Trained Innate Immunity, Epigenetics, and Covid-19

Authors: Alberto Mantovani, M.D., and Mihai G. Netea, M.D.

Innate immunity is mediated by different cell types and cell-associated or fluid-phase pattern-recognition molecules and plays a key role in tissue repair and resistance against pathogens.1 Exposure to selected vaccines, such as bacille Calmette–Guérin (BCG) or microbial components, can increase the baseline tone of innate immunity and trigger pathogen-agnostic antimicrobial resistance (known as trained innate immunity). Such training is directly relevant to resistance against infectious diseases, including Covid-19. A recent study by de Laval et al.2 pinpoints a driver of durable innate immune memory conferred by myeloid cells (monocytes, macrophages, and neutrophils).

Myeloid cells are central players in innate immunity: they produce effector molecules and contribute to the activation, orientation, and regulation of adaptive immune responses. Diversity and plasticity are fundamental properties of myeloid cells, particularly macrophages. To some extent, these properties are imprinted through ontogenetic origin (embryonal vs. adult bone marrow), but they are also influenced by environmental cues in the tissue. Moreover, in response to microbial molecules, metabolic products, or cytokines, macrophages increase effector function (“activation”), are primed for short-term responses (“priming”), or become unresponsive (“tolerance”). Microbial components can also cause long-term imprinting (“training”) of innate immunity and myeloid-cell function (Figure 1).3 (This type of imprinting is distinct from genomic imprinting whereby methyl groups are added to DNA in or near specific genes.)

For More Information: https://www.nejm.org/doi/10.1056/NEJMcibr2011679

Potential for False Positive Results with Antigen Tests for Rapid Detection of SARS-CoV-2 – Letter to Clinical Laboratory Staff and Health Care Providers

Authors: FDA

The U.S. Food and Drug Administration (FDA) is alerting clinical laboratory staff and health care providers that false positive results can occur with antigen tests, including when users do not follow the instructions for use of antigen tests for the rapid detection of SARS-CoV-2. Generally, antigen tests are indicated for the qualitative detection of SARS-CoV-2 antigens in authorized specimen types collected from individuals who are suspected of COVID-19 by their healthcare provider within a certain number of days of symptom onset. The FDA is aware of reports of false positive results associated with antigen tests used in nursing homes and other settings and continues to monitor and evaluate these reports and other available information about device safety and performance.

The FDA reminds clinical laboratory staff and health care providers about the risk of false positive results with all laboratory tests. Laboratories should expect some false positive results to occur even when very accurate tests are used for screening large populations with a low prevalence of infection. Health care providers and clinical laboratory staff can help ensure accurate reporting of test results by following the authorized instructions for use of a test and key steps in the testing process as recommended by the Centers for Disease Control and Prevention (CDC), including routine follow-up testing (reflex testing) with a molecular assay when appropriate, and by considering the expected occurrence of false positive results when interpreting test results in their patient populations.  

For More Information: https://www.fda.gov/medical-devices/letters-health-care-providers/potential-false-positive-results-antigen-tests-rapid-detection-sars-cov-2-letter-clinical-laboratory

Antigen and Molecular Tests

Diagnostic tests are used to detect current, active infections of the SARS-CoV-2 virus. Diagnostic tests can be antigen based (“rapid antigen” tests), which look for protein markers on the outside of the virus, or they can be molecular based (including PCR, LAMP, CRISPR), which look for viral genomic material specific to SARS-CoV-2. Molecular based tests that amplify genetic material are also called nucleic acid amplification tests (NAAT). 

More about antigen and molecular tests:

For More Information: https://www.centerforhealthsecurity.org/covid-19TestingToolkit/testing-basics/types-of-COVID-19-tests/antigen-and-molecular-tests.html

Performance of an Antigen-Based Test for Asymptomatic and Symptomatic SARS-CoV-2 Testing at Two University Campuses

Authors: Ian W. Pray, PhD1,2,3,*; Laura Ford, PhD1,2,*; Devlin Cole, MD3,4; Christine Lee, PhD1,5; John Paul Bigouette, PhD1,2; Glen R. Abedi, MPH1; Dena Bushman, MSN, MPH1,2; Miranda J. Delahoy, PhD1,2; Dustin Currie, PhD1,2; Blake Cherney, MS1; Marie Kirby, PhD1; Geroncio Fajardo, MD1; Motria Caudill, PhD1,6; Kimberly Langolf, MS7; Juliana Kahrs, MS7; Patrick Kelly, MD4,8; Collin Pitts, MD4,8; Ailam Lim, PhD9; Nicole Aulik, PhD9; Azaibi Tamin, PhD1; Jennifer L. Harcourt, PhD1; Krista Queen, PhD1; Jing Zhang, PhD1; Brett Whitaker, PhD1; Hannah Browne1; Magdalena Medrzycki, PhD1; Patricia Shewmaker, PhD1; Jennifer Folster, PhD1; Bettina Bankamp, PhD1; Michael D. Bowen, PhD1; Natalie J. Thornburg, PhD1; Kimberly Goffard, MBA10; Brandi Limbago, PhD1; Allen Bateman, PhD7,11; Jacqueline E. Tate, PhD1; Douglas Gieryn10; Hannah L. Kirking, MD1; Ryan Westergaard, MD, PhD3,4; Marie Killerby, VetMB1; CDC COVID-19 Surge Laboratory Group (View author affiliations)

Summary

What is already known about this topic?

Antigen tests for SARS-CoV-2 are inexpensive and can return results within 15 minutes, but test performance data in asymptomatic and symptomatic persons are limited.

What is added by this report?

Compared with real-time reverse transcription–polymerase chain reaction (RT-PCR) testing, the Sofia antigen test had a sensitivity of 80.0% and specificity of 98.9% among symptomatic persons; accuracy was lower (sensitivity 41.2% and specificity 98.4%) when used for screening of asymptomatic persons.

What are the implications for public health practice?

To account for reduced antigen test accuracy, confirmatory testing with a nucleic acid amplification test (e.g., RT-PCR) should be considered after negative antigen test results in symptomatic persons and positive antigen test results in asymptomatic persons.

For More Information: https://www.cdc.gov/mmwr/volumes/69/wr/mm695152a3.htm

Interim Guidance for Antigen Testing for SARS-CoV-2

Authors: CDC

Summary of Recent Changes

Updates as of May 13, 2021

  • Updated guidance based on new published studies on antigen test performance.
  • Clarification about which NAATs should be used for confirmatory testing.
  • Considerations for people who have had previous SARS-CoV-2 infections and those who have been fully vaccinated.
  • Two new antigen testing algorithms, one for congregate living settings, and one for community settings.
  • Updates to testing suggestions for fully vaccinated, asymptomatic people.
    View Previous Updates

Key Points

  • This interim guidance is intended for healthcare providers who order antigen tests, receive antigen test results, or perform point-of-care testing, as well as for laboratory professionals who perform antigen testing in a laboratory setting or at the point of care and report those results.
  • The purpose of this interim technical guidance is to support effective clinical and public health use of antigen tests for different testing situations.
  • This guidance applies to all clinical and consumer uses of antigen tests and is not specific to any particular age group.
  • This guidance incorporates considerations for fully vaccinated people and should be used in conjunction with CDC’s Interim Public Health Recommendations for Fully Vaccinated People.

For More Information: https://www.cdc.gov/coronavirus/2019-ncov/lab/resources/antigen-tests-guidelines.html

A long-term perspective on immunity to COVID

Determining the duration of protective immunity to infection by SARS-CoV-2 is crucial for understanding and predicting the course of the COVID-19 pandemic. Clinical studies now indicate that immunity will be long-lasting.

Authors: Andreas Radbruch & Hyun-Dong Chang

Generating immunity against the SARS-CoV-2 coronavirus is of the utmost importance for bringing the COVID-19 pandemic under control, protecting vulnerable individuals from severe disease and limiting viral spread. Our immune systems protect against SARS-CoV-2 either through a sophisticated reaction to infection or in response to vaccination. A key question is, how long does this immunity last? Writing in NatureTurner et al.1 and Wang et al.2 characterize human immune responses to SARS-CoV-2 infection over the course of a year.

There is ongoing discussion about which aspects of the immune response to SARS-CoV-2 provide hallmarks of immunity (in other words, correlates of immunological protection). However, there is probably a consensus that the two main pillars of an antiviral response are immune cells called cytotoxic T cells, which can selectively eliminate infected cells, and neutralizing antibodies, a type of antibody that prevents a virus from infecting cells, and that is secreted by immune cells called plasma cells. A third pillar of an effective immune response would be the generation of T helper cells, which are specific for the virus and coordinate the immune reaction. Crucially, these latter cells are required for generating immunological memory — in particular, for orchestrating the emergence of long-lived plasma cells3, which continue to secrete antiviral antibodies even when the virus has gone.

Immunological memory is not a long-lasting version of the immediate immune reaction to a particular virus; rather, it is a distinct aspect of the immune system. In the memory phase of an immune response, B and T cells that are specific for a virus are maintained in a state of dormancy, but are poised to spring into action if they encounter the virus again or a vaccine that represents it. These memory B and T cells arise from cells activated in the initial immune reaction. The cells undergo changes to their chromosomal DNA, termed epigenetic modifications, that enable them to react rapidly to subsequent signs of infection and drive responses geared to eliminating the disease-causing agent4. B cells have a dual role in immunity: they produce antibodies that can recognize viral proteins, and they can present parts of these proteins to specific T cells or develop into plasma cells that secrete antibodies in large quantities. About 25 years ago5, it became evident that plasma cells can become memory cells themselves, and can secrete antibodies for long-lasting protection. Memory plasma cells can be maintained for decades, if not a lifetime, in the bone marrow6.

The presence in the bone marrow of long-lived, antibody-secreting memory plasma cells is probably the best available predictor of long-lasting immunity. For SARS-CoV-2, most studies so far have analyzed the acute phase of the immune response, which spans a few months after infection, and have monitored T cells, B cells and secreted antibodies7. It has remained unclear whether the response generates long-lived memory plasma cells that secrete antibodies against SARS-CoV-2.

For More Information: https://www.nature.com/articles/d41586-021-01557-z

Here’s Why Viral Vector Vaccines Don’t Alter DNA

— It’s pretty simple — they can’t

Authors: by Veronica Hackethal, MD, MSc, Enterprise & Investigative Writer, MedPage Today March 12, 2021

Adenoviral vector vaccines have been in development for decades, but very few have been approved for use in humans. What does the history of adenoviral vector vaccine development tell us about their safety and their potential to alter DNA?

How Do Adenoviral Vector Vaccines Work?

Essentially, these types of vaccines act like delivery shuttles. They use an adenovirus — which has been engineered to be incapable of replicating and causing disease — to deliver the genes for making the antigen; in this case, that’s the SARS-CoV-2 spike protein. That in turn elicits an immune response and provides protection against the coronavirus.

Adenoviruses are basically common cold viruses that can cause illnesses ranging from cold-like symptoms to bronchitis, gastroenteritis, and conjunctivitis.

“I think people are unfortunately familiar with adenoviruses … [A]t far too many points, you know, you’ve had the sniffle. You’ve had the cough. You felt crummy. If it’s a cold it’s often adenovirus,” Daniel Griffin, MD, PhD, said on a recent episode of MedPage Today‘s “Track the Vax” podcast. Griffin is chief of infectious disease at ProHEALTH Care, an Optum unit.

Humans are infected with multiple different types of adenoviruses throughout their lifetimes. Most serotypes cause mild illness, although adenovirus serotype 7 has been associated with more severe illness. Older adults and people who are immunocompromised or have pre-existing respiratory or cardiac disease may have worse illness.

Precisely because adenoviruses are so common, one problem with using them in vaccines is that people may already have antibodies to them, overwhelming them before they can do their assigned work. Researchers get around that issue by using adenoviruses that humans are unlikely to have encountered before.

Currently, five adenovirus vector vaccines for COVID-19 are in use worldwide.

Each works on the same basic principle, although delivery platforms differ. The AstraZeneca/Oxford vaccine uses the ChAdOx1 platform, which is based on a modified version of a chimpanzee adenovirus.

The Johnson & Johnson vaccine uses a proprietary AdVac platform, made up of a recombinant human adenovirus (adv26). It’s the same platform used in the company’s Ebola virus vaccine (which is approved in Europe) and its investigational Zika, RSV, and HIV vaccines.

Russia’s Sputnik V uses recombinant human adenoviruses Ad26 and Ad5 for the first and second doses, respectively. Finally, China’s CanSino vaccine uses the recombinant human adenovirus Ad5.

For More Information: https://www.medpagetoday.com/special-reports/exclusives/91604

Endothelial dysfunction contributes to COVID-19-associated vascular inflammation and coagulopathy

Authors: Jun Zhang 1Kristen M Tecson 1Peter A McCullough 1 2 3

Great attention has been paid to endothelial dysfunction (ED) in coronavirus disease 2019 (COVID-19). There is growing evidence to suggest that the angiotensin converting enzyme 2 receptor (ACE2 receptor) is expressed on endothelial cells (ECs) in the lung, heart, kidney, and intestine, particularly in systemic vessels (small and large arteries, veins, venules, and capillaries). Upon viral infection of ECs by severe acute respiratory syndrome coronarvirus 2 (SARS-CoV-2), ECs become activated and dysfunctional. As a result of endothelial activation and ED, the levels of pro-inflammatory cytokines (interleukin -1, interleukin-6 (IL-6), and tumor necrosis factor-α), chemokines (monocyte chemoattractant protein-1), von Willebrand factor (vWF) antigen, vWF activity, and factor VIII are elevated. Higher levels of acute phase reactants (IL-6, C-reactive protein, and D-dimer) are also associated with SARS-CoV-2 infection. Therefore, it is reasonable to assume that ED contributes to COVID-19-associated vascular inflammation, particularly endotheliitis, in the lung, heart, and kidney, as well as COVID-19-associated coagulopathy, particularly pulmonary fibrinous microthrombi in the alveolar capillaries. Here we present an update on ED-relevant vasculopathy in COVID-19. Further research for ED in COVID-19 patients is warranted to understand therapeutic opportunities.

For More Information: https://pubmed.ncbi.nlm.nih.gov/33070537/