Feeds:
Posts
Comments

Archive for the ‘Serology tests for coronavirus antibodies’ Category


Detecting SARS-COV-2 antibodies in serum and plasma samples

Reporter: Irina Robu, PhD

Convalescent plasma therapy is a possible treatment under investigation where antibodies from recovered patients are transfused to current COVID-19 patients with the intent to help them fight the infection and buy time until their immune system can produce antibodies. Yet, not all recovered patients have the same quantity of antibody titers suitable for such transfusions. In some patients it will minimize the severity of the disease length.

The U.S. Food and Drug Administration authorized convalescent plasma therapy for patients with coronavirus disease 2019 and it permitted to be used during the pandemic because there is no approved treatment for COVID-19. The donated blood is processed to remove cells, leaving behind liquid and antibody.   

Companies like Forte Bío are developing instruments such as Octet HTX Instrument, Octet RED384 Octet RED96e Instrument and Octet K2 Instrument to detect SARS-COV-2 antibodies in serum and plasma samples. The Octet technology allows quantification with high resolution comparable to an HPLC . The instrument utilizes BLI enabling label-free detection for protein quantitation and kinetic characterization at unmatched speed and throughput. The instrument can  measure up to 96 samples simultaneously allowing both unlimited characterization capacity for various applications and custom assay tailoring to maximize analytical throughput or sensitivity and preventing bottlenecks. 

 How are antibodies tested ?

  1. Immobilize a virus protein such as the receptor binding domain (RBD) of the SARS CoV-2 spike protein.
  2. Dip the coronavirus biosensor into diluted patient plasma or serum samples.
  3. Block the biosensor with non-relevant serum or blocking buffer if needed to prevent non-specific binding.

Even the researchers believe that the risk to donors is low, there are additional risks such as allergic reactions, lung damage, difficulty breathing or infections such as HIV, hepatitis B and Donated blood must be tested for safety prior to administering to patients.

What to expect ? It is up to the doctor treating the patient, if convalescent plasma therapy is an option.  Even though data from clinical trials suggest that convalescent plasma may diminish the severity or duration of the COVID19, more research is needed to determine if convalescent plasma therapy is an effective treatment.

SOURCE

https://www.fortebio.com/covid19research19research

https://www.medrxiv.org/content/10.1101/2020.07.17.20156281v1

 

Other related articles were published in this Open Access Online Scientific Journal including the following:

https://pharmaceuticalintelligence.com/2020/05/18/race-to-develop-antibody-drugs-for-covid-19

https://pharmaceuticalintelligence.com/2020/05/18/race-to-develop-antibody-drugs-for-covid-19

 

 

Read Full Post »


Read Full Post »


FDA Authorizes Convalescent Plasma for COVID-19 Patients

Reporter: Irina Robu, PhD

The U.S. Food and Drug Administration authorized convalescent plasma therapy in August 2020 for people with coronavirus disease 2019. The convalescent plasma shows promising efficacy in hospitalized patients with COVID-19 and the benefits outweighs the risk  and FDA gave emergency use authorization. The approval is not  for any particular convalescent plasma product, but for preparation collected by FDA registered blood establishments from individuals whose plasma contains anti-SARS-CoV-2 antibodies, and who meet all donor eligibility requirements.

What exactly is convalescent plasma ? It is blood donated from patients who have recovered from COVID-19 has antibodies to the virus that causes it. The donated blood is processed by removing blood cells, leaving behind plasma and antibodies, which can be given to people with COVID-19 to boost their ability to fight the virus. According to FDA, COVID-19 covalescent plasma with high antibody titer can be effective in reducing mortality in hospitalized patients, but low antibody titer can be used based on health care provider discretion.  FDA also indicated that COVID-19 convalescent plasma may be effective in lessening the severity or shortening the length of COVID-19 illness in some hospitalized patients.

To confirm the results, the FDA recommended randomized trialsas COVID-19 convalescent plasma does not yet describe a new standard of care based on the current available evidence.

SOURCE

https://www.medpagetoday.com/infectiousdisease/covid19/88225?xid=NL_breakingnewsalert_2020-08-23

Read Full Post »


The Impact of COVID-19 on the Human Heart

Reporters: Justin D. Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

The Voice of Dr. Pearlman:

 

 

Editorial

September 22/29, 2020

The COVID-19 Pandemic and the JAMA Network

In 13 Viewpoints in this issue,214 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?
  • Cardiology and COVID-19

Cardiology and COVID-19 – Original Article

Bonow  RO, O’Gara  PT, Yancy  CW.  Cardiology and COVID-19.   JAMA. Published online September 22, 2020. doi:10.1001/jama.2020.15088
Article Google Scholar

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)

SOURCE

https://jamanetwork.com/journals/jama/fullarticle/2770858

Read Full Post »


Sex Differences in Immune Responses that underlie COVID-19 Disease Outcomes

Reporter: Aviva Lev-Ari, PhD, RN and Irina Robu, PhD COVID-19 is a non-discriminatory virus, it can infect anyone from young to old, but it seems that older men are twice more susceptible to it and most likely to become severely sick and die in comparison to women of the same age. Researchers from Yale university, published an article suggesting that men, particularly those over the age of 60 may need to depend more on vaccines to protect themselves from infection. According to their research published in Nature in August 2020, known sex differences between men and women pose challenges to the immune system. Women mount faster and stronger immune responses, possibly because their bodies are equipped to fight pathogens that threaten unborn or newborn children. Over time, an immune system in a constant state of high alert can be harmful. The findings underline the necessity for companies developing coronavirus vaccines to analyze their data by sex and may influence decisions about dosing. Dr. Iwasaki’s team from Yale  analyzed immune responses in 17 men and 22 women who were admitted to the hospital soon after they were infected with the coronavirus. The investigators collected blood, nasopharyngeal swabs, saliva, urine and stool from the patients every three to seven days. The researchers also analyzed data from an additional 59 men and women who did not meet those criteria. Over all, the scientists found, the women’s bodies produced more T cells, which can kill and stop the infection from spreading. Men on the other hand presented  a much weaker activation of T cells and that delay was linked to how sick the men became. The older the men, the weaker their T cell responses. Even though the study provided some more information about why men become sicker when diagnosed with coronavirus than women,  it did not offer a clear reason for the differences between men and women. SOURCE https://www.nature.com/articles/s41586-020-2700-3
Article

This is an unedited manuscript that has been accepted for publication. Nature Research are providing this early version of the manuscript as a service to our authors and readers. The manuscript will undergo copyediting, typesetting and a proof review before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers apply.

Sex differences in immune responses that underlie COVID-19 disease outcomes

Abstract

A growing body of evidence indicates sex differences in the clinical outcomes of coronavirus disease 2019 (COVID-19)1–5. However, whether immune responses against SARS-CoV-2 differ between sexes, and whether such differences explain male susceptibility to COVID-19, is currently unknown. In this study, we examined sex differences in
  • viral loads,
  • SARS-CoV-2-specific antibody titers,
  • plasma cytokines, as well as
  • blood cell phenotyping in COVID-19 patients.
By focusing our analysis on patients with moderate disease who had not received immunomodulatory medications, our results revealed that
  • male patients had higher plasma levels of innate immune cytokines such as IL-8 and IL-18 along with more robust induction of non-classical monocytes. In contrast,
  • female patients mounted significantly more robust T cell activation than male patients during SARS-CoV-2 infection, which was sustained in old age.
  • Importantly, we found that a poor T cell response negatively correlated with patients’ age and was associated with worse disease outcome in male patients, but not in female patients.
  • Conversely, higher innate immune cytokines in female patients associated with worse disease progression, but not in male patients.
  • These findings reveal a possible explanation underlying observed sex biases in COVID-19, and provide an important basis for the development of
  • a sex-based approach to the treatment and care of men and women with COVID-19.

Author information

Affiliations

Consortia

Corresponding author

Correspondence to Akiko Iwasaki.

Read Full Post »


Did FDA Reverse Course on Convalescent Plasma Therapy for COVID-19?

Reporter: Stephen J. Williams, PhD

 

Starting with a timeline of recent announcements by the FDA on convalescent plasma therapy

April 16, 2020

FDA STATEMENT

Coronavirus (COVID-19) Update: FDA Encourages Recovered Patients to Donate Plasma for Development of Blood-Related Therapies

 

As part of the all-of-America approach to fighting the COVID-19 pandemic, the U.S. Food and Drug Administration has been working with partners across the U.S. government, academia and industry to expedite the development and availability of critical medical products to treat this novel virus. Today, we are providing an update on one potential treatment called convalescent plasma and encouraging those who have recovered from COVID-19 to donate plasma to help others fight this disease.

Convalescent plasma is an antibody-rich product made from blood donated by people who have recovered from the disease caused by the virus. Prior experience with respiratory viruses and limited data that have emerged from China suggest that convalescent plasma has the potential to lessen the severity or shorten the length of illness caused by COVID-19. It is important that we evaluate this potential therapy in the context of clinical trials, through expanded access, as well as facilitate emergency access for individual patients, as appropriate.

The response to the agency’s recently announced national efforts to facilitate the development of and access to convalescent plasma has been tremendous. More than 1,040 sites and 950 physician investigators nationwide have signed on to participate in the Mayo Clinic-led expanded access protocol. A number of clinical trials are also taking place to evaluate the safety and efficacy of convalescent plasma and the FDA has granted numerous single patient emergency investigational new drug (eIND) applications as well.

Source: https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-encourages-recovered-patients-donate-plasma-development-blood

August 23, 2020

 

Recommendations for Investigational COVID-19 Convalescent Plasma

 

  • FDA issues guidelines on clinical trials and obtaining emergency enrollment concerning convalescent plasma

FDA has issued guidance to provide recommendations to health care providers and investigators on the administration and study of investigational convalescent plasma collected from individuals who have recovered from COVID-19 (COVID-19 convalescent plasma) during the public health emergency.

The guidance provides recommendations on the following:

Because COVID-19 convalescent plasma has not yet been approved for use by FDA, it is regulated as an investigational product.  A health care provider must participate in one of the pathways described below.  FDA does not collect COVID-19 convalescent plasma or provide COVID-19 convalescent plasma.  Health care providers or acute care facilities should instead obtain COVID-19 convalescent plasma from an FDA-registered blood establishment.

Excerpts from the guidance document are provided below.

Background

The Food and Drug Administration (FDA or Agency) plays a critical role in protecting the United States (U.S.) from threats including emerging infectious diseases, such as the Coronavirus Disease 2019 (COVID-19) pandemic.  FDA is committed to providing timely guidance to support response efforts to this pandemic.

One investigational treatment being explored for COVID-19 is the use of convalescent plasma collected from individuals who have recovered from COVID-19.  Convalescent plasma that contains antibodies to severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2 (the virus that causes COVID-19) is being studied for administration to patients with COVID-19. Use of convalescent plasma has been studied in outbreaks of other respiratory infections, including the 2003 SARS-CoV-1 epidemic, the 2009-2010 H1N1 influenza virus pandemic, and the 2012 MERS-CoV epidemic.

Although promising, convalescent plasma has not yet been shown to be safe and effective as a treatment for COVID-19. Therefore, it is important to study the safety and efficacy of COVID-19 convalescent plasma in clinical trials.

Pathways for Use of Investigational COVID-19 Convalescent Plasma

The following pathways are available for administering or studying the use of COVID-19 convalescent plasma:

  1. Clinical Trials

Investigators wishing to study the use of convalescent plasma in a clinical trial should submit requests to FDA for investigational use under the traditional IND regulatory pathway (21 CFR Part 312). CBER’s Office of Blood Research and Review is committed to engaging with sponsors and reviewing such requests expeditiously. During the COVID-19 pandemic, INDs may be submitted via email to CBERDCC_eMailSub@fda.hhs.gov.

  1. Expanded Access

An IND application for expanded access is an alternative for use of COVID-19 convalescent plasma for patients with serious or immediately life-threatening COVID-19 disease who are not eligible or who are unable to participate in randomized clinical trials (21 CFR 312.305). FDA has worked with multiple federal partners and academia to open an expanded access protocol to facilitate access to COVID-19 convalescent plasma across the nation. Access to this investigational product may be available through participation of acute care facilities in an investigational expanded access protocol under an IND that is already in place.

Currently, the following protocol is in place: National Expanded Access Treatment Protocol

  1. Single Patient Emergency IND

Although participation in clinical trials or an expanded access program are ways for patients to obtain access to convalescent plasma, for various reasons these may not be readily available to all patients in potential need. Therefore, given the public health emergency that the COVID-19 pandemic presents, and while clinical trials are being conducted and a national expanded access protocol is available, FDA also is facilitating access to COVID-19 convalescent plasma for use in patients with serious or immediately life-threatening COVID-19 infections through the process of the patient’s physician requesting a single patient emergency IND (eIND) for the individual patient under 21 CFR 312.310. This process allows the use of an investigational drug for the treatment of an individual patient by a licensed physician upon FDA authorization, if the applicable regulatory criteria are met.  Note, in such case, a licensed physician seeking to administer COVID-19 convalescent plasma to an individual patient must request the eIND (see 21 CFR 312.310(b)).

To Obtain a Single Patient Emergency IND  

The requesting physician may contact FDA by completing Form FDA 3926 (https://www.fda.gov/media/98616/download) and submitting the form by email to CBER_eIND_Covid-19@FDA.HHS.gov.

FACT SHEET FOR PATIENTS AND PARENTS/CAREGIVERS EMERGENCY USE AUTHORIZATION (EUA) OF COVID-19 CONVALESCENT PLASMA FOR TREATMENT OF COVID-19 IN HOSPITALIZED PATIENTS

  • FDA issues fact sheet for patients on donating plasma

August 23, 2020

 

FDA Issues Emergency Use Authorization for Convalescent Plasma as Potential Promising COVID–19 Treatment, Another Achievement in Administration’s Fight Against Pandemic

 

Today, the U.S. Food and Drug Administration issued an emergency use authorization (EUA) for investigational convalescent plasma for the treatment of COVID-19 in hospitalized patients as part of the agency’s ongoing efforts to fight COVID-19. Based on scientific evidence available, the FDA concluded, as outlined in its decision memorandum, this product may be effective in treating COVID-19 and that the known and potential benefits of the product outweigh the known and potential risks of the product.

Today’s action follows the FDA’s extensive review of the science and data generated over the past several months stemming from efforts to facilitate emergency access to convalescent plasma for patients as clinical trials to definitively demonstrate safety and efficacy remain ongoing.

The EUA authorizes the distribution of COVID-19 convalescent plasma in the U.S. and its administration by health care providers, as appropriate, to treat suspected or laboratory-confirmed COVID-19 in hospitalized patients with COVID-19.

Alex Azar, Health and Human Services Secretary:
“The FDA’s emergency authorization for convalescent plasma is a milestone achievement in President Trump’s efforts to save lives from COVID-19,” said Secretary Azar. “The Trump Administration recognized the potential of convalescent plasma early on. Months ago, the FDA, BARDA, and private partners began work on making this product available across the country while continuing to evaluate data through clinical trials. Our work on convalescent plasma has delivered broader access to the product than is available in any other country and reached more than 70,000 American patients so far. We are deeply grateful to Americans who have already donated and encourage individuals who have recovered from COVID-19 to consider donating convalescent plasma.”

Stephen M. Hahn, M.D., FDA Commissioner:
“I am committed to releasing safe and potentially helpful treatments for COVID-19 as quickly as possible in order to save lives. We’re encouraged by the early promising data that we’ve seen about convalescent plasma. The data from studies conducted this year shows that plasma from patients who’ve recovered from COVID-19 has the potential to help treat those who are suffering from the effects of getting this terrible virus,” said Dr. Hahn. “At the same time, we will continue to work with researchers to continue randomized clinical trials to study the safety and effectiveness of convalescent plasma in treating patients infected with the novel coronavirus.”

Scientific Evidence on Convalescent Plasma

Based on an evaluation of the EUA criteria and the totality of the available scientific evidence, the FDA’s Center for Biologics Evaluation and Research determined that the statutory criteria for issuing an EUA criteria were met.

The FDA determined that it is reasonable to believe that COVID-19 convalescent plasma may be effective in lessening the severity or shortening the length of COVID-19 illness in some hospitalized patients. The agency also determined that the known and potential benefits of the product, when used to treat COVID-19, outweigh the known and potential risks of the product and that that there are no adequate, approved, and available alternative treatments.

 

August 24, 2020

Donate COVID-19 Plasma

 

  • FDA posts video and blog about how to donate plasms if you had been infected with COVID

 

https://youtu.be/PlX15rWdBbY

 

 

Please go to https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/donate-covid-19-plasma

to read more from FDA

 

 

August 25, 2020

 

CLINICAL MEMORANDUM From: , OBRR/DBCD/CRS To: , OBRR Through: , OBRR/DBCD , OBRR/DBCD , OBRR/DBCD/CRS Re: EUA 26382: Emergency Use Authorization (EUA) Request (original request 8/12/20; amended request 8/23/20) Product: COVID-19 Convalescent Plasma Items reviewed: EUA request Fact Sheet for Health Care Providers Fact Sheet for Recipients Sponsor: Robert Kadlec, M.D. Assistant Secretary for Preparedness and Response (ASPR) Office of Assistant Secretary for Preparedness and Response (ASPR) U.S. Department of Health and Human Services (HHS) EXECUTIVE SUMMARY COVID-19 Convalescent Plasma (CCP), an unapproved biological product, is proposed for use under an Emergency Use Authorization (EUA) under section 564 of the Federal Food, Drug, and Cosmetic Act (the Act),(21 USC 360bbb-3) as a passive immune therapy for the treatment of hospitalized patients with COVID-19, a serious or life-threatening disease. There currently is no adequate, approved, and available alternative to CCP for treating COVID-19. The sponsor has pointed to four lines of evidence to support that CCP may be effective in the treatment of hospitalized patients with COVID-19: 1) History of convalescent plasma for respiratory coronaviruses; 2) Evidence of preclinical safety and efficacy in animal models; 3) Published studies of the safety and efficacy of CCP; and 4) Data on safety and efficacy from the National Expanded Access Treatment Protocol (EAP) sponsored by the Mayo Clinic. Considering the totality of the scientific evidence presented in the EUA, I conclude that current data for the use of CCP in adult hospitalized patients with COVID-19 supports the conclusion that CCP meets the “may be effective” criterion for issuance of an EUA from section 564(c)(2)(A) of the Act. It is reasonable to conclude that the known and potential benefits of CCP outweigh the known and potential risks of CCP for the proposed EUA. Current data suggest the largest clinical benefit is associated with high-titer units of CCP administered early course of the disease.

Source: https://www.fda.gov/media/141480/download

 

And Today August 26, 2020

  • A letter, from Senator Warren, to Commissioner Hahn from Senate Committee asking for documentation for any communication between FDA and White House

August 25, 2020 Dr. Stephen M. Hahn, M.D. Commissioner of Food and Drugs U.S. Food and Drug Administration 10903 New Hampshire Avenue Silver Spring, MD 20993 Dear Commissioner Hahn: We write regarding the U.S. Food and Drug Administration’s (FDA) troubling decision earlier this week to issue an Emergency Use Authorization (EUA) for convalescent plasma as a treatment for coronavirus disease 2019 (COVID-19).1 Reports suggests that the FDA granted the EUA amid intense political pressure from President Trump and other Administration officials, despite limited evidence of convalescent plasma’s effectiveness as a COVID-19 treatment.2 To help us better understand whether the issuance of the blood plasma EUA was motivated by politics, we request copies of any and all communications between FDA and White House officials regarding the blood plasma EUA.

Source: https://www.warren.senate.gov/imo/media/doc/2020.08.25%20Letter%20to%20FDA%20re%20Blood%20Plasma%20EUA.pdf

…….. which may have been a response to this article

FDA chief walks back comments on effectiveness of coronavirus plasma treatment

 

From CNBC: https://www.cnbc.com/2020/08/25/fda-chief-walks-back-comments-on-effectiveness-of-coronavirus-plasma-treatment.html

PUBLISHED TUE, AUG 25 202010:45 AM EDTUPDATED TUE, AUG 25 20204:12 PM EDT

Berkeley Lovelace Jr.@BERKELEYJR

Will Feuer@WILLFOIA

KEY POINTS

  • The authorization will allow health-care providers in the U.S. to use the plasma to treat hospitalized patients with Covid-19.
  • The FDA’s emergency use authorization came a day after President Trump accused the agency of delaying enrollment in clinical trials for vaccines or therapeutics.
  • The criticism from Trump and action from the FDA led some scientists to believe the authorization, which came on the eve of the GOP national convention, was politically motivated.

FDA Commissioner Dr. Stephen Hahn is walking back comments on the benefits of convalescent plasma, saying he could have done a better job of explaining the data on its effectiveness against the coronavirus after authorizing it for emergency use over the weekend.

Commisioners responses over Twitter

https://twitter.com/SteveFDA/status/1298071603675373569?s=20

https://twitter.com/SteveFDA/status/1298071619236245504?s=20

August 26, 2020

In an interview with Bloomberg’s , FDA Commissioner Hahn reiterates that his decision was based on hard evidence and scientific fact, not political pressure.  The whole interview is at the link below:

https://www.bloomberg.com/news/articles/2020-08-25/fda-s-hahn-vows-to-stick-to-the-science-amid-vaccine-pressure?sref=yLCixKPR

Some key points:

  • Dr. Hahn corrected his initial statement about 35% of people would be cured by convalescent plasma. In the interview he stated:

I was trying to do what I do with patients, because patients often understand things in absolute terms versus relative terms. And I should’ve been more careful, there’s no question about it. What I was trying to get to is that if you look at a hundred patients who receive high titre, and a hundred patients who received low titre, the difference between those two particular subset of patients who had these specific criteria was a 35% reduction in mortality. So I frankly did not do a good job of explaining that.

  • FDA colleagues had frank discussion after the statement was made.  He is not asking for other people in HHS to retract their statements, only is concerned that FDA has correct information for physicians and patients
  • Hahn is worried that people will not enroll due to chance they may be given placebo
  • He gave no opinion when asked if FDA should be an independent agency

 

For more articles on COVID19 please go to our Coronavirus Portal at

https://pharmaceuticalintelligence.com/coronavirus-portal/

 

Read Full Post »


50,008 views
Apr 22, 2020

496K subscribers

Dmitry Korkin is a professor of bioinformatics and computational biology at Worcester Polytechnic Institute, where he specializes in bioinformatics of complex disease, computational genomics, systems biology, and biomedical data analytics. I came across Dmitry’s work when in February his group used the viral genome of the COVID-19 to reconstruct the 3D structure of its major viral proteins and their interactions with human proteins, in effect creating a structural genomics map of the coronavirus and making this data open and available to researchers everywhere. We talked about the biology of COVID-19, SARS, and viruses in general, and how computational methods can help us understand their structure and function in order to develop antiviral drugs and vaccines.
This conversation is part of the Artificial Intelligence podcast.
Support this podcast by signing up with these sponsors: – Cash App – use code “LexPodcast” and download: – Cash App (App Store): https://apple.co/2sPrUHe – Cash App (Google Play): https://bit.ly/2MlvP5w
EPISODE LINKS: Dmitry’s Website: http://korkinlab.org/ Dmitry’s Twitter: https://twitter.com/dmkorkin
Dmitry’s Paper that we discuss: https://bit.ly/3eKghEM
INFO:
Podcast website: https://lexfridman.com/ai
Apple Podcasts: https://apple.co/2lwqZIr
OUTLINE: 0:00 – Introduction 2:33 – Viruses are terrifying and fascinating 6:02 – How hard is it to engineer a virus? 10:48 – What makes a virus contagious? 29:52 – Figuring out the function of a protein 53:27 – Functional regions of viral proteins 1:19:09 – Biology of a coronavirus treatment 1:34:46 – Is a virus alive? 1:37:05 – Epidemiological modeling 1:55:27 – Russia 2:02:31 – Science bobbleheads 2:06:31 – Meaning of life
CONNECT: – Subscribe to this YouTube channel
– Support on Patreon: https://www.patreon.com/lexfridman
SOURCE

Read Full Post »


Recent Grim COVID-19 Statistics in U.S. and Explanation from Dr. John Campbell: Why We Need to be More Proactive

Reporter: Stephen J. Williams, Ph.D.

In case you have not been following the excellent daily YouTube sessions on COVID-19 by Dr. John Campbell I am posting his latest video on how grim the statistics have become and the importance of using proactive measures (like consistent use of facial masks, proper social distancing) instead of relying on reactive measures (e.g. lockdowns after infection spikes).  In addition, below the video are some notes from his presentation and some links to sites discussed within the video.

 

Notes from the video:

  • approaching 5 million confirmed cases in US however is probably an underestimation
  • 160,00 deaths as of 8/08/2020

From the University of Washington Institute for Health Metrics and Evaluation in Seattle WA

  • 295,000 US COVID-19 related deaths estimated by December 1, 2020
  • however if 95% of people in US consistently and properly wear masks could save 66,000 lives
  • however this will mean a remaining 228,271 deaths which is a depressing statistic
  • Dr. John Campbell agrees with Dr. Christopher Murray, director of the Institute for Health Metrics that “people’s inconsistent use of these measures (face masks, social distancing) is a serious problem”
  • States with increasing transmission like Colorado, Idaho, Kansas, Kentucky, Mississippi, Missouri, Ohio, Oklahoma, Oregon, and Virginia are suggested to have a lockdown when death rate reaches 8 deaths per million population however it seems we should be also focusing on population densities rather than geographic states
  • Dr. Campbell and Dr. Murray stress more proactive measures than reactive ones like lockdowns
  • if mask usage were to increase to 95% usage reimposition to shutdown could be delayed 6 to 8 weeks

 

New IHME COVID-19 Forecasts See Nearly 300,000 Deaths by December 1

SEATTLE (August 6, 2020) – America’s COVID-19 death toll is expected to reach nearly 300,000 by December 1; however, consistent mask-wearing beginning today could save about 70,000 lives, according to new data from the Institute for Health Metrics and Evaluation (IHME) at the University of Washington’s School of Medicine.The US forecast totals 295,011 deaths by December. As of today, when, thus far, 158,000 have died, IHME is projecting approximately 137,000 more deaths. However, starting today, if 95% of the people in the US were to wear masks when leaving their homes, that total number would decrease to 228,271 deaths, a drop of 49%. And more than 66,000 lives would be saved.Masks and other protective measures against transmission of the virus are essential to staying COVID-free, but people’s inconsistent use of those measures is a serious problem, said IHME Director Dr. Christopher Murray.

“We’re seeing a rollercoaster in the United States,” Murray said. “It appears that people are wearing masks and socially distancing more frequently as infections increase, then after a while as infections drop, people let their guard down and stop taking these measures to protect themselves and others – which, of course, leads to more infections. And the potentially deadly cycle starts over again.”

Murray noted that there appear to be fewer transmissions of the virus in Arizona, California, Florida, and Texas, but deaths are rising and will continue to rise for the next week or two. The drop in infections appears to be driven by the combination of local mandates for mask use, bar and restaurant closures, and more responsible behavior by the public.

“The public’s behavior had a direct correlation to the transmission of the virus and, in turn, the numbers of deaths,” Murray said. “Such efforts to act more cautiously and responsibly will be an important aspect of COVID-19 forecasting and the up-and-down patterns in individual states throughout the coming months and into next year.”

Murray said that based on cases, hospitalizations, and deaths, several states are seeing increases in the transmission of COVID-19, including Colorado, Idaho, Kansas, Kentucky, Mississippi, Missouri, Ohio, Oklahoma, Oregon, and Virginia.

“These states may experience increasing cases for several weeks and then may see a response toward more responsible behavior,” Murray said.

In addition, since July 15, several states have added mask mandates. IHME’s statistical analysis suggests that mandates with no penalties increase mask wearing by 8 percentage points. But mandates with penalties increase mask wearing by 15 percentage points.

“These efforts, along with media coverage and public information efforts by state and local health agencies and others, have led to an increase in the US rate of mask wearing by about 5 percentage points since mid-July,” Murray said. Mask-wearing increases have been larger in states with larger epidemics, he said.

IHME’s model assumes that states will reimpose a series of mandates, including non-essential business closures and stay-at-home orders, when the daily death rate reaches 8 per million. This threshold is based on data regarding when states and/or communities imposed mandates in March and April, and implies that many states will have to reimpose mandates.

As a result, the model suggests which states will need to reimpose mandates and when:

  • August – Arizona, Florida, Mississippi, and South Carolina
  • September – Georgia and Texas
  • October – Colorado, Kansas, Louisiana, Missouri, Nevada, North Carolina, and Oregon.
  • November – Alabama, Arkansas, California, Iowa, New Mexico, Oklahoma, Utah, Washington, and Wisconsin.

However, if mask use is increased to 95%, the re-imposition of stricter mandates could be delayed 6 to 8 weeks on average.

Source: http://www.healthdata.org/news-release/new-ihme-covid-19-forecasts-see-nearly-300000-deaths-december-1

 

Read Full Post »


 

Contagious

We are in the midst of a pandemic that is impacting people and society in ways that are hard to grasp. The most apparent impact is on physical health. It also effects our attitudes in society, our economy and our cultural life. Throughout history, humanity has had to face the challenge of understanding, managing and fighting viruses.

In the exhibition Contagious we are highlighting Nobel Prize-awarded researchers who have expanded our knowledge about viruses, mapped our immune system and developed vaccines. We also examine the perspectives from Literature and Economics Laureates about the impact of epidemics on life and society. Visit us at the museum or on these pages.

Museums have an important role to play in times of crisis, since they can help people tackle existential questions and provide a broader context. The Nobel Museum is about ideas that have changed the world. The Nobel Prize points to the ability of humans to find solutions to difficult challenges that we face time and time again. It is a source of hope, even in the midst of the crisis.

SOURCE

Nobel Prize Museum

https://nobelprizemuseum.se/en/whats-on/contagious/?utm_content=contagious_text

Coronavirus

On March 11 this year, the World Health Organization announced that the spread of the coronavirus should be classified as a pandemic, that is “an infectious disease that spreads to large parts of the world and affects a large proportion of the population of each country”. Today, nobody knows how many will die in this pandemic, or when, or if, we can have a vaccine against the disease.

SARS-CoV-2, or Severe acute respiratory syndrome coronavirus 2, is an RNA virus from the family coronavirus that causes the respiratory disease covid-19.

The virus was detected at the end of last year in the Wuhan sub-province of China, and in most cases causes milder disease symptoms that disappear within two weeks. But sometimes, especially in certain groups such as the elderly and people with certain other underlying illnesses, the infection becomes more severe and can in some cases lead to death.

The virus is believed to have zoonotic origin, that is, it has been transmitted to humans from another animal. Where the origin of the disease comes from, that is to say from which host animal the virus originates, is still unknown. However, the virus has close genetic similarity to a corona virus carried by some bats, which might indicate where the virus comes from.

This model shows the SARS-CoV-2 virus, which causes the illness covid-19. The globe-shaped envelope has a membrane of fat-like substances. Inside the envelope are proteins bound to RNA molecules, that contain the virus’s genes. Short spikes of proteins and longer spikes of glycoprotein stick out of the envelope and attach to receptors on the surface of attacked cells. The spikes, which are bigger at the top, give the virus its appearance reminiscent of the Sun’s corona. This where the coronavirus’s name comes from.

Testing is an important tool for tracking and preventing the spread of infection during an epidemic.

One type of test looks at if a person is infected by looking for traces of the virus’s RNA genetic material. The test is taken using a swab stick inserted into the throat. The small amounts of RNA or DNA that attach to the swab are analyzed using the PCR technique, which was invented by Kary Mullis in 1983. Ten years later he was awarded the Nobel Prize in Chemistry.

Another type of test looks for antibodies to the virus in the blood. This indicates that the person has had the disease.

https://nobelprizemuseum.se/en/coronavirus/

The first virus ever discovered

We have understood since the 19th century that many diseases are caused by microscopic bacteria that cannot be seen by the naked eye. It turned out that there were even smaller contagions: viruses. Research on viruses has been recognized with several Nobel Prizes.

https://nobelprizemuseum.se/en/the-first-virus-ever-discovered/

Spanish flu

The worst pandemic of the 20th century was the Spanish flu, which swept across the world 1918–1920.

The Spanish flu was caused by an influenza virus. American soldiers at military facilities at the end of World War I were likely an important source of its spread in Europe. The war had just ended, and the pandemic claimed even more lives than the war. Between 50 and 100 million people died in the pandemic.

The Red Cross, an international aid organization, which received the Nobel Peace Prize for its efforts during the war, also took part in fighting the Spanish flu. International Committee of the Red Cross received the prize in 1917, 1944 and 1963.

This photo shows personnel from the Red Cross providing transportation for people suffering from the Spanish flu in St. Louis, Missouri in the United States.

https://nobelprizemuseum.se/en/spanish-flu/

Polio

Polio is an illness that often affects children and young people and that can lead to permanent paralysis.

Polio is a highly infectious RNA virus belonging to the genus Enterovirus. The virus only infects humans and enters the body via droplets such as sneezing and coughing, or through contact with infected people’s feces. Usually, polio infects our respiratory and intestinal tract, but sometimes the virus spreads to the spinal cord and can then cause paralysis. The virus mainly affects children, but most of those infected show no or very mild symptoms.

Vaccines are a way to help our immune system fight viruses. The immune system is the body’s defence mechanism against attacks from viruses and bacteria. A number of Nobel Laureates have researched the immune system and contributed to the development of vaccines.

Hepatitis B

The virus can infect people without them becoming sick. Discoveries in the 1960s enabled both vaccines and tests to prevent the spread.

Hepatitis B can infect humans and apes, and is most common in West Africa and in sub-Saharan Africa. The disease also occurs in the rest of Africa, as well as in areas from the Caspian Sea through to China and Korea and further down to Southeast Asia.

Baruch Blumberg discovered the virus behind hepatitis B and developed a vaccine against the disease.

There are many varieties of hepatitis, or jaundice, that cause inflammation in the liver. When studying blood proteins from people from different parts of the world at the end of the 1960s, Baruch Blumberg unexpectedly discovered an infectious agent for hepatitis B. He showed that the infectious agent was linked to a virus of previously unknown type. The virus can infect people without them becoming sick. The discoveries enabled both vaccines and tests to prevent the spread through blood transfusions.

Baruch Blumberg was awarded the Nobel Prize in Physiology or Medicine 1976. He has summarized what the Nobel Prize meant to him.

https://nobelprizemuseum.se/en/hepatitis-b/

Yellow fever

Each year, Yellow fever causes about 30,000 deaths. The vaccine against yellow fever was produced in the 1930s. A work awarded the Nobel Prize.

Yellow fever is a serious disease caused by a virus that is spread by mosquitos in tropical areas of Africa and South America.

Each year, Yellow fever causes about 200,000 infections and 30,000 deaths. About 90% of the cases occur in Africa. The disease is common in warm, tropical climates such as South America and Africa, but it is not found in Asia.

You may think that the number of people infected would be decreasing, but since the 1980s the number of yellow fever cases has unfortunately increased. This is believed to be due to the fact that more and more people are living in cities, that we are traveling more than before, and an increased climate impact.

Since there is no cure for the disease, preventive vaccination is a very important measure. Max Theiler successfully infected mice with a virus in the 1930s, which opened the door to more in-depth studies. When the virus was transferred between mice, a weakened form of the virus was created that gave monkeys immunity. In 1937, Theiler was able to develop an even weaker version of the virus. This version could be used as a vaccine for people.

Max Theiler was awarded the Nobel Prize in Physiology or Medicine in 1951.

https://nobelprizemuseum.se/en/yellow-fever/

HIV/AIDS

In the early 1980s, reports began to emerge about young men that suffered from unusual infections and cancers that normally only affect patients with weakened immune systems. It turned out to be a previously unknown epidemic, HIV, which spread rapidly across the world.

HIV, which is an abbreviation of human immunodeficiency virus, is a sexually transmitted retrovirus that attacks our immune system. An untreated infection eventually leads to AIDS, or acquired immune deficiency syndrome. In 2008, French scientists Luc Montagnier and Françoise Barré-Sinoussi were awarded the Nobel Prize in Physiology or Medicine for the detection of human immunodeficiency virus.

Watch the interview where Françoise Barré-Sinoussi talks about what it is like to meet patients affected by the virus she discovered.

https://nobelprizemuseum.se/en/hiv-aids/

 

Viruses captured in photos

Viruses are incredibly small and cannot be seen in normal microscopes.

The electron microscope, which was invented by Ernst Ruska and Max Knoll in 1933, made it possible to take pictures of much smaller objects than was previously possible. Ernst Ruska’s brother, Helmut Ruska, was a doctor and biologist, and used early electron microscopes to make images of viruses and other small objects. The tobacco mosaic virus was the first virus captured on film. The development of the electron microscope has enabled increasingly better images to be taken.

Ernst Ruska was awarded the 1986 Nobel Prize in Physics together with Gerd Binnig and Heinrich Röhrer, who developed the scanning electron microscope.

Read more about Ernst Ruska – his life and research. https://www.nobelprize.org/prizes/physics/1986/ruska/facts/

https://nobelprizemuseum.se/en/viruses-captured-in-photos/

 

Epidemics and literature

When epidemics and pandemics strike the world, it isn’t just the physical health of people that are impacted but also ways of life, thoughts and feelings. Nobel Laureates in literature have been effected by epidemics and written about life under real and fictive epidemics.

The coronavirus crisis has had a dramatic impact on our lives and our view of our lives. Olga Tokarczuk is one of the authors who has reflected on this.

Tokarczuk argues that the coronavirus has swept away the illusion that we are the masters of creation and that we can do anything since the world belongs to us. She wonders if the pandemic has forced us into a slower, more natural rhythm in life, but also worries about how it may increase distrust of strangers and worsen inequality among people.

Orhan Pamuk has worked for many years on a novel about a bubonic plague epidemic that struck primarily Asia in 1901. The coronavirus crisis has caused him to consider the similarities between the ongoing pandemic and past epidemics throughout history.

He sees several recurring behaviors when epidemics strike: denial and false information, distrust of individuals belonging to other groups, and theories about a malicious intent behind the pandemic. But epidemics also remind us that we are not alone and allow us to rediscover a sense of solidarity. He writes in The New York Times.

https://nobelprizemuseum.se/en/epidemics-and-literature/

Economics Laureates on the current pandemic

Pandemics have wide-ranging impacts on the economy. Paul Romer and Paul Krugman are two economists who have been active in the public discourse during the coronavirus crisis.

Paul Romer has expressed concerns about the pandemic’s effects on the economy but is optimistic about the possibilities of technology. He supports widespread testing. Those who are infected have to stay home for two weeks while others can work and take part in other ways in society.

Paul Romer was awarded the prize “for integrating technological innovations into long-run macroeconomic analysis.” Paul Romer has demonstrated how knowledge can function as a driver of long-term economic growth. He showed how economic forces govern the willingness of firms to produce new ideas.

His thoughts are developed in his lecture during the Nobel Week 2018.

https://nobelprizemuseum.se/en/economics-laureates-on-the-current-pandemic/

 

Other SOURCE

https://www.nobelprize.org/

 

Read Full Post »


Is SARS-COV2 Hijacking the Complement and Coagulation Systems?

Reporter: Stephen J. Williams, PhD

In a recent Nature Medicine paper “Immune complement and coagulation dysfunction in adverse outcomes of SARS-CoV-2 infection” Ramlall et al. demonstrate, in a retrospective study, that a significant number of patients presenting SARS-CoV2 complications had prior incidences of macular degeneration and coagulation disorders and these previous indications are risk factors for COVID-related complications.

 

Abstract

Understanding the pathophysiology of SARS-CoV-2 infection is critical for therapeutic and public health strategies. Viral–host interactions can guide discovery of disease regulators, and protein structure function analysis points to several immune pathways, including complement and coagulation, as targets of coronaviruses. To determine whether conditions associated with dysregulated complement or coagulation systems impact disease, we performed a retrospective observational study and found that history of macular degeneration (a proxy for complement-activation disorders) and history of coagulation disorders (thrombocytopenia, thrombosis and hemorrhage) are risk factors for SARS-CoV-2-associated morbidity and mortality—effects that are independent of age, sex or history of smoking. Transcriptional profiling of nasopharyngeal swabs demonstrated that in addition to type-I interferon and interleukin-6-dependent inflammatory responses, infection results in robust engagement of the complement and coagulation pathways. Finally, in a candidate-driven genetic association study of severe SARS-CoV-2 disease, we identified putative complement and coagulation-associated loci including missense, eQTL and sQTL variants of critical complement and coagulation regulators. In addition to providing evidence that complement function modulates SARS-CoV-2 infection outcome, the data point to putative transcriptional genetic markers of susceptibility. The results highlight the value of using a multimodal analytical approach to reveal determinants and predictors of immunity, susceptibility and clinical outcome associated with infection.

Introduction

As part of a separate study, the authors mapped over 140 cellular proteins that are structurally mimicked by coronaviruses (CoVs) and identified complement and coagulation pathways as targets of this strategy across all CoV strains4. The complement system is a critical defense against pathogens, including viruses5 and when dysregulated (by germline variants or acquired through age-related effects or excessive tissue damage) can contribute to pathologies mediated by inflammation5,6,7.

“So, virally encoded structural mimics of complement and coagulation factors may contribute to CoV-associated immune-mediated pathology and indicate sensitivities in antiviral defenses.”

 

Methods and Results

  • Between 1 February 2020 and 25 April 2020, 11,116 patients presented to New York-Presbyterian/Columbia University Irving Medical Center with suspected SARS-CoV-2 infection, of which 6,398 tested positive
  • Electronic health records (EHRs) were used to define sex, age and smoking history status as well as histories of macular degeneration, coagulatory disorders (thrombocytopenia, thrombosis and hemorrhage), hypertension, type 2 diabetes (T2D), coronary artery disease (CAD) and obesity (see Methods). A Python algorithm was used to analyze all confounders.
  • identified 88 patients with history of macular degeneration, 4 with complement deficiency disorders and 1,179 with coagulatory disorders).
  • observed a 35% mortality rate among patients that were put on mechanical ventilation and that 31% of deceased patients had been on mechanical respiration.
  • patients with AMD (a proxy for complement activation disorders) and coagulation disorders (thrombocytopenia, thrombosis and hemorrhage) were at significantly increased risk of adverse clinical outcomes (including mechanical respiration and death) following SARS-CoV-2 infection
  • 650 NP swabs from control and SARS-CoV-2-infected patients who presented to Weill-Cornell Medical Center were evaluated by RNA-Seq. Gene set enrichment analysis (GSEA) of Hallmark gene sets found that SARS-CoV-2 infection (as defined by presence of SARS-CoV-2 RNA and stratified into ‘positive’, ‘low’, ‘medium’ or ‘high’ based on viral load; induces genes related to pathways with known immune modulatory functions (Fig. 2a). Moreover, among the most enriched gene sets, SARS-CoV-2 infection induces robust activation of the complement cascade (false discovery rate (FDR) P < 0.001), with increasing enrichment and significance with viral load (FDR P < 0.0001).
  • KEGG Pathway Analysis revealed KEGG_Complement_and_Coagulation_Cascades’, ‘GO_Coagulation’ and ‘Reactome_initial_triggering_of_complement’ to be significantly enriched in expression profiles of SARS-CoV-2-infected samples
  • conducted a candidate-driven study to evaluate whether genetic variation within a 60-Kb window around 102 genes with known roles in regulating complement or coagulation cascades (2,888 genetic variants fulfill this criteria of the 805,426 profiled in the UK Biobank) is associated with poor SARS-CoV-2 clinical outcome
  • identified 11 loci representing seven genes with study-wide significance. A variant of coagulation factor III (F3), variant rs72729504, was found to be associated with increased risk of adverse clinical outcome associated with SARS-CoV-2 infection. The analysis also identified that four variants previously reported to be associated with AMD (rs45574833, rs61821114, rs61821041 and rs12064775)15predispose carriers to hospitalization following SARS-CoV-2 infection

As authors state:

“Among the implications, the data warrant heightened public health awareness for the most vulnerable individuals and further investigation into an existing menu of complement and coagulation targeting therapies that were recently shown to be beneficial in a small cohort of patients with SARS-CoV-2 infection.” 26,27.

 

References

Ramlall, V., Thangaraj, P.M., Meydan, C. et al. Immune complement and coagulation dysfunction in adverse outcomes of SARS-CoV-2 infection. Nat Med (2020). https://doi.org/10.1038/s41591-020-1021-2

 

4.

Lasso, G., Honig, B. & Shapira, S. D. A sweep of earth’s virome reveals host-guided viral protein structural mimicry; with implications for human disease. Preprint at bioRxiv https://doi.org/10.1101/2020.06.18.159467 (2020).

 

SUMMARY

Viruses deploy an array of genetically encoded strategies to coopt host machinery and support viral replicative cycles. Molecular mimicry, manifested by structural similarity between viral and endogenous host proteins, allow viruses to harness or disrupt cellular functions including nucleic acid metabolism and modulation of immune responses. Here, we use protein structure similarity to scan for virally encoded structure mimics across thousands of catalogued viruses and hosts spanning broad ecological niches and taxonomic range, including bacteria, plants and fungi, invertebrates and vertebrates. Our survey identified over 6,000,000 instances of structural mimicry, the vast majority of which (>70%) cannot be discerned through protein sequence. The results point to molecular mimicry as a pervasive strategy employed by viruses and indicate that the protein structure space used by a given virus is dictated by the host proteome. Interrogation of proteins mimicked by human-infecting viruses points to broad diversification of cellular pathways targeted via structural mimicry, identifies biological processes that may underly autoimmune disorders, and reveals virally encoded mimics that may be leveraged to engineer synthetic metabolic circuits or may serve as targets for therapeutics. Moreover, the manner and degree to which viruses exploit molecular mimicry varies by genome size and nucleic acid type, with ssRNA viruses circumventing limitations of their small genomes by mimicking human proteins to a greater extent than their large dsDNA counterparts. Finally, we identified over 140 cellular proteins that are mimicked by CoV, providing clues about cellular processes driving the pathogenesis of the ongoing COVID-19 pandemic.

 

26.

Risitano, A. M. Complement as a target in COVID-19?. Nat. Rev. Immunol. 20, 343–344 (2020).

 

27.

Mastaglio, S. et al. The first case of COVID-19 treated with the complement C3 inhibitor AMY-101. Clin. Immunol. 215, 108450 (2020).

 

28.

Polubriaginof, F. C. G. et al. Challenges with quality of race and ethnicity data in observational databases. J. Am. Med. Inf. Assoc. 26, 730–736 (2019).

 

Read Full Post »

Older Posts »