COVID-19 Pandemic: An Urgent Need for Human-Based Research

While the COVID-19 coronavirus is a novel infection, it is part of a large family of viruses that includes the common cold, as well as more serious conditions like SARS (Severe Acute Respiratory Syndrome).

COVID-19 also attacks the respiratory system much like SARS, and the virus that causes it has been named SARS-CoV-2 for severe acute respiratory syndrome coronavirus 2.

All coronaviruses contain a spiky protein on the surface, allowing them to attack the cells of the infected individual. SARS-CoV-2 needs a specific receptor (ACE2) to enter cells. Even though mice and rats have this receptor, its structure is so different from humans that it cannot bind to their receptors, and they cannot become infected.

In order for rats and mice to be used in COVID-19 research, they have to be extensively genetically engineered. Even then they do not become sick as people do with COVID-19. While this has not stopped labs around the world from subjecting mice to gene modification, it’s not only time-consuming, but largely ineffective: genetically engineered mice have consistently failed to produce results for human cures.

Canadian biotechnology company, STEMCELL Technologies has developed an extensive line of human lung tissue cell culture systems. Their Air-Liquid Interface Human Airway Epithelium (ALI) provided the ideal in vitro substrate to study the virus. Being a physiologically relevant model, these ALI cultures allowed two research groups to rapidly isolate, characterize and determine the gene sequence of SARS-CoV-2. Without characterization and gene sequencing, subsequent research into a viable vaccine would not be possible.

The Wyss Lung Chips are lined with human lung epithelial cells, replicating an actual human lung, and have previously been shown to mimic the human lung’s response to an influenza virus with a high degree of precision.

To study COVID-19, the team created a COVID-19 infection model consisting of a laboratory-safe pseudovirus of SARS- CoV2 that contains the key surface spike proteins necessary for entering cells.  They then exposed the Lung Chips to the pseudovirus, demonstrating that it successfully infected the Lung Chips. 

One of the Wyss researchers, Girija Goyal, has previously carried out vaccine research utilizing another chip, the Human Lymphoid Follicle Chip. That study describes how “Mice and conventional two-dimensional (2D) cultures of circulating human immune cells, even together, can fail to replicate human biology, leading to low efficacy and unpredicted, sometimes severe toxicity in clinical trials.”

Viscient Biosciences announced that it will utilize its impressive 3D bioprinting technology to engineer lung tissue that can help further the search for COVID-19 treatments.

The company’s aim is “transformational drug discovery focused on utilizing 3D technology” and this past December it became the first company to find drug targets through 3D bioprinted disease models. Specifically, it validated drug targets that can be used to treat non-alcoholic steatohepatitis (NASH).

Using the same 3D technology, the firm is developing lung tissue models using cells from patients infected with COVID-19.

Founder and Chief Executive Officer Keith Murphy says “When you can remove diseased cells from the human body and reproduce that disease in a dish, you can see the true biology and quickly find a therapy that will work in clinical trials. Drugs found in animal models so often fail because of the species gap, but as we proved with our NASH liver work, important novel drug targets can be found using 3D bioprinting technology. We now are moving quickly to apply the same technology to create 3D human lung tissue to test potential COVID-19 therapies to accelerate development."

Viscient takes a clear stand in addressing the inefficiency of animal tests, stating on its website: "The traditional reliance on animal models of disease today often leads to clinical trial failures due to species differences that prevent accurately reproducing human disease. Viscient is creating a more faithful picture of specific human diseases by relying on human cells and a 3D reconstruction of the tissue to show the truest possible biology in vitro." 

Biotech company InSphero, based in Switzerland, has developed a human cell-based technology that is modeled after the human liver and can be used to test the safety of potential treatments through a precise understanding of how they are metabolized by the liver. With the advent of the COVID-19 crisis, the company has announced it is offering its 3D InSight™ Human Liver free of charge to anyone studying treatments for COVID-19. 

This 3D in vitro liver toxicology platform, comprised of native liver cells, such as primary human hepatocytes and non-parenchymal cells, mimics the human liver, making it far more predictive of human physiological responses than tests done on animals.  It is particularly useful for scientists researching RNA-based vaccines for COVID-19, since traditional animal testing is inadequate for this type of vaccine research. 

Due to its quick turn-around time of approximately 3 weeks, InSphero’s liver model can be used to quickly assess the safety of already approved drugs that researchers hope to repurpose to treat COVID-19.

Emulate has created a Human Emulation System comprised of various organ chips that offer “unprecedented insights into human biology and health.”  Emulate is currently developing new applications for its organ chips in infectious diseases to focus on COVID-19.  

The products, which include Liver-Chip, Kidney-chip and Intestine-Chip, are lab-ready and easy to use without prior training.  The chips come with the Zoë® Culture Module, which allows for control over the cell environment of up to 12 chips, and all necessary application tools.

The platform enables precise disease modeling and safety assessment of drug development that more closely mimics human biology.  President Geraldine A. Hamilton states that Emulate’s Organ Chip platform offers “a range of applications, including human-relevant disease modeling and studies to gain insights related to new drug modalities and mechanisms that are not feasible with conventional animal models or cell cultures”.

The world’s fastest supercomputer, IBM’s Summit, has already run simulations on 8,000 compounds that could potentially bind to the coronavirus protein and disable its spread.

The spike protein is the major surface protein that COVID-19 uses to bind to a human cell receptor. Once it binds, the viral membrane fuses with the human cell membrane. This allows the virus to enter the human cell and replicate.

Summit identified 77 potential disabling compounds and ranked them based on how likely they were to bind to the spike. This supercomputing tool can be used continuously as more data on coronavirus becomes available.

IBM is collaborating with The White House to help launch the COVID-19 High Performance Computing Consortium which will allow researchers around the world to harness top-notch computing resources and leverage them to fight COVID-19.

Similar efforts are underway at the Barcelona Supercomputing Center (BSC) in Spain. Researchers are using data on the viral genomes, structure of virus proteins, drugs and other compounds to run simulations that can advance our understanding of how the virus behaves and impact the transmission of COVID-19, including its ability to mutate.

Computer-based, or in silico, modeling allows researchers to experiment with potential vaccine, antibody, and drug treatment compounds, without experimenting on a living organism. This process is known as “docking”, and it allows scientists to efficiently simulate the interaction between the coronavirus and an enormous variety of potential treatments.

As the deadly coronavirus spreads exponentially across the globe, researchers are racing to develop a vaccine that brings the pandemic to a halt. In their urgency for developing a COVID-19 vaccine, some researchers are bypassing this step, exposing animal testing for what it is: wasteful, unnecessary and inapplicable to humans.

With unprecedented speed, biotech company Moderna began testing its vaccine candidate mid-March. In a clinical trial funded by the National Institutes of Health (NIH), 45 healthy human volunteers in Seattle, WA were given doses of a potential COVID-19 vaccine developed by Moderna. The company’s chief medical officer, Tal Zaks MD, compellingly says “I don’t think proving this in an animal model is on the critical path to getting this to a clinical trial.”

This should make it clear that the animal testing phase is redundant, gratuitous and an impediment to urgent progress. Another company, Inovio, has also begun testing its vaccine candidate in expedited human trials in early April that have bypassed much of the animal testing phase.

Rather than spare animals completely, both Moderna and Inovio are using animal tests in parallel with human trials. The use of animals is so entrenched in drug and vaccine development that scientists feel animals must be used despite their questionable efficacy.

In February 2020, the World Health Organization assembled scientists and drug developers from across the globe to discuss how to confront COVID-19. Their decision was that the dangers posed by the virus are so serious that human vaccine trials should move forward without waiting for results from animal tests. That conclusion was supported by the U.S. Food and Drug Administration, the most influential drug agency in the world.

Critics of the accelerated trials point to incidents where vaccines led to serious “disease enhancement,” citing vaccines for respiratory syncytial virus in the 1960s and more recently in 2017 when 130 children given the Dengue vaccine died in the Philippines. But those vaccines had undergone extensive animal trials prior to human use, again demonstrating that animal testing is no guarantee of safe vaccines.

Both the Moderna and Inovio vaccine candidates were able to advance to clinical testing at unprecedented speed because they used pioneering methods of generating vaccines using COVID-19’s genome sequencing. Whereas previous vaccines have used inactivated versions of the actual virus, Moderna and Inovio both injected RNA or DNA codes for COVID-19 antigens which prompts the body to build immunity to the virus. The success of this method will signal a new age of developing advanced therapeutics that are well-aligned with using animal-free methods of testing safety and efficacy.

In their race to develop a treatment for thousands of people ill with COVID-19, scientists are turning to a method that uses antibodies from the blood plasma of recovered people and infuses them into infected patients. The method is referred to as “passive immunity” in contrast to the “active immunity” acquired through a vaccine.

Passive immunity through blood plasma of recovered individuals is an old and time-tested method that has been used for at least a century. During the “Spanish Flu” pandemic in 1918, fatality rates were reportedly cut in half for patients treated with plasma antibodies compared to those who were not.  It has also been used to treat measles, Hantavirus, MERS, SARS and Ebola. Indeed, during the 2003 SARS outbreak, an all human study demonstrated that the method alleviated the severity of symptoms in some patients.

Despite this long history of human use, some current COVID-19 trials are testing plasma’s efficacy using mice.  Because of the vast differences between mice and humans, researchers must use genetically engineered mice who are made receptive to COVID-19 in order for them to produce antibodies.  Even then, mice have been shown to be poor models for studying human physiological reactions.

But the urgency of the situation has allowed totally human trials to move forward with the necessary speed to treat people immediately, demonstrating that the animal tests are unjustified and unnecessary.

Many preliminary human trials have already shown positive results. In one study carried out in China during the current pandemic, five critically ill patients were treated with convalescent plasma and all showed an improvement in their clinical status.

As a result, infectious disease experts in the U.S. have been urgently calling for the use of convalescent antibodies to battle the current COVID-19 pandemic. In response, the Food and Drug Administration (FDA) announced on March 24, 2020 that it will permit the use of plasma treatments for COVID patients at the same time that it will review protocols for human clinical trials taking place at Johns Hopkins and a number of affiliated hospitals.

On March 23, 2020 Governor Cuomo of New York announced that his state will allow treatment with convalescent plasma. Patients who are recovering from COVID-19 have been enthusiastic about participating in plasma donation and volunteers will be screened to meet strict criteria.

Dr. Timothy Sheahan of the University of North Carolina, Chapel Hill states “It’s funny how the virus can have such devastation in humans, and then you can give a million particles to a mouse and it’s inert.”  A team at Peking Medical Union College in China reported that even when subjecting the transgenic mice to the COVID-19 virus, they showed only very mild symptoms.

Likewise, ferret models have failed to mimic human disease.  When infected with COVID-19, they showed elevated body temperatures but no other symptoms. 

Rhesus macaques and other nonhuman primates are also being heavily relied upon for COVID-19 experiments. In March, the Trump Administration placed a $1.8 million order for “premium quality non-human primate models” from Worldwide Primates.

Even monkeys, who are expected to be “our near clinical model that we’re going to rest heavily on,” according to Dr. Chad Roy of Tulane National Primate Research Center, fail to develop symptoms when infected with COVID-19. 

Nevertheless, Dr Roy intends to create monkeys who have diseases like hypertension or diabetes and then infect them with the virus, to study COVID-19’s effect on people with underlying conditions.  Even with these induced diseases, the monkeys will still not replicate the human disease. “Monkeys, in general are pretty resilient animals and they handle viral diseases pretty well,” says Roy.