New Uses for Old Drugs: Remdesivir and COVID-19

With the COVID-19 pandemic far from over in the United States and worldwide, the battle against the disease continues to intensify. Much hope has been pinned on vaccine development. However, vaccines are a long-term, preventative strategy. The immediate need for drugs to fight COVID-19 has accelerated efforts for a variety of potential treatments (see The Race to Develop New Therapeutics Against Coronaviruses).

The Remdesivir Origin Story

3d model of coronavirus

One drug that has received widespread attention is remdesivir. It was developed from research by Gilead Sciences that began in 2009, originally targeting hepatitis C virus (HCV) and respiratory syncytial virus (RSV) (1). At present, remdesivir is classified as an investigational new drug (IND) and has not been approved for therapeutic use anywhere in the world.

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Connecting and Collaborating: How Scientists Across the Globe are Supporting Each Other During The COVID-19 Pandemic

Many research labs around the world have temporarily closed their doors in response to the COVID-19 pandemic, while others are experiencing unprecedented need for reagents to perform viral testing. This urgency has led many scientists to make new connections and build creative, collaborative solutions.

“In labs that are still open for testing or other purposes, there’s certainly heightened anxiety,” says Tony Vanden Bush, Client Support Specialist. “I feel that right now, I need to help them deal with that stress however possible.”

Last week, Tony was contacted by a lab at the University of Minnesota that was preparing to serve as a secondary COVID-19 testing facility for a nearby hospital lab. The two labs needed to process up to 6,000 samples per day, and the university lab was far short of that capacity.

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Emergency Use Authorization: The What, the Why and the How

This blog is written by guest blogger, Heather Tomlinson, Director of Clinical Diagnostics at Promega.

Finding safe and effective treatments for human diseases takes time.  Medication and diagnostic tests can take decades to discover, develop and prove safe and effective.  In the United States, the FDA stands as the gold-standard gatekeeper to ensure that treatments and tests are reliable and safe. The time we wait in review and clearance means less risk of ineffective or unsafe treatments.

And yet, in a pandemic, we are behind before we even start the race to develop diagnostic tests, so critical for understanding how an infectious disease is spreading. That is when processes like the FDA’s fast track of Emergency Use Authorization (EUA) are critical. Such authorization allows scientists and clinicians to be nimble and provide the best possible test protocol as quickly as possible, with the understanding that these protocols will continue to be evaluated and improved as new information becomes available. The EUA focuses resources and accelerates reviews that keep science at the fore and gets us our best chance at staying safe and healing.

The Maxwell 48 RSC Instrument and the Maxwell RSC Total Viral Nucleic Acid Isolation Kit are now listed as options within the CDC EUA protocol.

For scientists working around the clock, the FDA’s EUA process is ready to review and respond. Getting an EUA  gives clinical labs a very specific and tested resource to guide them to the tools and tests to use in a crisis.

Typically the Centers for Disease Control (CDC) will develop the first test or protocol that receives FDA EUA in response to a crisis like a pandemic.  For COVID-19 the CDC 2019-Novel Coronavirus Real-Time RT-PCR Diagnostic Panel received FDA EUA clearance in early February. This is the test protocol used by the public health labs that work with the CDC and test manufacturers around the world.

Throughout a crisis such as the current pandemic, scientists continually work to improve the testing protocols and add options to the EUA protocols. This enables more flexibility in the test protocols. Promega is fortunate to play a part of the CDC EUA equation for diagnostic testing. Our GoTaq® Probe 1-Step PRT-qPCR System is one of a few approved options for master mixes in the  CDC qPCR diagnostic test,  and now our medium-throughput Maxwell 48 Instrument and Maxwell Viral Total Nucleic Acid Purification Kit  have been added to the CDC protocol as an option for the RNA isolation step as well. These additions to the CDC EUA means that laboratories have more resources at their disposal for the diagnostic testing which is so critical to effective pandemic response.

The Emergency Use Authorization provides the FDA guidance to strengthen our nation’s public health during emergencies, such as the current COVID-19 pandemic. The EUA allows continual improvement of an authorized protocol through the collaborative efforts scientists in all academia, government and industry to identify and qualify the most reliable technologies and systems, giving labs more flexibility as new products are added as options.

Dr. Tomlinson is the Director for the Global Clinical Diagnostics Strategic Business Unit at Promega Corporation with over 15 years of experience in clinical diagnostic test development. She is responsible for leading the team that drives strategy in the clinical market for Promega. Her background is in infectious disease diagnostic testing, with a focus on HIV drug resistance and evolution.  Her recent work has been in oncology companion diagnostic test development.  Heather has is an accomplished international presenter, delivering conference presentations in the United States, Europe, Asia, and Africa.

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Antibodies, Immunity and Vaccines: A Short Primer on the Adaptive Immune Response

MERS-CoV credit: NIAID

Our skin, respiratory system and gastrointestinal tract are continually bombarded by environmental challenges from potential pathogens like SARS-CoV-2. Yet, these exposures do not often cause illness because our immune system protects us. The human immune system is complex. It has both rapid, non-specific responses to injury and disease as well as long-term, pathogen-specific responses. Understanding how the immune response works helps us understand how some pathogens get past it and how to stop that from happening. It also provides key information to help us develop safe and effective vaccines.

The immune response involves two complementary pathways: Innate Immunity and Adaptive Immunity. Innate immunity is non-specific, rapid and occurs quickly after an injury or infection. As a result of the innate immune response, cytokines (small signaling molecules) are secreted to recruit immune cells to an injury or infection site.  Innate immunity does not develop “memory” of an antigen or confer long-term immunity.

The immune response involves to complementary pathways: Innate Immunity and Adaptive Immunity.

Unlike innate immunity, adaptive immunity is both antigen-dependent and antigen-specific, meaning that adaptive immune response requires the presence of a triggering antigen—something like a spike protein on the surface of a virus. The adaptive immune response is also specific to the antigen that triggers the response. The adaptive immune response takes longer to develop, but it has the capacity for memory in the form of memory B and T cells. This memory is what enables a fast, specific immune response (immunity) upon subsequent exposure to the antigen.

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Getting Back to the Bench

Today’s blog is written by Technical Services Scientist, Joliene Lindholm, PhD.

Many of us have come back to the lab after a summer of field work or a vacation break, but there is usually someone checking in on the lab to make sure the gel electrophoresis box did not completely overflow with dead bugs and the water baths are not completely overrun with exciting new algae. Maybe this was just because I worked in an older building in an entomology department, but why do insects like running buffer so much? Some labs have been completely shut down for months at this point or maybe just a few essential people have been in keeping stocks and colonies going. Some labs have adapted to the new normal and developed guidelines to keep researchers safe while still doing essential work in the lab. See how the Promega Scientific Applications group has maintained this balance.

Headed back to the lab bench? Take some time to make sure you have everything you need to start up your research projects.

Here are a few tips from what I learned in managing a lab after a period of field work to get back into the swing of things:

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Choices for Measuring Luciferase-Tagged Reporter Pseudotyped Viral Particles in Coronavirus Research

Coronavirus (CoV) researchers are working quickly to understand the entry of SARS-CoV-2 into cells. The Spike or S proteins on the surface of a CoV is trimer. The monomer is composed of an S1 and S2 domain. The division of S1 and S2 happens in the virus producing cell through a furin cleavage site between the two domains. The trimer binds to cell surface proteins. In the case of the SARS-CoV, the receptor is angiotensin converting enzyme 2. (ACE2). The MERS-CoV utilizes the cell-surface dipeptidyl peptidase IV protein. SARS-CoV-2 uses ACE2 as well. Internalized S protein goes though a second cleavage by a host cell protease, near the S1/S2 cleavage site called S2′, which leads to a drastic change in conformation thought to facilitate membrane fusion and entry of the virus into the cell (1).  

CDC / Alissa Eckert, MS; Dan Higgins, MAMS

Rather than work directly with the virus, researchers have chosen to make pseudotyped viral particles. Pseudotyped viral particles contain the envelope proteins of a well-known parent virus (e.g., vesicular stomatitis virus) with the native host cell binding protein (e.g., glycoprotein G) exchanged for the host cell binding protein (S protein) of the virus under investigation. The pseudotyped viral particle typically carries a reporter plasmid, most commonly firefly luciferase (FLuc), with the necessary genetic elements to be packaged in the particle. 

To create the pseudotyped viral particle, plasmids or RNA alone are transfected into cells and the pseudotyped viruses work their way through the endoplasmic reticulum and golgi to bud from the cells into the culture medium. The pseudoviruses are used to study the process of viral entry via the exchanged protein from the virus of interest. Entry is monitored through assay of the reporter. The reporter could be a luciferase or a fluorescent protein.   

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38 Years After First Release, RNasin Protects COVID-19 Tests

A protein first purified and sold by Promega almost four decades ago has emerged as a crucial tool in many COVID-19 testing workflows. RNasin® Ribonuclease Inhibitor was first released in 1982, only four years after the company was started. At that time, the entire Promega catalog fit on a single sheet of 8.5 × 11” paper, and RNasin was one of the first products to draw widespread attention to Promega. Today, the demand for this foundational product has skyrocketed as it supports labs responding to the COVID-19 pandemic.

What is RNasin® Ribonuclease Inhibitor?

RNA is notoriously vulnerable to contamination by RNases. These enzymes degrade RNA by breaking the phosphodiester bonds forming the backbone of the molecule. To say that RNases are everywhere is barely an exaggeration – almost every known organism produces some form of RNase, and they’re commonly found in all kinds of biological samples. They’re easily introduced into experimental systems, since even human skin secretes a form of RNase. Once they’re present, it’s very hard to get rid of them. Even an autoclave can’t inactivate RNases; the enzymes will refold and retain much of their original activity.

RNasin® Ribonuclease Inhibitor is a protein that has been shown to inhibit many common contaminating RNases, but without disrupting the activity of enzymes like reverse transcriptase that may be essential to an experiment. It works by binding to the RNase enzyme, prevent it from acting on RNA molecules. This is important for ensuring that RNA samples are intact before performing a complex assay.

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Working from Home: Finding Productivity in this New Normal

During this time of adjusting to a new normal, one of the most difficult things that I have had to get used to is being productive in my own home. Work from home (WFH) days are embraced by some people and not by others. For me, transitioning from working in an office and school setting, to working at-home and completing online courses, has led me on a search for answers about how to get the most out of my day. After creating a productive at-home work environment for me, I wanted to share some of my findings with you.

Here are some of the tips that I have found useful:

Section out a portion of your home for work only.

When I first started working from home, I moved room to room working wherever I felt most comfortable. I soon found this affected my organization and time management, so I started keeping all my work in one area. Now, as I sit here writing this post, I know where all of my work is, and I also know that when I walk out of this area I can ‘power down’ my mind knowing I no longer have to do work.

Power off your electronics when not working.

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Neutralizing Antibodies to SARS-CoV-2 Shown to Lessen Infection in Mice

Here in the US, as around the world, we’re beginning to come out of COVID-19 hiding, whether mandated or voluntary. We are slowly starting to leave the confines of home and “safer at home” orders. Many of us are donning masks and venturing out as needed, still under social distancing considerations.

We’re looking forward to a time when social distancing won’t be necessary, when we can see our relatives and friends, and give them a hug without concern for their safety or ours.

When will that time come? Many believe that it won’t be completely safe until there is an effective vaccine to protect us from SARS-CoV-2.

How does a vaccine protect us? Effective vaccines cause our immune system to produce antibodies that are specific for SARS-CoV-2, so that if we come into contact with the virus, it will be neutralized, preventing infection.

At this time, many questions remain about whether SARS-CoV-2 virus causes production of antibodies. And if antibodies are produced, are they protective?

In some exciting news this week, scientists studying SARS-CoV-2 have shown that neutralizing antibodies to this virus are made in humans. Here’s a look at their work.

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Antibody From Humanized Mice Blocks SARS-CoV-2 Infection in Cells

As the SARS-CoV-2 coronavirus continues to spread throughout the world, the race is on to produce antivirals and vaccines to treat and prevent COVID-19. One potential treatment is the use of human monoclonal antibodies, which are antibodies engineered to target and block specific antigens. A recent study by Wang, C. and colleagues published in Nature Communications showed that human monoclonal antibodies can be used to block SARS-CoV-2 from infecting cells.

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