A SARS-CoV-2 NanoLuc® Reporter Virus for Rapid Screening of Antivirals

nanoluc invivo imaging

Before the COVID-19 global pandemic began, Dr. Xuping Xie, Assistant Professor of the University of Texas Medical Branch at Galveston, TX has been studying viruses, such as Dengue and Zika, for more than 10 years. Once the pandemic hit in early 2020, he was prepared to join the fight against the virus. “There was an urgent need to know: Is there a quicker way to develop therapeutics or antibodies to target SARS-CoV-2?” says Dr. Xie. “That’s why we immediately launched our SARS-CoV-2 project.”

His goal was to create an assay that could 1) screen for antiviral drugs and 2) quickly measure neutralizing antibody levels. The assay could be used to determine the immune status of previously infected individuals and to evaluate various vaccines under development. To achieve this, he wanted to create a reporter virus that is genetically stable and replicates similarly to the wild-type virus in cell culture. 

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COVID-19 Therapies: Are We There Yet?

A year after COVID-19 was declared a pandemic, collaborative efforts among pharma/biotech and academic researchers have led to remarkable progress in vaccine development. These efforts include novel mRNA vaccine technology, as well as more conventional approaches using adenoviral vectors. While vaccine deployment understandably has captured the spotlight in the fight against COVID-19, there remains an urgent need to develop therapeutic agents directed against SARS-CoV-2.

COVID-19 therapeutic drugs

In the March 12 issue of Science, an editorial by Dr. Francis Collins, director of the U.S. National Institutes of Health (NIH), examines lessons learned over the past 12 months (1). Collins points out that many clinical trials of potential therapeutics were not designed to suit a public health emergency. Some were poorly designed or underpowered, yet they received considerable publicity—as was the case with hydroxychloroquine. Collins advises developing antiviral agents targeted at all major known classes of pathogens, to head off the next potential pandemic before it becomes one. A news feature in the same issue discusses the current state of coronavirus drug development (2).

The present crop of drug candidates is remarkably diverse, including repurposed drugs that were originally developed to treat diseases quite different from COVID-19. Typically, however, the mainstream candidates belong to two broad classes: small-molecule antiviral agents and large-molecule monoclonal antibodies (mAbs).

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Impact of COVID-19 Pandemic on Cancer Diagnosis—When Fewer Cases of Cancer is Not Good News

The year 2020 was a year filled with things we didn’t do. The global COVID-19 pandemic meant we didn’t gather with family and friends; we didn’t attend concerts or sporting events; we didn’t even go to work or school in the same way. We also didn’t go to the doctor, and as a result, many countries and organizations are reporting that there was an alarming drop in the number of new cancer cases (1–6). Unfortunately, while fewer diagnosis might sound like a good thing, there is no evidence that the actual rate of new cancer occurrence is declining (7).  

COVID-19 Restrictions Impact Cancer Screening and Diagnosis

The drop in cancer diagnosis happened after countries began to put into place new restrictions intended to slow the spread of the SARS-CoV-2 virus. These measures often included limiting or pausing many routine screenings and doctor visits, which also limited or paused opportunities to diagnosis cancer. The resulting decline in new cancer diagnosis was dramatic. In the United States, there was a 46.4% decline in the number of newly diagnosed cases of six of the most common cancer types (breast, colorectal, esophageal, gastric, lung and pancreatic) per week between March 1, 2020 and April 18, 2020 (1,2,8).

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From Primate Models to SARS-CoV-2 Sequencing and Testing

As the SARS-CoV-2 virus spread around the world in early 2020, many researchers shifted their focus to support the global endeavors to address the challenge. For two professors at the University of Wisconsin, their efforts started with animal models to study pathogenicity and grew into massive SARS-CoV-2 sequencing and COVID-19 testing projects.

Virologists David and Shelby O'Connor (shown running along Lake Mendota) have worked extensively in SARS-CoV-2 Sequencing and COVID-19 Testing

“Being a scientist in this field gives a sense of purpose, but also a sense of obligation and responsibility,” says David O’Connor, PhD. “You always want to feel like you’re living up to that.”

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Engineering a Safer SARS-CoV-2 for Use in the Research Laboratory

This illustration, created at the Centers for Disease Control and Prevention (CDC), reveals ultrastructural morphology exhibited by coronaviruses such as SARS-CoV-2. Photo Credit: Alissa Eckert, MS; Dan Higgins, MAM CDC
SARS-CoV-2 illustration from CDC; Photo Credit: Alissa Eckert, MS; Dan Higgins, MAM
E = envelope; M = membrane

A worldwide pandemic requires scientific research to understand the viral pathogen. The focused efforts of global scientists are even more necessary in the face of a novel coronavirus like SARS-CoV-2, the causative agent of COVID-19. However, because SARS-CoV-2 causes human disease, research efforts are restricted by the need for physical laboratories that are equipped to handle the required level of containment and personnel trained to handle pathogens in these facilities. But what if we could bypass the restrictive facility requirements by engineering a synthetic, replication-defective version of SARS-CoV-2 that more researchers could use to study the pandemic coronavirus, expanding the capacity to test and develop methods to attenuate its devastating effect on humans?

The challenge is to develop a derivative of SARS-CoV-2 that reflects how it behaves in the cell but is compromised such that it is unable to infect cells more than a single time. That is, the virus can get into a cell or be introduced into cells and replicate but is unable to produce infectious virus would offer a pathway to expand research capacity without the use of special laboratory facilities. This replication-defective SARS-CoV-2 could be created to encode as much or as little of the genome needed to examine its lifecycle without becoming a fully infectious virus. In fact, this replication-defective version of SARS-CoV-2 could include additional genetic elements that could be used to control its expression, track the virus in cells and measure the level of its replication. This task has been undertaken by Dr. Bill Sudgen’s group at the University of Wisconsin–Madison McArdle Laboratory for Cancer Research, explained by graduate student Rebecca Hutcheson during her presentation “Making the Virus Causing COVID-19 Safe for Research”.

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Buckling Down to Scale Up: Providing Support Through the Pandemic

The past year has been a challenge. Amidst the pandemic, we’re thankful for the tireless work of our dedicated employees. With their support, we have continuously stayed engaged and prepared during all stages of the COVID-19 pandemic so that we can serve our customers at the highest levels.

How We Got Here

The persistent work by our teams has made a great impact on the support we can provide for scientists and our community during the pandemic. From scaling up manufacturing to investing in new automation, every effort has helped.

Promega has a long history of manufacturing reagents, assays, and benchtop instruments for both researching and testing viruses. When the pandemic began in 2020, we responded quickly and efficiently to unprecedented demands. In the past year, we experienced an approximately 10-fold increase in demand for finished catalog and custom products for COVID-19 testing. In response to these demands, we increased production lines. One year ago, we ran one shift five days per week. Currently, we run three shifts seven days per week. This change has allowed 50 different Promega products to support SARS-CoV-2 testing globally in hospitals, clinical diagnostic laboratories, and molecular diagnostic manufacturers. Additionally, our clinical diagnostics materials make up about 2/3 of COVID-19 PCR tests on the global market today. Since January 2020, Promega has supplied enough reagents to enable testing an estimated 700 million samples for SARS-CoV-2 worldwide.

Developments and Advances

Promega products are used in viral and vaccine research. This year, our technologies have been leveraged for virtually every step of pandemic response from understanding SARS-CoV-2 to testing to research studies looking at vaccine response.

Promega product: The Lumit™ Dx SARS-CoV-2 Immunoassay

Who Got Us Here

We are extremely grateful for our employees. In the past year, we hired over 100 people and still have positions open today. While welcoming newcomers, this challenging year also reinforced the importance of our collaborative culture. Relationships at Promega have been built over multiple years. The long history of our teams allows us to stay coordinated while prioritizing product distribution to customers across the globe. It also leads to effective communication with colleagues and vendors. Those leading our manufacturing operations team, for example, have an average tenure of 15 years. Their history in collaborating through challenging situations helps them quickly focus where needed most.

Our 600 on-site employees support product manufacturing, quality, and R&D. They do it all while remaining COVID-conscious by social distancing, wearing masks, working split shifts, and restricting movement between buildings. While we continue to practice physical safety precautions, we also prioritize our employees’ mental health and wellness. Promega provides a variety of wellness resources including phone and video mental health sessions, virtual fitness and nutrition classes, and stress and anxiety tools.

What’s to Come

While we acknowledge that the COVID-19 is not over, we are proud of the support we have been able to provide to customers working both on pandemic research and critical research not related to COVID-19. Our policies of long-term planning and investing in the future has allowed us to respond quickly and creatively and learn from the experience.


Related Posts

Your Brain on COVID-19: Neurotropic Properties of the SARS-CoV-2 Virus

Artist conception of coronavirus in the brain. Researchers are investigating the neurotropic effects of SARS-CoV-2

Viruses are both fascinating and terrifying. Stealthy, insidious and often deadly, they turn our own cells against us. Over the past year, we have all had a firsthand view of what a new and unknown virus can do. The SARS-CoV-2 virus has caused a global pandemic, and left scientists and medical professionals scrambling to unravel its mysteries and find ways to stop it.

COVID-19 is considered a respiratory disease, but we know that the SARS-CoV-2 virus can affect other systems in the body including the vascular and central nervous systems. In fact, some of the most noted symptoms of SARS-CoV-2 infection, headache, and the loss of the sense of taste and smell, are neurological— not respiratory— symptoms.

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Intranasal COVID-19 Vaccines: What the Nose Knows

COVID-19 vaccine distribution efforts are underway in several countries. Recently, the Serum Institute of India celebrated the nationwide rollout of its Covishield vaccine, kicking off the country’s largest ever vaccination program. Meanwhile, many other vaccines against the coronavirus that causes COVID-19 are in either preclinical studies or clinical trials. At present, 19 vaccine candidates are in Phase 3 clinical trials, while 8 vaccines have been granted emergency use authorization (EUA) in at least one country.

intranasal covid-19 vaccine coronavirus

In the US, mRNA vaccines from Pfizer/BioNTech and Moderna are in distribution. Adenoviral vector vaccines authorized for distribution include Oxford/AstraZeneca AZD1222 in the UK (Covishield in India) and Gamaleya Sputnik V in Russia. A third type of vaccine consists of inactivated coronavirus particles, such as those developed by Sinopharm and Sinovac in China.

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Ramping Up COVID-19 Testing with the Maxwell® HT Viral TNA Kit

COVID-19 testing with Maxwell HT

John Longshore admits that he was not a big Promega customer before the COVID-19 pandemic. His team uses a wide variety of suppliers to assemble the types of testing protocols needed to serve over 50 hospitals. However, when he began to face supply chain disruptions in early 2020, he needed a supplier he could depend on to support the rapid scale-up of COVID-19 testing, and Promega rose to the occasion.

“When we started working with Promega for bulk isolation reagents, our ask was, ‘Can you supply us with 15,000 isolation reagents per week?’” John says. “The answer was yes, and we have gotten everything we’ve asked for on the dates that it was promised.”

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UWCCC Small Molecule Screening Facility Validates the Lumit™ Dx SARS-CoV-2 Immunoassay for High-Throughput SARS-CoV-2 Antibody Screening

Three researchers from the University of Wisconsin and the Small Molecule Screening Facility (SMSF) at the University of Wisconsin Carbone Cancer Center (UWCCC) have expanded their collaboration in new directions because of COVID-19. Before the pandemic, Gene Ananiev, PhD, Facility Manager of the SMSF, Tim Bugni, PhD, a Professor in the School of Pharmacy, and David Andes, MD, Professor of Medicine and Medical Microbiology and Immunology and Head of the Division of Infection Disease, worked together on antibiotic compound discovery and development, now they have added Covid-19-related projects to that list.

“It was kind of an interesting aside…” said David Andes “To try to see a need, fill a need.”

The need they saw was for tools that are necessary around any pandemic or infectious disease outbreak: Ways to quickly diagnose and manage those who are infected and ways to study the epidemiology of the disease—the distribution pattern and frequency, causes and risk factors for infection within a population. Specifically, the three were interested in an antibody test that could be used not only to understand the proportion of the population that might have already been infected with SARS-CoV-2, but that also could be used to evaluate the response to different vaccine candidates. 

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