Within days of the first reports of a potentially deadly new coronavirus coming out of China, TGen scientists began developing a genomic-based clinical test to determine whether a person had contracted the virus.
“David [Dr. David Engelthaler, Director of TGen’s infectious disease division, TGen North] called and said, ‘Jeff, this is going to be a monster. We need to join the groups developing FDA supported tests and we need to begin today,’ ” recalls TGen President and Research Director Dr. Jeffrey Trent.
Five weeks later — one day before the first reported death — the scientists at TGen North had developed and received FDA authorization for a PCR-based genetic test for the COVID-19 virus, while simultaneously receiving state certification for its new CLIA laboratory, a step necessary to return testing results to patients and their physicians.
The tools, technologies and approaches TGen is known for in cancer and infectious disease research were applied full force to the genome of the virus, which has since enabled the institute to develop serology (a blood plasma test that looks for antibodies in individuals who have been exposed to the virus) and saliva-based tests, track how the disease moves and mutates, and work toward developing treatments for COVID-19.
“This has been a devastating pandemic,” said Dr. Engelthaler, citing the global toll, “certainly the most significant infectious-disease event in our lifetime. Yet, in a way, TGen North has been preparing for it for years.”
Established in 2006, the faculty at TGen North apply their genomic expertise to pathogen diagnostics and microbial forensics. They are internationally known for their work identifying and tracing infectious disease outbreaks, large and small. Their investigative highlights include pinpointing the source of a cholera outbreak in earthquake-ravaged Haiti; identifying an extremely rare and highly fatal fungal infection infecting residents of Joplin, Missouri, in the wake of one of the most devastating tornados in American history; and helping CDC and FDA solve a medical product contamination case resulting in fungal meningitis outbreak that affected hundreds of patients and killed dozens of people in 20 states. COVID-19 is the latest.
To date, TGen has tested over 45,000 Arizonans and sequenced 5,000 SARS-CoV-2 genomes, providing a trove of genomic information to researchers racing to defeat COVID-19; a disease that has infected more than 226,000 Arizonans and claimed the lives of more than 5,700.
“It is important to understand that this pandemic is dynamic and will continue to shift genomically and geographically,” said Dr. Engelthaler. “We will likely see additional waves as numbers continue to fluctuate in different locales, but hopefully not on the scale we saw throughout the spring and summer.”
One thing that hasn't changed throughout the pandemic is that COVID-19 is first and foremost a deadly disease for those over 70, especially those with chronic lung or heart conditions. Over two thirds of all deaths occur in this age group, even though it makes up less than 15 percent of total cases. Dr. Engelthaler cites one statistic when discussing who should be among the first to receive immunization.
“While the case fatality rate for most Arizonan’s falls below 1 percent, it is currently 16 percent for the elderly. This age group is also experiencing the most adverse effects from social isolation, which can be just as devastating;” he said, “these individuals, and their caregivers need the vaccine first.”
In terms of a vaccine by year’s end, Dr. Engelthaler remains optimistic. He notes there has been tremendous success in vaccine development and identifying good candidates that have been moving through the series of clinical trials that are necessary to ensure that they are safe and effective. It is likely that one or more of these vaccine candidates will conclude their clinical trials and be approved for use before the end of the year.
The Centers for Disease Control, World Health Organization and other health entities have worked on distribution plans for months, as have state and local health departments. Dr. Engelthaler points out that vaccines have been distributed in mass quantities for decades, whether for influenza, childhood immunizations, or other vaccine preventable-diseases, so the infrastructure is in place and ready.
“Until then,” said Dr. Engelthaler, “the best precaution is caution; we need to maintain vigilance, protect each other and stay resilient."
COVID Immunity Study
“A FEW DROPS of blood could reveal insights into how antibodies could stop COVID-19,” says Dr. John Altin, a TGen North Assistant Professor.
Through a research effort called The COVID Immunity Study, Dr. Altin, his team, and colleagues at City of Hope are studying, in depth, the immune response to COVID-19. The results could eventually lead to new methods of diagnosing COVID-19, and help in the development of antibody therapies, and perhaps vaccines.
Ultimately, the study will help researchers learn more about how, when and why the body produces antibodies in response to a COVID-19 infection. One class of antibodies with the human body tackles the infection first, and then another comes in to finish the job. Knowing when these different immune responses occur, and how long they last, could help scientists understand why some patients gain a certain degree of immunity against reinfection
while others seem to gain little benefit.
“Antibody testing will be critical very soon as we emerge from the COVID-19 pandemic, so this project is immensely important,” says Dr. John Zaia, Director of the Center for Gene Therapy at City of Hope, one of Dr. Altin’s collaborators.
Dr. Zaia leads a research project at City of Hope, in collaboration with Dr. Altin’s lab, that will hopefully result in the development of a COVID-19 virus antibody neutralization test.
The COVID Immunity Study collects blood spot samples that are remotely collected and sent to TGen by citizen scientists that have recovered from COVID-19. For more information, or to see if you qualify to participate, please visit covidimmunity.org/ or contact a TGen Clinical Research Coordinator at [email protected].
Treatment
IN LATE APRIL, TGen — in collaboration with HonorHealth — launched a clinical trial for patients with COVID-19. The trial features a combination of the drugs atovaquone and azithromycin. Predictive modeling suggests that atovaquone may be an active drug in the treatment of COVID-19 and its combination with azithromycin, studied in the rare infectious disease babesiosis, makes for an intriguing combination.
“I’m excited to be working on this project and am hopeful that the translational aspects of this and other studies at TGen will open new avenues for diagnosis and treatment of COVID-19 in the future,” said TGen’s Sunil Sharma, M.D., a trial principal investigator who holds dual appointments at TGen and the HonorHealth Research Institute. The trail expects to enroll approximately 25 patients. Eligibility criteria can be found at clinicaltrials.gov.
Tracking COVID
In early April, Faculty at TGen, Northern Arizona University, the University of Arizona, and Arizona State University formed the Arizona COVID-19 Genomics Union (ACGU).
The goal was to sequence positive patient samples of SARS-CoV-2 with the express purpose of tracking the causative agent of COVID-19, SARS-CoV-2: how it evolves and how it spreads, within and outside of Arizona. The move may eventually prove to be the one of the most consequential long-term scientific responses to the global pandemic.
“Genomic sequencing and advanced analyses allows us to fully understand this disease at the molecular level and reveal the virus’ inner workings,” said TGen’s Dr. David Engelthaler, Director of TGen North and Co-founder of the ACGU, who also coordinates the Union’s genomic epidemiology efforts. The former State Epidemiologist and Biodefense Coordinator has led investigations of local, national and international disease outbreaks for over 25 years.
Initial findings suggest that following Arizona’s first reported case of COVID-19 in late January, the state experienced no cases that went undetected and was COVID-free until at least 11 distinct incursions occurred between mid-February and early April.
Similar to other groups across the globe, the ACGU mobilized quickly to openly share data and analysis with epidemiologists and virologists critical to the scientific, medical and public health understanding of the pandemic.
The ACGU sequenced the SARS-CoV-2 genomes in as many virus-positive samples as possible, and working with Arizona’s public health officials, applied the results toward statewide efforts to test and track patients, as well as provide guidance for Arizona public policy makers.
The published results, derived using molecular clock analysis, recently appeared in the scientific journal mBio. The molecular clock is a figurative term for a technique that uses biomolecular sequence data — DNA, RNA — to determine the development or mutation rate of a given organism, in this case COVID-19. This enables the Union to track both where and when the virus is moving through the state, helping public health officials identify hot spots where contact tracing efforts can be
best applied.
NAU’s Dr. Paul Keim, who serves as the ACGU director, credits much of the ACGU’s abilities to the state’s decades-long investment in fast, high capacity super-computers dedicated to probing the human genome.
“Our ability to advance the science here in Arizona in a way that informs public health, and helps us understand not only where we’ve been but where we’re going with this disease is directly attributable to the state’s investment in the latest technology and big data analysis, all of which helps us understand how the virus evolves and how it is transmitted through the general population,” said Keim.
Dr. Keim, a world-renowned expert in pathogens such as bubonic plague and anthrax, holds the Cowden Endowed Chair in Microbiology and is Executive Director of The Pathogen and Microbiome Institute at NAU. He is also a distinguished professor at TGen and co-director of TGen's Pathogen and Microbiome Division.
Dr. Keim, a self-described optimist, notes that new discoveries are on the horizon; there are more than 100 vaccines using more than a dozen different technologies in development.
“When a safe and effective vaccine is eventually found, it’s likely going to be based on amazing technological advances,” said Keim, “and it will prepare us for future pandemics. This isn’t the first, and it won’t be the last, virus we have encountered. Ultimately, what we learn through our work with COVID-19 better prepares us for
future outbreaks.”
Listen to the Podcast
For an oral perspective on TGen's efforts to combat COVID-19, check out our series of TGen Talks podcasts recorded at various points of the pandemic. Listen to these, and more, at tgen.org/tgentalks
