Infections/diagnosis , Cross Infection/prevention & control , Pneumonia, Viral/diagnosis , Trauma Centers/standards , Betacoronavirus/isolation & purification , Betacoronavirus/pathogenicity , COVID-19 , COVID-19 Testing , Coronavirus Infections/epidemiology , Coronavirus Infections/prevention & control , Coronavirus Infections/transmission , Cross Infection/epidemiology , Cross Infection/transmission , Cross Infection/virology , Humans , Infection Control/standards , Infectious Disease Transmission, Patient-to-Professional/prevention & control , Pandemics/prevention & control , Patient Admission/standards , Pneumonia, Viral/epidemiology , Pneumonia, Viral/prevention & control , Pneumonia, Viral/transmission , Prevalence , Retrospective Studies , Risk Factors , SARS-CoV-2 , Time Factors , Trauma Centers/organization & administration
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