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Why do some people with COVID-19 get sicker than others? Maybe exposure to a particularly high dose of the causative virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), accounts for the difference. Perhaps deficiencies in diet, exercise, or sleep contribute to worse illness. Although many factors govern how sick people become, a key driver of the severity of COVID-19 appears to be genetic, which is common for other human viruses and infectious agents (1). On page 579 of this issue, Wickenhagen et al. (2) show that susceptibility to severe COVID-19 is associated with a single-nucleotide polymorphism (SNP) in the human gene 2′-5′-oligoadenylate synthetase 1 (OAS1).The authors reasoned that SARS-CoV-2 should be inhibited by interferon-mediated antiviral responses, which are among the first cellular defense mechanisms produced in response to a viral infection. Interferons are a group of cytokines that induce the transcription of a large cadre of genes, many of which encode proteins with the potential to directly inhibit the invading virus. Wickenhagen et al. interrogated many hundreds of these putative antiviral proteins for their ability to suppress SARS-CoV-2 in cultured cells and found that OAS1 was particularly potent against SARS-CoV-2.OAS1 is an enzyme that is activated in the presence of double-stranded RNA, which is scattered along an otherwise singlestranded SARS-CoV-2 genome because of an assortment of RNA hairpins and other secondary structures. Once activated, OAS1 catalyzes the polymerization of adenosine triphosphate (ATP) into a second messenger, 2′-5′-oligoadenylate. This then triggers the conversion of ribonuclease L (RNaseL) into its active form so that it can cleave viral RNA, effectively blunting viral replication (3). Wickenhagen et al. found that OAS1 is expressed in respiratory tissues of healthy donors and COVID-19 patients and that it interacts with a region of the SARS-CoV-2 genome that contains double-stranded RNA secondary structures (see the figure).OAS1 exists predominantly as two isoforms in humans—a longer isoform (p46) and a shorter version (p42). Genetic variation dictates which isoform will be expressed. In humans, p46 is expressed in people who have a SNP that causes alternative splicing of the OAS1 messenger RNA (mRNA). This results in the utilization of a terminal exon that is not used to translate p42. Thus, the carboxyl terminus of the p46 OAS1 protein contains a distinct four–amino acid motif that forms a prenylation site. Prenylation is a posttranslational modification that targets proteins to membranes. In cell culture experiments, Wickenhagen et al. showed that only OAS1 p46, but not p42, could inhibit SARS-CoV-2. However, when the prenylation site of p46 was engineered into p42, this chimeric p42 protein was able to inhibit SARS-CoV-2, which strongly implicates a role for OAS1 specifically at membranes.Why are membranes important? SARS-CoV-2, like all coronaviruses, co-opts cellular membranes at the endoplasmic reticulum to form double-membrane vesicles, in which the virus replicates its genome. Thus, membrane-bound OAS1 p46 may be specifically activated by RNA viruses that form membrane-bound vesicles for replication. Indeed, the unrelated cardiovirus A, which also forms vesicular membranous structures, was inhibited by OAS1. Conversely, other respiratory RNA viruses, such as human parainfluenza virus type 3 and human respiratory syncytial virus, which do not use membrane-tethered vesicles for replication, were not inhibited by p46.Wickenhagen et al. examined a cohort of 499 COVID-19 patients hospitalized in the UK. Whereas all patients expressed OAS1, 42.5% of them did not express the antiviral p46 isoform. These patients were statistically more likely to have severe COVID-19 (be admitted to the intensive care unit). This suggests that OAS1 is an important antiviral factor in the control of SARS-CoV-2 infection and that its inability to activate RNaseL results in prolonged infections and severe disease, although other factors likely contribute. The authors also examined animals known to harbor different coronaviruses. They found evidence for prenylated OAS1 proteins in mice, cows, and camels. Notably, horseshoe bats, which are considered a possible reservoir for SARS-related coronaviruses (4), lack a prenylation motif in their OAS1 because of genomic changes that eliminated the critical four-amino acid motif. A horseshoe bat (Rhinolophus ferrumequinum) OAS1 was unable to inhibit SARS-CoV-2 infection in cell culture. Conversely, the black flying fox (Pteropus alecto)—a pteropid bat that is a reservoir for the Nipah and Hendra viruses, which can also infect humans—possesses a prenylated OAS1 that can inhibit SARS-CoV-2. These findings indicate that horseshoe bats may be genetically and evolutionarily primed to be optimal reservoir hosts for certain coronaviruses, like SARS-CoV-2.Other studies have now shown that the p46 OAS1 variant, which resides in a genomic locus inherited from Neanderthals (5–7), correlates with protection from COVID-19 severity in various populations (8, 9). These findings mirror previous studies indicating that outcomes with West Nile virus (10) and hepatitis C virus (11) infection, both of which also use membrane vesicles for replication, are also associated with genetic variation at the human OAS1 locus. Another elegant functional study complements the findings of Wickenhagen et al. by also demonstrating that prenylated OAS1 inhibits multiple viruses, including SARS-CoV-2, and is associated with protection from severe COVID-19 in patients (12).There is a growing body of evidence that provides critical understanding of how human genetic variation shapes the outcome of infectious diseases like COVID-19. In addition to OAS1, genetic variation in another viral RNA sensor, Toll-like receptor 7 (TLR7), is associated with severe COVID-19 (13–15). The effects appear to be exclusive to males, because TLR7 is on the X chromosome, so inherited deleterious mutations in TLR7 therefore result in immune cells that fail to produce normal amounts of interferon, which correlates with more severe COVID-19. Our knowledge of the host cellular factors that control SARS-CoV-2 is rapidly increasing. These findings will undoubtedly open new avenues into SARS-CoV-2 antiviral immunity and may also be beneficial for the development of strategies to treat or prevent severe COVID-19.
Degrading viral RNAOnce inside a host cell, coronaviruses form double-membrane vesicles (DMVs) to replicate their RNA genome. When anchored to membranes, 2′-5′-oligoadenylate synthetase 1 (OAS1) detects double-stranded RNA (dsRNA) secondary structure and activates ribonuclease L (RNaseL), which degrades viral RNA. The OAS1 p42 isoform lacks the prenylation motif, so it is not membrane bound and RNaseL is not activated, leading to unrestrained viral replication and correlating with severe COVID-19.GRAPHIC: KELLIE HOLOSKI/SCIENCE Source: Shroggins SCIENCE
28 Oct 2021
Vol 374, Issue 6567
pp. 535-536
DOI: 10.1126/science.abm3921
Accurate and near real-time data about the trajectory of the COVID-19 pandemic have been crucial in informing mitigation policies. Because choosing the right mitigation policies relies on an accurate assessment of the current state of the local epidemic, the potential ramifications of misinterpreting data are serious. Each data source has inherent biases and pitfalls in interpretation. The more data sources that are interpreted in combination, the easier it is to detect genuine changes in an epidemic. Recently, in many countries, this has involved disentangling the varying impact of rising but heterogeneous vaccination rates, relaxation of mitigations, and the emergence of new variants such as Delta.The exact data collected and their accuracy will vary by country. Typical data common to many countries are numbers of tests, confirmed cases, hospital and intensive care unit (ICU) admissions and occupancy, deaths, and vaccinations (1). Many countries additionally sequence a proportion of new positive tests to identify and track emerging variants. Some countries also now collect and publish data on infections, hospitalizations, and deaths by vaccination status (e.g., Israel and the UK). Stratifying all available data by different demographic factors (e.g., age, location, measures of deprivation, and ethnicity) is crucial for understanding patterns of spread, potential impact of policies, and efficacy of vaccines (age, timing of breakthrough infections, and prevalent variants).It is also necessary to be aware of what data are not being collected. For example, persistent symptoms of COVID-19 (Long Covid) were recognized as a long-term adverse outcome by the autumn of 2020. However, no simple diagnostic test has been associated with the up to 200 different reported symptoms (2). Counting Long Covid relies on a clinical diagnosis, based on a history of having had COVID-19 and a failure to fully recover, with development of some characteristic symptoms and with no obvious alternative cause (3). These features make it very difficult to measure routinely, and so it rarely is. As a result, Long Covid is often neglected in decision-making. Failure to account for the disease load associated with Long Covid may lead to an unnecessary long-term societal health burden.The feedback between different types of outcomes, different severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, different mitigation policies (including vaccination), and individual risks (a combination of exposure and clinical risk) is complex and must be factored into both interpretation of data and the development of policy. Using all available data to quantify transmission is crucial to ensuring rapid and effective responses to early phases of renewed exponential growth and to evaluating mitigation measures. Relying too much on a single data source, or without disaggregating data, risks fundamentally misunderstanding the state of the epidemic.The inherent biases and lags in data are particularly important to understand from the point of view of policy-makers. Because of the natural time scales of COVID-19 disease progression (see the figure), policy changes can take several weeks to show up in the data. Purely reactive policy-making is likely to be ineffective. When cases are rising, increases in hospital admissions and deaths will follow. When a new variant is outcompeting existing strains, it is likely to become dominant without action to suppress. The precautionary principle suggests acting early and emphatically. Conversely, when releasing restrictions, governments must wait long enough to assess them before continuing with re-opening.The most up-to-date indicator of the state of the epidemic is typically the number of confirmed cases, as ascertained through testing of both symptomatic individuals and those tested frequently regardless of symptoms. Symptom-based testing is likely to pick up more adults and fewer younger individuals (4). Infections in children are harder to detect: children are more likely to be asymptomatic than adults, are harder to administer tests to (particularly young children), are often exposed to other viruses with similar symptoms, and can present with symptoms that are atypical in adults (e.g., abdominal pain or nausea). Children under 12 are not routinely offered the COVID-19 vaccination, and their mixing in schools provides ongoing opportunities for the virus to circulate, so it will be important for countries to track infections in children as accurately as possible. Other testing biases include accessibility, reporting lags, and the ability to act lawfully upon receiving a positive result. Substantial changes in the number of people seeking tests may further confound case figures (5). Case positivity rates may provide a more accurate reflection of the state of the epidemic (6) but are dependent on the mix of symptomatic and asymptomatic people being tested.SARS-CoV-2 variants have been an important driver of local epidemics in 2021. The four main SARS-CoV-2 variants of concern, to date, are B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), and B.1.617.2 (Delta). Some have been more transmissible (Alpha), some have substantial resistance to previous infection or vaccines (Beta), and some have elements of both (Gamma and Delta) (7). Currently, the high transmissibility of Delta combined with some immune evasion has made it the world’s dominant variant. Determining which variants pose a substantial threat is difficult and takes time, particularly when many variants cocirculate. This is especially true for situations in which a dominant variant is declining, and a new one growing. While the declining variant remains dominant, its decrease masks increases in the new variant because case numbers remain unchanged or fall overall. Only when a new variant becomes dominant does its growth become apparent in aggregated case data, by which time it is, by definition, too late to contain its spread. This dynamic has been observed across the world with Delta over the latter half of 2021.With multiple variants circulating, there are, effectively, multiple epidemics occurring in parallel, and they must be tracked separately. This typically requires the availability of sequencing data, which is unfortunately limited in most countries. Sequencing takes time and so is typically a few weeks out of date. These lags, and the uncertainty in sampling, can lead to hesitancy in acting. The rapid path to dominance of the Delta variant in the UK highlights the need for action when a quickly growing variant represents a few percent (or less) of overall cases.Hospital admissions or occupancy data do not suffer the same biases associated with testing behaviors and provide unequivocal evidence of widespread transmission, its geography, and demographics. However, hospital admissions lag infections more than reported cases do, rendering these data less useful for proactive decision-making. Hospital data are also biased toward older people, who are more likely to suffer severe COVID-19, and now, unvaccinated populations. ICU occupancy data show a younger age profile than admissions because younger patients have a better chance of benefitting from the invasive treatment procedures (8).Deaths are the most lagged indicator, typically occurring 3 or more weeks after infection and with an additional lag in registration and reporting. Death data should never be used to inform real-time policy decisions. Instead, death figures can act as an eventual measure of the success of a country’s epidemic strategy and implementation. The age distribution of those who eventually die from COVID-19 is different from other metrics of the epidemic—skewed furthest toward older age groups (9). Those with clinical risk factors (such as immunodeficiency, obesity, or existing lung conditions), high exposure (health care workers and low-income workers), and the unvaccinated are overrepresented in COVID-19 deaths.In countries with high vaccination rates, vaccination has had a substantial impact—reducing COVID-19 cases, hospitalizations, and deaths. However, when looking at the raw numbers in highly vaccinated populations, it can be the case that more fully vaccinated people are dying of COVID-19 than unvaccinated. If these raw statistics are misinterpreted—or worse, deliberately misused—they can damage vaccine confidence. More vaccinated people may die than unvaccinated because such a high proportion of people are vaccinated (10). This does not mean vaccines are not effective at preventing death. Looking at the rates of death in vaccinated and unvaccinated individuals separately within age groups demonstrates that vaccines provide considerable protection against severe disease and death. This example illustrates how important it is to curate and manage the way in which data are presented.
COVID-19 progressionAn approximate timeline from infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to various outcomes. When current infections show up in different data sources depends on this timeline. Collecting data for Long Covid, asymptomatic infection, and vaccine history will improve understanding of the pandemic.GRAPHIC: N. CARY/SCIENCE
Each country has established its own vaccination priority lists and dosing schedules to best achieve its goals (11, 12). Each of these strategies will manifest differently in the data. Additionally, many countries are using multiple vaccines in tandem and administer them differently for different demographics. Some countries are vaccinating adolescents, and others are not or not offering them the full approved dose. Most vaccines require two doses, spaced between 3 and 12 weeks apart, except for the Johnson & Johnson single-dose vaccine. This matters, particularly as variants spread, because different vaccines have different effectiveness after one and two doses, different timelines to full effectiveness, and different effectiveness against variants (13).Data published on the vaccination delivery itself must thus go beyond the raw numbers of people vaccinated. Vaccine uptake must be reported by whether fully or partially (one-dose in a two-dose regimen) vaccinated and using the whole population as a denominator. It is vital to disaggregate vaccine data by age, gender, and ethnicity as well as location so that it is possible, for example, to understand the impact of deprivation on vaccine coverage or vaccine hesitancy in particular demographics. When interpreting vaccination data, it is important to remember that there is also a lag between delivery and the build-up of immunity.Data on reinfection and post-vaccination (breakthrough) infection are also important to determine the relative benefits of infection-mediated and vaccine-mediated immunity and the length of protection offered. Studies that show those who were immunized earlier were acquiring COVID-19 with higher rates than those vaccinated more recently may suggest waning vaccine protection (14). Such studies have already prompted vaccine booster programs in some countries. However, any study that suggests waning immunity must be extremely careful to ensure that the “early” and “recent” subgroups are properly controlled. Differences in prior exposure, affluence, education level, age, and other demographic factors between these cohorts may be enough to explain the disparities in SARS-CoV-2 infection rates, even in the absence of waning immunity. Waning immunity must also be reported separately for different outcomes; for example, there might be waning in terms of preventing symptomatic infection but far less or none in preventing death (15). Additionally, there are ethical concerns about mass booster programs in high-income countries while many lower-income countries have been unable to procure vaccines.Moving into the vaccination era, reported cases, hospitalizations, and deaths should also be disaggregated by vaccination status (and by which vaccine), which will be easier in countries where national linked datasets exist. Additionally, incorporating Long Covid into routine reporting and policy-making is crucial. Consistent diagnostic criteria and well-controlled studies will be vital to this effort. These elusive data will be of critical importance to navigate our way successfully out of the pandemic.
Start Quote from European Medicines Agency document
Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 3-6 May 2021
News 07/05/2021
This month EMA’s safety committee (PRAC) reviewed a number of safety signals related to COVID-19 vaccines. The evaluation of safety signals is a routine part of pharmacovigilance and is essential to ensuring that regulatory authorities have a comprehensive knowledge of a medicine’s benefits and risks.
PRAC concludes review of signal of facial swelling with COVID-19 vaccine Comirnaty
PRAC has recommended a change to Comirnaty’s product information. After reviewing all the available evidence, including cases reported to the European database for suspected side effects (EudraVigilance) and data from the scientific literature, PRAC considered that there is at least a reasonable possibility of a causal association between the vaccine and the reported cases of facial swelling in people with a history of injections with dermal fillers (soft, gel-like substances injected under the skin). Therefore, PRAC concluded that facial swelling in people with a history of injections with dermal fillers should be included as a side effect in section 4.8 of the summary of product characteristics (SmPC) and in section 4 of the patient information leaflet (PIL) for Comirnaty. The benefit-risk balance of the vaccine remains unchanged.
PRAC concludes review of unusual blood clots with low blood platelets1 with Janssen’s COVID-19 vaccine
PRAC has now concluded its review of COVID-19 Vaccine Janssen and confirmed, as previously communicated, that the benefits of the vaccine in preventing COVID-19 outweigh the risks of side effects. In finalising the review, the Committee recommended on 20 April further refinement of the warning about thrombosis (formation of blood clots in the vessels) with thrombocytopenia (low blood platelets) syndrome, which was listed previously in the product information for COVID-19 Vaccine Janssen. The product information will now also include advice that patients who are diagnosed with thrombocytopenia within three weeks of vaccination should be actively investigated for signs of thrombosis. Similarly, patients who present with thromboembolism within three weeks of vaccination should be evaluated for thrombocytopenia. Lastly, thrombosis with thrombocytopenia syndrome will be added as an ‘important identified risk’ in the risk management plan for the vaccine. Furthermore, the marketing authorisation holder will provide a plan to further study the possible underlying mechanisms for these very rare events.
PRAC continues to closely review Comirnaty and COVID-19 Vaccine Moderna for unusual blood clots with low blood platelets2
The PRAC is closely monitoring whether mRNA vaccines might also be linked to cases of rare, unusual blood clots with low blood platelets, a side effect that has been reported in Vaxzevria and COVID-19 vaccine Janssen. Following a review of reports of suspected side effects, the PRAC considers at this stage that there is no safety signal for the mRNA vaccines. Only few cases of blood clots with low blood platelets have been reported. When seen in the context of the exposure of people to the mRNA vaccines, these numbers are extremely low, and their frequency is lower than the one occurring in people who have not been vaccinated. In addition, these cases do not seem to present the specific clinical pattern observed with Vaxzevria and COVID-19 Vaccine Janssen. Overall, the current evidence does not suggest a causal relation.
EMA will continue to monitor this issue closely and communicate further if necessary.
Topics of interests from enhanced monitoring of COVID-19 vaccines
Enhanced safety monitoring in the form of pandemic summary safety reports is one of the commitments required from the marketing authorisation holders in the context of the conditional marketing authorisation. Marketing authorisation holders are required to submit pandemic summary safety reports to EMA on a monthly basis. These reports are reviewed by the PRAC and any areaof concern further investigated, if needed.
PRAC assessing reports of Guillain-Barre syndrome with AstraZeneca’s Covid-19 vaccine
As part of the review of the regular pandemic summary safety reports for Vaxzevria, AstraZeneca’s Covid-19 vaccine, the PRAC is analysing data provided by the marketing authorisation holder on cases of Guillain-Barre syndrome (GBS) reported following vaccination. GBS is an immune system disorder that causes nerve inflammation and can result in pain, numbness, muscle weakness and difficulty walking. GBS was identified during the marketing authorisation process as a possible adverse event requiring specific safety monitoring activities. PRAC has requested the marketing authorisation holder to provide further detailed data, including an analysis of all the reported cases in the context of the next pandemic summary safety report.
PRAC will continue its review and will communicate further when new information becomes available.
PRAC assessing reports of myocarditis with Comirnaty and COVID-19 Vaccine Moderna
EMA is aware of cases of myocarditis (inflammation of the heart muscle) and pericarditis (inflammation of the membrane around the heart) mainly reported following vaccination with Comirnaty. There is no indication at the moment that these cases are due to the vaccine. However, PRAC has requested the marketing authorisation holder to provide further detailed data, including an analysis of the events according to age and gender, in the context of the next pandemic summary safety report and will consider if any other regulatory action is needed. Additionally, the PRAC has requested the marketing authorisation holder for COVID-19 Vaccine Moderna– also an mRNA vaccine – to monitor similar cases with their vaccine and to also provide a detailed analysis of the events in the context of the next pandemic summary safety report. EMA will communicate further when new information becomes available.
1Thrombosis with thrombocytopenia syndrome 2Thrombosis with thrombocytopenia syndrome
Nir Hacohen and Marcia Goldberg, Researchers at MGH and the Broad Institute identify protein “signature” of severe COVID-19
Curator and Reporter: Aviva Lev-Ari, PhD, RN
Longitudinal proteomic analysis of plasma from patients with severe COVID-19 reveal patient survival-associated signatures, tissue-specific cell death, and cell-cell interactions
16% of COVID-19 patients display an atypical low-inflammatory plasma proteome
Severe COVID-19 is associated with heterogeneous plasma proteomic responses
Death of virus-infected lung epithelial cells is a key feature of severe disease
Lung monocyte/macrophages drive T cell activation, together promoting epithelial damage
Summary
Mechanisms underlying severe COVID-19 disease remain poorly understood. We analyze several thousand plasma proteins longitudinally in 306 COVID-19 patients and 78 symptomatic controls, uncovering immune and non-immune proteins linked to COVID-19. Deconvolution of our plasma proteome data using published scRNAseq datasets reveals contributions from circulating immune and tissue cells. Sixteen percent of patients display reduced inflammation yet comparably poor outcomes. Comparison of patients who died to severely ill survivors identifies dynamic immune cell-derived and tissue-associated proteins associated with survival, including exocrine pancreatic proteases. Using derived tissue-specific and cell type-specific intracellular death signatures, cellular ACE2 expression, and our data, we infer whether organ damage resulted from direct or indirect effects of infection. We propose a model in which interactions among myeloid, epithelial, and T cells drive tissue damage. These datasets provide important insights and a rich resource for analysis of mechanisms of severe COVID-19 disease.
The quest to identify mechanisms that might be contributing to death in COVID-19: Why do some patients die from this disease, while others — who appear to be just as ill do not?
Researchers at Massachusetts General Hospital (MGH) and the Broad Institute of MIT and Harvard have identified the protein “signature” of severe COVID-19
Interest was to develop methods for studying human immune responses to infections, which they had applied to the condition known as bacterial sepsis. The three agreed to tackle this new problem with the goal of understanding how the human immune system responds to SARS-CoV-2, the novel pathogen that causes COVID-19.
How scientists launched a study in days to probe COVID-19’s unpredictability
Collecting these specimens required a large team of collaborators from many departments, which worked overtime for five weeks to amass blood samples from 306 patients who tested positive for COVID-19, as well as from 78 patients with similar symptoms who tested negative for the coronavirus.
Credit : Alexandra-Chloé VillaniResearch associates at Mass General who worked countless hours to process blood samples for the COVID Acute Cohort Study (from left to right: Anna Gonye, Irena Gushterova, and Tom Lasalle)By Leah Eisenstadt
As the COVID-19 surge began in March, Mass General and Broad researchers worked around the clock to begin learning why some patients fare worse with the disease than others
The study found that most patients with COVID-19 have a consistent protein signature, regardless of disease severity; as would be expected, their bodies mount an immune response by producing proteins that attack the virus. “But we also found a small subset of patients with the disease who did not demonstrate the pro-inflammatory response that is typical of other COVID-19 patients,” Filbin said, yet these patients were just as likely as others to have severe disease. Filbin, who is also an assistant professor of emergency medicine at Harvard Medical School (HMS), noted that patients in this subset tended to be older people with chronic diseases, who likely had weakened immune systems.
Among other revelations, this showed that the most prevalent severity-associated protein, a pro-inflammatory protein called interleukin-6 (IL-6) rose steadily in patients who died, while it rose and then dropped in those with severe disease who survived. Early attempts by other groups to treat COVID-19 patients experiencing acute respiratory distress with drugs that block IL-6 were disappointing, though more recent studies show promise in combining these medications with the steroid dexamethasone.
Hacohen, who is a professor of medicine at HMS and director of the Broad’s Cell Circuits Program:
“You can ask which of the many thousands of proteins that are circulating in your blood are associated with the actual outcome,” he said, “and whether there is a set of proteins that tell us something.”
Goldberg, who is a professor of emergency medicine at HMS:
They are highly likely to be useful in figuring out some of the underlying mechanisms that lead to severe disease and death in COVID-19,” she said, noting her gratitude to the patients involved in the study. Their samples are already being used to study other aspects of COVID-19, such as identifying the qualities of antibodies that patients form against the virus.
Why wait for more info? A new case of cerebral sinus venus thrombosis was reported in a 25 year old man who became critically ill from a cerebral hemorrhage. And for women age 20-50, CSVT occurred in 1 in 13,000, or 4-15X higher than background.
UPDATED on 4/14/2021
How UK doctor linked rare blood-clotting to AstraZeneca Covid jab
We have put together the following mechanism for thrombosis including central vein sinus thrombosis as a complication of both J&J and the AstraZeneca vaccines. This unifying mechanism explains the predilection of cerebral veins and higher risk in younger women. Please share your thoughts on the proposed mechanism.
We have submitted the attached manuscript to SSRN. Sharing this promptly considering the public health significance.
Thanks
Figure 1. AstraZeneca or Janssen COVID-19 vaccine induced thromboinflammation and cerebral venous sinus thrombosis (CVST)-Proposed Mechanisms: Adenovirus carrier delivers SARS-CoV-2 DNA encoding the Spike (S) protein to the lung megakaryocytes via the coxsackie-adenovirus receptor (CAR). Spike protein induces COX-2 expression in megakaryocytes leading to megakaryocyte activation, biogenesis of activated platelets that express COX-2 and generate thromboxane A2 (TxA2). Cerebral vein sinus endothelial cells express podoplanin, a natural ligand for CLEC2 receptors on platelets. Platelets traversing through the cerebral vein sinuses would be further activated by TxA2 dependent podoplanin-CLEC2 signaling, leading to release of extracellular vesicles, thereby promoting CLEC5A and TLR2 mediated neutrophil activation, thromboinflammation, CVST, and thromboembolism in other vascular beds. Young age and female gender are associated with increased TxA2 generation and platelet activation respectively, and hence increased risk of thromboembolic complications following vaccination.
Best regards,
Ajay
Ajay Gupta, M.B.,B.S., M.D.
Clinical Professor,
Division of Nephrology, Hypertension and Kidney Transplantation
University of California Irvine
President & CSO, KARE Biosciences (www.karebio.com)
Title: SARS-CoV-2 vaccination induced thrombosis: Is chemoprophylaxis with antiplatelet agents warranted?
Guest Authors:
Kate Chander Chiang1
Ajay Gupta, MBBS, MD1,2
Affiliations
(1) KARE Biosciences, Orange, CA 92869
(2) Department of Medicine, University of California Irvine (UCI) School of Medicine, Orange, CA 92868
*Corresponding author:
Ajay Gupta, MBBS, MD
Clinical Professor of Medicine,
Division of Nephrology, Hypertension and Kidney Transplantation
University of California Irvine (UCI) School of Medicine,
Orange, CA 92868
Tel: +1 (562) 412-6259
E-mail: ajayg1@hs.uci.edu
Word Count
Abstract: 359
Main Body: 1,648
Funding: No funding was required.
Conflict of Interest: AG and KCC have filed a patent for use of Ramatroban as an anti-thrombotic and immune modulator in SARS-CoV-2 infection. The patents have been licensed to KARE Biosciences. KCC is an employee of KARE Biosciences.
Author Contributions: AG and KCC conceptualized, created the framework, wrote and reviewed the manuscript.
The COVID-19 vaccines, Vaxzevria® (AstraZeneca) and the Janssen vaccine (Johnson & Johnson) are highly effective but associated with rare thrombotic complications. These vaccines are comprised of recombinant, replication incompetent, chimpanzee adenoviral vectors encoding the Spike (S) glycoprotein of SARS-CoV-2. The adenovirus vector infects epithelial cells expressing the coxsackievirus and adenovirus receptor (CAR). The S glycoprotein of SARS-CoV-2 is expressed locally stimulating neutralizing antibody and cellular immune responses, which protect against COVID-19. The immune responses are highly effective in preventing symptomatic disease in adults irrespective of age, gender or ethnicity. However, both vaccines have been associated with thromboembolic events including cerebral venous sinus thrombosis (CVST). Megakaryocytes also express CAR, leading us to postulate adenovirus vector uptake and expression of spike glycoprotein by megakaryocytes. Spike glycoprotein induces expression of cyclooxygenase -2 (COX-2), leading to generation of thromboxane A2 (TxA2). TxA2 promotes megakaryocyte activation, biogenesis of activated platelets and thereby increased thrombogenicity. Cerebral vein sinus endothelial cells express podoplanin, a natural ligand for CLEC2 receptors on platelets. Platelets traversing through the cerebral vein sinuses would be further activated by TxA2 dependent podoplanin-CLEC2 signaling, leading to CVST. The mechanisms proposed are consistent with the following clinical observations. First, a massive increase in TxA2 generation promotes platelet activation and thromboinflammation in COVID-19 patients. Second, TxA2 generation and platelet activation is increased in healthy women compared to men, and in younger mice compared to older mice; and, younger age and female gender appear to be associated with increased risk of thromboembolism as a complication of adenoviral vector based COVID-19 vaccine. The roll out of both AstraZeneca and Janssen vaccines has been halted for adults under 30-60 years of age in many countries. We propose that antiplatelet agents targeting TxA2 receptor signaling should be considered for chemoprophylaxis when administering the adenovirus based COVID-19 vaccines to adults under 30-60 years of age. In many Asian and African countries, only adenovirus-based COVID-19 vaccines are available at present. A short course of an antiplatelet agent such as aspirin could allow millions to avail of the benefits of the AstraZeneca and Janssen COVID-19 vaccines which could be otherwise either denied to them or put them at undue risk of thromboembolic complications.
COVID-19 disease is caused by a novel positive-strand RNA coronavirus (SARS-CoV-2), which belongs to the Coronaviridae family, along with the severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS) coronaviruses.1 The genome of these viruses encodes several non-structural and structural proteins, including spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins.2 The majority of the vaccines for COVID-19 that employ administration of viral antigens or viral gene sequences aim to induce neutralizing antibodies against the viral spike protein (S), preventing uptake through the ACE2 receptor, and thereby blocking infection.3
The Janssen COVID-19 vaccine (Johnson & Johnson) is comprised of a recombinant, replication- incompetent Ad26 vector, encoding a stabilized variant of the SARS-CoV-2 Spike (S) protein. The ChAdOx1 nCoV-19 vaccine (AZD1222, Vaxzevria®) was developed at Oxford University and consists of a replication-deficient chimpanzee adenoviral vector ChAdOx1, encoding the S protein.4 In US Phase III trials, Vaxzevria has been demonstrated to have 79% efficacy at preventing symptomatic COVID-19, and 100% efficacy against severe or critical disease and hospitalization, with comparable efficacy across ethnicity, gender and age.5 However, Vaxzevria has been associated with thrombotic and embolic events including disseminated intravascular coagulation (DIC) and cerebral venous sinus thrombosis (CVST), occurring within 14 days after vaccination, mostly in people under 55 years of age, the majority of whom have been women.6 Data from Europe suggests that the event rate for thromboembolic events may be about 10 per million vaccinated. Antibodies to platelet factor 4/heparin complexes have been recently reported in a few patients.7 However, the significance of this finding remains to be established. As of April 12, 2021, about 6.8 million doses of the Janssen vaccine have been administered in the U.S.8 CDC and FDA are reviewing data involving six reported U.S. cases of CVST in combination with thrombocytopenia.8 All six cases occurred among women between the ages of 18 and 48, and symptoms occurred 6 to 13 days after vaccination.8
SARS-CoV-2 is known to cause thromboinflammation leading to thrombotic microangiopathy, pulmonary thrombosis, pedal acro-ischemia (“COVID-toes”), arterial clots, strokes, cardiomyopathy, coronary and systemic vasculitis, deep venous thrombosis, pulmonary embolism, and microvascular thrombosis in renal, cardiac and brain vasculature.9-14 Cerebral venous sinus thrombosis (CVST) has also been reported in COVID-19 patients.15 Amongst 34,331 hospitalized COVID-19 patients, CVST was diagnosed in 28.16 In a multicenter, multinational, cross sectional, retrospective study of 8 patients diagnosed with CVST and COVID-19, seven were women.17 In another series of 41 patients with COVID-19 and CVST, the average age was about 50 years (SD, 16.5 years).17 The pathobiology of thrombotic events associated with the AstraZeneca vaccine should be viewed in the context of mechanisms underlying thromboinflammation that complicates SARS-CoV-2 infection and COVID-19 disease.
A. Role of COX-2 and thromboxane A2 in thromboinflammation complicating adenovirus based COVID-19 vaccine encoding the Spike protein of SARS-CoV-2
Thromboinflammation in COVID-19 seems to be primarily caused by endothelial, platelet and neutrophil activation, platelet-neutrophil aggregates and release of neutrophil extracellular traps (NETs).13,18 Platelet activation in COVID-19 is fueled by a lipid storm characterized by massive increases in thromboxane A2 (TxA2) levels in the blood and bronchoalveolar lavage fluid.19,20 Cyclooxygenase (COX) enzymes catalyze the first step in the biosynthesis of TxA2 from arachidonic acid, and COX-2 expression is induced by the spike (S) protein of coronaviruses.21 We postulate that an aberrant increase in TxA2 generation induced by the spike protein expression from the AstraZeneca vaccine leads to thromboinflammation, thromboembolism and CVST. 4
The support for the above proposed mechanism comes from the following observations. First, when mice of different age groups were infected with SARS-CoV virus, the generation of TxA2 was markedly increased in younger mice compared to middle aged mice.22 Furthermore, in children with asymptomatic or mildly symptomatic SARS-CoV-2 infection, microvascular thrombosis and thrombotic microangiopathy occur early in infection.20 These observations are consistent with the higher risk for thrombosis in adults under 60 years of age, compared with the older age group.6,7 Second, platelets from female mice are much more reactive than from male mice.23 Furthermore, TxA2 generation, TxA2-platelet interaction and activation is increased in women compared to men.24,25 These observations are consistent with disproportionately increased risk of thrombosis in women following AstraZeneca and Janssen COVID-19 vaccines.
The adenoviral vector ChAdOx1, containing nCoV-19 spike protein gene, infects host cells through the coxsackievirus and adenovirus receptor (CAR).26 CAR-dependent cell entry of the viral vector allows insertion of the SARS-CoV-2 spike protein gene and expression of Spike protein by host cells (Figure 1). CAR is primarily expressed on epithelial tight junctions.27 CAR expression has also been reported in platelets,28 and since platelets are anucleate cells CAR expression by megakaryocytes can be inferred. Therefore, AstraZeneca and Janssen vaccines would be expected to induce expression of Spike protein in megakaryocytes and platelets (Figure 1).
Spike protein of coronaviruses in known to induce COX-2 gene expression.21,29 COX-2 expression is induced during normal human megakaryopoiesis and characterizes newly formed platelets.30 While in healthy controls <10% of circulating platelets express COX-2, in patients with high platelet generation, up to 60% of platelets express COX-2.30 Generation of TxA2 by platelets is markedly suppressed by COX-2 inhibition in patients with increased megakaryopoiesis versus healthy subjects.30 Therefore, we postulate that expression of Spike protein induces COX-2 expression and generation of thromboxane A2 by megakaryocytes. TxA2 promotes biogenesis of activated platelets expressing COX-2. Platelet TxA2 generation leads to platelet activation and aggregation, and thereby thromboinflammation (Figure 1).
Extravascular spaces of the lungs comprise populations of mature and immature megakaryocytes that originate from the bone marrow, such that lungs are a major site of platelet biogenesis, accounting for approximately 50% of total platelet production or about 10 million platelets per hour.31 More than 1 million extravascular megakaryocytes have been observed in each lung of transplant mice.31 Following intramuscular injection of the AstraZeneca and Janssen vaccines, the adenovirus vector will traverse the veins and lymphatics to be delivered to the pulmonary circulation thereby exposing lung megakaryocytes in the first pass. Interestingly, under thrombocytopenic conditions, haematopoietic progenitors migrate out of the lung to repopulate the bone marrow and completely reconstitute blood platelet counts.31
B. Predilection of cerebral venous sinuses for thrombosis following vaccination
Recent studies have demonstrated that arterial, venous and sinusoidal endothelial cells in the brain uniquely express markers of the lymphatic endothelium including podoplanin.32 Podoplanin serves as a ligand for CLEC2 receptors on platelets.33 Thromboxane A2 dependent CLEC2 signaling leads to platelet activation (Figure 1), while a TxA2 receptor antagonist nearly abolish CLEC2 signaling and platelet activation.33 TxA2 dependent CLEC2 signaling promotes release of exosomes and microvesicles from platelets, leading to activation of CLEC5A and TLR2 receptors respectively on neutrophils, neutrophil activation and release of neutrophil extracellular traps (NETs) (Figure 1).34 Neutrophil activation, more than platelet activation, is associated with thrombotic complications in COVID-19.13,18,35 As proposed above, the expression of podoplanin, a unique molecular signature of cerebral endothelial cells, may be responsible for the predilection of brain vascular bed to thromboinflammation and CVST as a complication of COVID-19 vaccines. 5
C. Chemoprophylaxis with antiplatelet agents
In animal models of endotoxin mediated endothelial injury and thromboinflammation, antagonism of TxA2 signaling prevents ARDS, reduces myocardial damage and increases survival.36-38
Considering the key role played by platelets in thromboinflammation, we propose consideration of antiplatelet agents, either aspirin or TxA2 receptor antagonists, as chemoprophylactic agents when the AstraZeneca vaccine is administered to adults between 18 and 60 years of age.39 High bleeding risk because of another medical condition or medication would be contraindications to use of antiplatelet agents.39 Medical conditions that increase bleeding risk include previous gastrointestinal bleeding, peptic ulcer disease, blood clotting problems, and kidney disease.39 Medications that increase bleeding risk include nonsteroidal anti-inflammatory drugs, steroids, and other anticoagulants or anti-platelet agents.39 Aspirin appears to be safe in COVID-19. In a retrospective observational study in hospitalized patients with COVID-19, low-dose aspirin was found to be effective in reducing morbidity and mortality; and was not associated with any safety issues including major bleeding.40 Therefore, aspirin is likely to be safe as an adjunct to COVID-19 vaccines even in the event of a subsequent infection with SARS-CoV-2 virus.
Can aspirin influence the host immune response to the COVID-19 vaccines? This issue merits further investigation. When healthy adults > 65 years of age were given influenza vaccine and randomized to receive 300 mg aspirin or placebo on days 1, 2, 3, 5 and 7, the aspirin group showed 4-fold or greater rise in influenza specific antibodies.41 The risk-benefit analysis, based on above information, suggests that a one to three week course of low-dose aspirin merits consideration in order to prevent the thromboembolic events associated with the AstraZeneca vaccine.
SUMMARY
Thromboembolic disease including disseminated intravascular coagulation and cerebral venous sinus thrombosis have been reported in association with AstraZeneca and Janssen COVID-19 vaccines. Many countries have halted use of these vaccines either entirely or for adults under 30 to 60 years of age. European and North American countries generally have access to mRNA vaccines. However, in Asian and African countries the choices are limited to adenovirus based COVID-19 vaccines. The governments in such countries are forging ahead with vaccinating all adults, including those under 60 years of age, with Vaxzevria, Covishield (the version of Vaxzevria manufactured by the Serum Institute of India) or the Janssen vaccines. This has led to grave concern and anxiety amongst the citizens and medical professionals. Considering the profound global public health implications of limiting the use of these vaccines, it is critical to understand the pathobiology of vaccination induced thrombotic events in order to guide strategies aimed at prevention. In this regard, studies are urgently needed to examine lipid mediators and thromboxane A2 – platelet axis following vaccination with these vaccines, compared with mRNA vaccines. The risk-benefit analysis based on information presented here suggests that chemoprophylaxis using a short course of low-dose aspirin in adults under 60 years of age may be justified in conjunction with adenovirus based COVID-19 vaccines in order to prevent thromboembolic events and enhance safety. 6
Figure 1. AstraZeneca or Janssen COVID-19 vaccine induced thromboinflammation and cerebral venous sinus thrombosis (CVST)-Proposed Mechanisms: Adenovirus carrier delivers SARS-CoV-2 DNA encoding the Spike (S) protein to the lung megakaryocytes via the coxsackie-adenovirus receptor (CAR). Spike protein induces COX-2 expression in megakaryocytes leading to megakaryocyte activation, biogenesis of activated platelets that express COX-2 and generate thromboxane A2 (TxA2). Cerebral vein sinus endothelial cells express podoplanin, a natural ligand for CLEC2 receptors on platelets. Platelets traversing through the cerebral vein sinuses would be further activated by TxA2 dependent podoplanin-CLEC2 signaling, leading to release of extracellular vesicles, thereby promoting CLEC5A and TLR2 mediated neutrophil activation, thromboinflammation, CVST, and thromboembolism in other vascular beds. Young age and female gender are associated with increased TxA2 generation and platelet activation respectively, and hence increased risk of thromboembolic complications following vaccination.
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Subject: APRIL 13. 2021 – J&J Statement – Out of an abundance of caution, the CDC and FDA have recommended a pause in the use of our vaccine. ->> Are there relations between these FINDINGS?
Johnson & Johnson Statement on COVID-19 Vaccine
NEW BRUNSWICK, N.J., April 13, 2021– The safety and well-being of the people who use our products is our number one priority. We are aware of an extremely rare disorder involving people with blood clots in combination with low platelets in a small number of individuals who have received our COVID-19 vaccine. The United States Centers for Disease Control (CDC) and Food and Drug Administration (FDA) are reviewing data involving six reported U.S. cases out of more than 6.8 million doses administered. Out of an abundance of caution, the CDC and FDA have recommended a pause in the use of our vaccine.
In addition, we have been reviewing these cases with European health authorities. We have made the decision to proactively delay the rollout of our vaccine in Europe.
We have been working closely with medical experts and health authorities, and we strongly support the open communication of this information to healthcare professionals and the public.
The CDC and FDA have made information available about proper recognition and management due to the unique treatment required with this type of blood clot. The health authorities advise that people who have received our COVID-19 vaccine and develop severe headache, abdominal pain, leg pain, or shortness of breath within three weeks after vaccination should contact their health care provider.
For more information on the Janssen COVID-19 vaccine, click here.
Please All send me your Expert Opinion on the relations between these FINDINGS?
Linking Thrombotic Thrombocytopenia to ChAdOx1 nCov-19 Vaccination, AstraZeneca | Leaders in Pharmaceutical Business Intelligence (LPBI) Group
Glycosylation and its Role in SARS-CoV-2 Viral Pathogenesis
Author: Meg Baker, PhD
N-Glycosylation and COVID19
Glycobiology
N-linked glycosylation (NLG) is a complex biosynthetic process that regulates proper folding of proteins through and intracellular transport of proteins to the secretory pathway. This co- and post-translational modification occurs by a series of enzymatic reactions, which results in the transfer of a core glycan from the lipid carrier to a protein substrate and the possibility for further remodeling of the glycan. The enzymes are located in the cytosolic and the luminal side of the ER membrane. The study of NLG and related effects of glycans is called glycobiology.
NLG takes place at sites specified in the protein sequence itself. N-linked oligosaccharides are attached via a GlcNAc linked to the side chain nitrogen of Asn found in the consensus sequence NXT/S (X ≠ P) known as the ‘glycosylation sequon’. Formation of a precursor branched carbohydrate chain, the lipid-linked oligosaccharide (LLO) structure, takes place in the endoplasmic reticulum. The LLO consists of a Glc3Man9GlcNAc2 molecule (three glucose, nine mannose, and two N-acetylglucosamine sugars) linked to a dolicholpyrophosphate. The enzyme oligosaccharyltransferase then moves it to an Asn in the polypeptide.
The removal of the three glucose sugars from the new N-linked glycan signals that the structure is ready for transport to the Golgi where mannose is removed yielding a carbohydrate chain containing five–nine mannose sugars. Further removal of mannose residues can lead to the core structure containing three mannose and two N-acetylglucosamine residues, which may then be elongated with a variety of different monosaccharides including galactose, N-acetylglucosamine (aka NAG or GlcNac), N-acetylgalactosamine, fucose, and sialic acid, many of which can also exist in sulfated form.
The enzymes involved in this essential process are evolutionarily conserved. However, the genes and their specific functions, have evolved uniquely for each selected organism. Therefore, each organism and each individual cell, depending on genetic background and influenced by nutritional and such things as disease status, will decorate secreted proteins in a unique manner.
The advent of biologic medicines (protein based therapeutics) presents the challenge of making sure that the primary protein sequence is specified but also that the manufacture of the protein – typically in a eukaryotic cell host capable of glycosylation – will take place with some degree of reproducibility. The large number of monoclonal antibody therapeutics absolutely require glycosylation for proper structural integrity but are generally made in rodent or other nonhuman cells. Thus, the term “biosimilar” rather than generic is the term being used to connote the variation which will necessarily result due to different manufacturing process even of the same genetic sequence.
Viral Glycoproteins
It should be obvious that the viral genome is not large enough to encompass the collection of enzymes required for glycosylation of any type and viral glycoproteins are formed by the host cell in which the virus is replicating. The study of the impact of glycan content and composition on viral infectivity and, more importantly, vaccine development is a subject which has been late to be addressed largely due to the technical difficulty and lack of methods for analyzing protein glycan composition. However, progress is being made. Raska et al. (J Biol Chem 2010 Jul 2; 285(27): 20860–20869. Glycosylation Patterns of HIV-1 gp120 Depend on the Type of Expressing Cells and Affect Antibody Recognition) was able to perform such an analysis on the HIV-1 virus albeit almost 30 years after its emergence in human populations. The findings of this study may explain, in part, the difficulty in developing a vaccine against HIV.
SARS-CoV-2 spike protein (P0DTC2 uniprot.org) – as so popularly depicted – is a trimer poking out of the lipid coat that protects it’s genome. The spike protein, like gp120 in HIV, is the point of contact with the human cell ACE2 receptor it uses to gain entry. The spike protein contains two functional external subunits, designated S1 and S2. S1 separated by a furin cleavage site from S2, forms the apex of the trimeric spike structure, is responsible for attachment to the ACE2 receptor. S2 is responsible for fusion to the cell membrane. (PDB: 6VSB shows a 3D image of the protein structure, including glycan positions). There are 22 glycans per polypeptide or 66 per spike trimer protein (Watanabe et al. 2021 Site-specific glycan analysis of the SARS-CoV-2 spike. Science 17 Jul 2020:Vol. 369, Issue 6501, pp. 330-333 ).
Although shielding of receptor binding sites by glycans is a common feature of viral glycoproteins, Watanabe (ibid) note the low mutation rate of SARS-CoV-2 and that as yet, there have been no observed mutations to N-linked glycosylation sites.
The development of a vaccine or individual antibodies or antibody cocktails with neutralizing (viral entry blocking or virocidal activity) is also influenced by the presence or absence of glycans and how well they target the natural conformation of the spike protein. Papageorgiou et al. The SARS-CoV-2 Spike Glycoprotein as a Drug and Vaccine Target: Structural Insights into Its Complexes with ACE2 and Antibodies. Cells 2020 Oct 22;9(11):2343. doi: 10.3390/cells9112343.SARS-CoV-2 Spike – Stanford Coronavirus Antiviral Research Database It should be noted that the mRNA vaccines (or other nucleic acid formats) may obviate these analysis because the immune response is to a spike protein made and glycosylated in the human host’s own body and therefore will be customized to each individual in some sense.
Glycans may themselves represent drug targets. Casolino et al. suggest an essential structural role of N-glycans at sites N165 and N234 in modulating the conformational dynamics of the spike’s receptor binding domain (RBD), which is responsible for ACE2 recognition (Casolino et al. 2020. Beyond Shielding: The Roles of Glycans in the SARS-CoV-2 Spike Protein ACS Cent Sci. 2020 Oct 28; 6(10): 1722–1734),
COVID19 Variants
SARS-CoV-2 lineage B.1.1.7 likely arose in the United Kingdom in September 2019 and is characterized by 17 mutations, including 8 in the spike protein (Rambaut et al., 2020). Other lineages, including B.1.351, initially detected in South Africa (Tegally et al., 2020), and most recently lineage P.1, first documented in the Amazonia region of Brazil (Faria et al., 2020), carry additional mutations. All three lineages are characterised by a N501Y (Asn to Tyr) mutation in the spike protein, while both B.1.351 and P.1 also carry the spike mutation E484K. In addition, both B.1.1.7 and B.1.351, but not P.1, have acquired short sequence deletions in the spike protein. N501Y is in the receptor-binding domain (RBD) but is not a glycosylation site.
Comparing COVID-19 Vaccine Schedule Combinations, or “Com-COV” – First-of-its-Kind Study will explore the Impact of using eight different Combinations of Doses and Dosing Intervals for Different COVID-19 Vaccines
Reporter: Aviva Lev-Ari, PhD, RN
The UK’s COVID-19 vaccine rollout commenced in December, and requires an individual to receive two doses of the same vaccine, either Pfizer/BioNTech’s BNT162b2 or AstraZeneca/Oxford’s ChAdOx1, with a maximum interval of 12 weeks between doses. As of February 3, 10 million first doses have been administered.
Com-COV has been classified as an “Urgent Public Health” study by the National Institutes for Health and Research (NIHR), and it’s hoped that the data produced may offer greater flexibility for vaccine delivery going forward.
“Given the inevitable challenges of immunizing large numbers of the population against COVID-19 and potential global supply constraints, there are definitely advantages to having data that could support a more flexible immunization program, if ever needed and approved by the medicines regulator,” –Jonathan Van-Tam, deputy chief medical officer and senior responsible officer for the study, said in a press release.
The study will run for a 13-month period and will recruit over 800 patients across eight sites in the UK, including London – St George’s and UCL, Oxford, Southampton, Birmingham, Bristol, Nottingham and Liverpool.
Com-COV has eight different arms that will test eight different combinations of doses and dose intervals. This is tentative and subject to change should more COVID-19 vaccines be approved for use in the UK. The eight arms include the following dose combinations:
Pfizer/BioNTech and Pfizer/BioNTech – 28 days apart
Pfizer/BioNTech and Pfizer/BioNTech – 12 weeks apart – (control group)
Oxford/AstraZeneca and Oxford/AstraZeneca – 28 days apart
Oxford/AstraZeneca and Oxford/AstraZeneca – 12 weeks apart – (control group)
Oxford/AstraZeneca and Pfizer/BioNTech – 28 days apart
Oxford/AstraZeneca and Pfizer/BioNTech – 12 weeks apart
Pfizer/BioNTech and Oxford/AstraZeneca – 28 days apart
Pfizer/BioNTech and Oxford/AstraZeneca – 12 weeks apart
Aside from the logistical benefits of using alternative vaccines, there is scientific value to exploring how different vaccines and doses affect the human immune system.
Dr Peter English, consultant in communicable disease control, pointed out that the antigen used across the currently authorized COVID-19 vaccines is the same Spike protein. Therefore, the immune system can be expected to respond just as well if a different product is used for boosting. “It is also the case that many vaccines work better if a different vaccine is used for boosting – an approach described as heterologous boosting,” English said, referencing previously successful trials using Hepatitis B vaccines.
“It is also even possible that by combining vaccines, the immune response could be enhanced giving even higher antibody levels that last longer; unless this is evaluated in a clinical trial we just won’t know,” added Van-Tam.
If warranted by the study data, the Medicines and Healthcare products Regulatory Agency may consider reviewing and authorizing modifications to the UK’s vaccine regimen approach – but only time will tell.
“We need people from all backgrounds to take part in this trial, so that we can ensure we have vaccine options suitable for all. Signing up to volunteer for vaccine studies is quick and easy via the NHS Vaccine Research Registry,” Professor Andrew Ustianowski, national clinical lead for the NIHR COVID Vaccine Research Program, said
SOURCE
First-of-its-Kind Study Will Test Combination of Different COVID-19 Vaccines | Technology Networks
Human coronaviruses (HCoVs) were first isolated from patients with the common cold in the 1960s [1–3]. Seven HCoVs known to cause disease in humans have since been identified: HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1, the SARS coronavirus (SARS-CoV), the Middle East respiratory syndrome coronavirus and the novel SARS-CoV-2 [4]. The latter was identified after a spike in cases of pneumonia of unknown etiology in Wuhan, Hubei Province, China during December 2019 and was initially named novel coronavirus (2019-nCoV) [5,6]. The virus was renamed SARS-CoV-2 according to the International Committee on Taxonomy of Viruses classification criteria due to its genomic closeness to SARS-CoV; the disease caused by this virus was named coronavirus disease (COVID-19) according to the WHO criteria for naming emerging diseases [7]. SARS-CoV-2 belongs to the genera Betacoronavirus and shares a different degree of genomic similarity with the other two epidemic coronaviruses: SARS-CoV (∼79%) and Middle East respiratory syndrome coronavirus (∼50%) [8].
COVID-19 has caused considerable morbidity and mortality worldwide and has become the central phenomenon that is shaping our current societies. Human-to-human transmission is the main route of spread of the virus, mainly through direct contact, respiratory droplets and aerosols [9–12]. Management of COVID-19 has been extremely challenging due to its high infectivity, lack of effective therapeutics and potentially small groups of individuals (i.e., asymptomatic or mild disease) rapidly spreading the disease [13–17]. Although research describing COVID-19 and the mechanisms of infection by SARS-CoV-2 and its pathogenesis has expanded rapidly, there is still much to be learnt. Important gaps in knowledge which remain to be elucidated are the dynamic and complex interactions between the virus and the host’s immune system, as well as the potential interspecies communications occurring between ecological niches encompassing distinct microorganisms in both healthy individuals and persons living with chronic diseases, and how these interactions could determine or modulate disease progression and outcomes.
In this review, we describe recent insights into these topics, as well as remaining questions whose answers will allow us to understand how interactions between the virus, the immune system and microbial components could possibly be related to disease states in patients with COVID-19, as well as existing studies of the microbiome in patients with COVID-19.
Science’s COVID-19 reporting is supported by the Pulitzer Center and the Heising-Simons Foundation.
Researchers have used CRISPR gene-editing technology to come up with a test that detects the pandemic coronavirus in just 5 minutes. The diagnostic doesn’t require expensive lab equipment to run and could potentially be deployed at doctor’s offices, schools, and office buildings.
“It looks like they have a really rock-solid test,” says Max Wilson, a molecular biologist at the University of California (UC), Santa Barbara. “It’s really quite elegant.”
CRISPR diagnostics are just one way researchers are trying to speed coronavirus testing. The new test is the fastest CRISPR-based diagnostic yet. In May, for example, two teams reported creating CRISPR-based coronavirus tests that could detect the virus in about an hour, much faster than the 24 hours needed for conventional coronavirus diagnostic tests.CRISPR tests work by identifying a sequence of RNA—about 20 RNA bases long—that is unique to SARS-CoV-2. They do so by creating a “guide” RNA that is complementary to the target RNA sequence and, thus, will bind to it in solution. When the guide binds to its target, the CRISPR tool’s Cas13 “scissors” enzyme turns on and cuts apart any nearby single-stranded RNA. These cuts release a separately introduced fluorescent particle in the test solution. When the sample is then hit with a burst of laser light, the released fluorescent particles light up, signaling the presence of the virus. These initial CRISPR tests, however, required researchers to first amplify any potential viral RNA before running it through the diagnostic to increase their odds of spotting a signal. That added complexity, cost, and time, and put a strain on scarce chemical reagents. Now, researchers led by Jennifer Doudna, who won a share of this year’s Nobel Prize in Chemistry yesterday for her co-discovery of CRISPR, report creating a novel CRISPR diagnostic that doesn’t amplify coronavirus RNA. Instead, Doudna and her colleagues spent months testing hundreds of guide RNAs to find multiple guides that work in tandem to increase the sensitivity of the test.
That’s still not as good as the conventional coronavirus diagnostic setup, which uses expensive lab-based machines to track the virus down to one virus per microliter, says Melanie Ott, a virologist at UC San Francisco who helped lead the project with Doudna. However, she says, the new setup was able to accurately identify a batch of five positive clinical samples with perfect accuracy in just 5 minutes per test, whereas the standard test can take 1 day or more to return results.
The new test has another key advantage, Wilson says: quantifying a sample’s amount of virus. When standard coronavirus tests amplify the virus’ genetic material in order to detect it, this changes the amount of genetic material present—and thus wipes out any chance of precisely quantifying just how much virus is in the sample.
By contrast, Ott’s and Doudna’s team found that the strength of the fluorescent signal was proportional to the amount of virus in their sample. That revealed not just whether a sample was positive, but also how much virus a patient had. That information can help doctors tailor treatment decisions to each patient’s condition, Wilson says.
Doudna and Ott say they and their colleagues are now working to validate their test setup and are looking into how to commercialize it.
In 13 Viewpoints in this issue,2–14 JAMA Network editors reflect on the clinical, public health, operational, and workforce issues related to COVID-19 in each of their specialties. Questions and concerns they identify in their clinical communities include the following:
Benefits and harms of treatments and identifying mortality risk markers beyond age and comorbidities
Cardiovascular consequences of COVID-19 infection, including risks to those with comorbid hypertension and risks for myocardial injury
Risk for direct central nervous system invasion and COVID-19 encephalitis and for long-term neuropsychiatric manifestations in a post–COVID-19 syndrome
Risks related to SARS-CoV-2 infection for patients with compromised immunity, such as those receiving treatment for cancer
Challenges unique to patients with acute kidney injury and chronic kidney disease
Risks of viral transmission from aerosol-generating procedures, including most minimally invasive surgeries, and the need for eye protection as well as personal protective equipment as part of universal precautions
The prevalence and pathophysiology of skin findings in patients with COVID-19, determining if they are primary or secondary cutaneous manifestations of infection, and how best to manage them
The prevalence and significance of eye findings in patients with COVID-19 and the risk of transmission and infection through ocular surfaces
The role of anticoagulation for managing the endotheliopathy and coagulopathy characteristic of the infection in some patients
Developmental effects on children of the loss of family routines, finances, older loved ones, school and education, and social-based activities and milestone events
Effects of the pandemic, mitigation efforts, and economic downturn on the mental health of patients and frontline clinicians
Seasonality of transmission as the pandemic enters its third season
How to implement reliable seroprevalence surveys to document progression of the pandemic and effects of public health measures
Effects of the pandemic on access to care and the rise of telehealth
Consequences of COVID-19 for clinical capabilities, such as workforce availability in several specialties, delays in performing procedures and operations, and implications for medical education and resident recruitment.
Additional important questions that require careful observation and research include
Randomized evaluations of treatment: what is effective and safe, and what timing of which drug will reduce morbidity and mortality? Will a combination of therapies be more effective than any single drug?
Randomized evaluations of preventive interventions, including convalescent plasma, monoclonal antibodies, and vaccines. Which are effective and safe enough to prevent COVID-19 at a population level?
How can COVID-19 vaccines and therapeutics be distributed and paid for in ways that are fair and equitable?
Is immunity complete or partial, permanent or temporary, what is its mechanism, and how best is it measured? Can the virus mutate around host defenses?
How important are preadolescent children to the spread of infection to older family members and adult communities, and what are the implications for parent, caregiver, and teacher personal risk and disease transmission?
Is SARS-CoV-2 like influenza (continually circulating without or with seasonality), measles (transmissible but containable beneath threshold limits), or smallpox and polio (eradicable, or nearly so)?
Has the pandemic fundamentally altered the way health care is financed and delivered? By shining a spotlight on health inequities, can the pandemic motivate changes in health care finance, organization, and delivery to reduce those inequities?
The initial reports on the epidemiology of coronavirus disease 2019 (COVID-19) emanating from Wuhan, China, offered an ominous forewarning of the risks of severe complications in elderly patients and those with underlying cardiovascular disease, including the development of acute respiratory distress syndrome, cardiogenic shock, thromboembolic events, and death. These observations have been confirmed subsequently in numerous reports from around the globe, including studies from Europe and the US. The mechanisms responsible for this vulnerability have not been fully elucidated, but there are several possibilities. Some of these adverse consequences could reflect the basic fragility of older individuals with chronic conditions subjected to the stress of severe pneumonia similar to influenza infections. In addition, development of type 2 myocardial infarction related to increased myocardial oxygen demand in the setting of hypoxia may be a predominant concern, and among patients with chronic coronary artery disease, an episode of acute systemic inflammation might also contribute to plaque instability, thus precipitating acute coronary syndromes, as has also been reported during influenza outbreaks.
However, in the brief timeline of the current pandemic, numerous publications highlighting the constellation of observed cardiovascular consequences have emphasized certain distinctions that appear unique to COVID-19.1 Although the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) gains entry via the upper respiratory tract, its affinity and selective binding to the angiotensin-converting enzyme 2 (ACE2) receptor, which is abundant in the endothelium of arteries and veins as well as in the respiratory tract epithelium, create a scenario in which COVID-19 is as much a vascular infection as it is a respiratory infection with the potential for serious vascular-related complications. This may explain why hypertension is one of the cardiovascular conditions associated with adverse outcomes. In the early stages of the pandemic, the involvement of the ACE2 receptor as the target for viral entry into cells created concerns regarding the initiation or continuation of treatment with ACE inhibitors and angiotensin receptor antagonists in patients with hypertension, left ventricular dysfunction, or other cardiac conditions. Subsequently, many studies have shown that these drugs do not increase susceptibility to infection or increase disease severity in those who contract the disease,2 thus supporting recommendations from academic societies that these drugs should not be discontinued in patients who develop COVID-19 infections.
Thrombosis, arterial or venous, is a hallmark of severe COVID-19 infections, related both to vascular injury and the prothrombotic cytokines released during the intense systemic inflammatory and immune responses.3 This sets the stage for serious thrombotic complications including acute coronary syndromes, ischemic strokes, pulmonary embolism, and ischemic damage to multiple other organ systems. Such events can complicate the course of any patient with COVID-19 but would be particularly devasting to individuals with preexisting cardiovascular disease.
Another unique aspect of COVID-19 infections that is not encountered by patients with influenza is myocardial injury, manifested by elevated levels of circulating troponin, creatinine kinase-MB, and myoglobin. Hospitalized patients with severe COVID-19 infections and consequent evidence of myocardial injury have a high risk of in-hospital mortality.4 Troponin elevations are most concerning, and when accompanied by elevations of brain natriuretic peptide, the risk is further accentuated. Although myocardial injury could reflect a COVID-19–related acute coronary event, most patients with troponin elevations who undergo angiography do not have epicardial coronary artery obstruction. Rather, those with myocardial injury have a high incidence of acute respiratory distress syndrome, elevation of D-dimer levels, and markedly elevated inflammatory biomarkers such as C-reactive protein and procalcitonin, suggesting that the combination of hypoxia, microvascular thrombosis, and systemic inflammation contributes to myocardial injury. Myocarditis is a candidate explanation for myocardial injury but has been difficult to confirm consistently. However, features of myocarditis have been reported in case reports5 based on clinical presentation and results of noninvasive imaging, but thus far confirmation of myocarditis based on myocardial biopsy or autopsy examinations has been a rare finding.6 Instead, myocardial tissue samples more typically show vascular or perivascular inflammation (endothelialitis) without leukocytic infiltration or myocyte damage.
There remain important unknowns regarding the intermediate and long-term sequelae of COVID-19 infection among hospital survivors. In an autopsy series of patients who died from confirmed COVID-19 without clinical or histological evidence of fulminant myocarditis,7 viral RNA was identified in myocardial tissue in 24 of 39 cases, with viral load of more than 1000 copies/μg of RNA in 16 cases. A cytokine response panel demonstrated upregulation of 6 proinflammatory genes (tumor necrosis factor, interferon γ, CCL4, and interleukin 6, 8, and 18) in the 16 myocardial samples with the high viral RNA levels.
Whether a subclinical viral load and associated cytokine response such as this in survivors of COVID-19 could translate into subsequent myocardial dysfunction and clinical heart failure require further investigation. However, the results of a recent biomarker and cardiac magnetic resonance (CMR) imaging study provide evidence to support this concern.6 Among 100 patients who were studied by CMR after recovery from confirmed COVID-19 infection, of whom 67 did not require hospitalization during the acute phase, left ventricular volume was greater and ejection fraction was lower than that of a control group. Furthermore, 78 patients had abnormal myocardial tissue characterization by CMR, with elevated T1 and T2 signals and myocardial hyperenhancement consistent with myocardial edema and inflammation, and 71 patients had elevated levels of high-sensitivity troponin T. Three patients with the most severe CMR abnormalities underwent myocardial biopsy, with evidence of active lymphocytic infiltration.6 It is noteworthy that all 100 patients in this series had negative COVID-19 test results at the time of CMR study (median, 71 days; interquartile range [IQR], 64-92 days after acute infection). The results of these relatively small series should be interpreted cautiously until confirmed by larger series with longer follow-up and with confirmed clinical outcomes. But the findings do underscore the uncertainty regarding the long-term cardiovascular consequences of COVID-19 in patients who have ostensibly recovered. Of note, a randomized clinical trial of anticoagulation to reduce the risk of thrombotic complications in the posthospital phase of COVID-19 infection is under development through the National Institutes of Health’s set of ACTIV (Accelerating COVID-19 Therapeutic Interventions and Vaccines) initiatives.
In addition, the indirect effects of COVID-19 have become a major concern. Multiple observations during the COVID-19 pandemic confirm a sudden and inexplicable decline in rates of hospital admissions for ST–segment elevation myocardial infarction and other acute coronary syndromes beginning in March and April 2020. This has been a universal experience, with similar findings reported from multiple countries around the world in single-center observations, multicenter registries, and national databases. A concerning increase in out-of-hospital cardiac arrests has also been reported.8 These data suggest that COVID-19 has influenced health care–seeking behavior resulting in fewer presentations of acute coronary syndromes in emergency departments and more out-of-hospital events. Failure to seek appropriate emergency cardiac care could contribute to the observations of increased number of deaths and cardiac arrests, more than the anticipated average during this period8,9 with worse outcomes among those who ultimately do seek care.10 Recent data suggest that admission rates for myocardial infarction may be returning to baseline,10 but outcomes will improve only if patients seek care promptly and hospital systems are not overwhelmed by COVID-19 surges.
Given the ongoing activity of COVID-19, very clear messaging to the public and patients should include the following: heed the warning signs of heart attack, act promptly to initiate emergency medical services, and seek immediate care in hospitals, which have taken every step needed to be safe places. And especially, the messaging should continuously underscore the most important considerations that have been extant since this crisis began—wear a mask and practice physical distancing. In the meantime, the generation of rigorous evidence to inform best practices for diagnosis and management of COVID-19–related cardiovascular disease is a global imperative.
Corresponding Author: Robert O. Bonow, MD, MS, Division of Cardiology, Northwestern University Feinberg School of Medicine, 676 N St Clair St, Ste 600, Chicago, IL 60611 (r-bonow@northwestern.edu)
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