Despite a COVID-19 surge hospitalizing more younger people, the 18-29 age group targeted by the Prevent COVID U trial has the lowest adult vaccination rates

Tampa, FL (July 29, 2021) — The USF Health Morsani College of Medicine has begun enrolling university students and other young adults, including those not planning to be vaccinated, for an expanded nationwide study evaluating coronavirus infection and transmission in people ages 18 through 29. Individuals must not be vaccinated or have a positive SARS-CoV-2 test result before they start the study.

USF Health is one of more than 50 sites across the U.S. participating in the “Prevent COVID U” randomized controlled clinical trial. For this two-arm study using the Moderna COVID-19 mRNA vaccine, 6,000 individuals will be randomly selected to receive the vaccine right away at enrollment. Another 6,000 will be randomized to follow local guidance and their preference for vaccination timing or be vaccinated through the study after four months.

Additionally, the expanded study will enroll up to 6,000 young adults who choose not to be vaccinated. This control group will help ensure a large enough group of non-vaccinated people to compare infection and transmission rates with study participants vaccinated right away at enrollment.

Prevent COVID U was designed to test whether, and to what degree, the Moderna vaccine can prevent infection with SARS-CoV-2 (including asymptomatic infection), limit virus in the nose, and reduce transmission of the virus from young adults to their close contacts. The study, headquartered at Fred Hutchinson Cancer Research Center and conducted through the COVID-19 Prevention Network (CoVPN), is funded by the federal COVID-19 Response program and the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH).

Kami Kim, MD, director of the USF Health Morsani College of Medicine Division of Infectious Disease, is principal investigator for the Prevent COVID U study at the University of South Florida.

“This study has implications for public health guidance as new COVID-19 variants continue to emerge,” said principal investigator Kami Kim, MD, division director of Infectious Disease and International Medicine at the USF Health Morsani College of Medicine. “It will help us answer critical questions about whether a person can become infected after vaccination, and if the vaccine will stop the virus from spreading to others.”

Dr. Kim emphasized that the 18-to-29 age group has the lowest COVID-19 vaccination rate among all adults. This group, including many students on college campuses like USF, are more likely to show no symptoms when infected, so may pass on the virus to less healthy individuals, she added.

“The Delta variant outbreaks in Florida and other states are sending much younger people to the hospital and reports indicate that nearly all are not vaccinated,” Dr. Kim said. “The few vaccinated people who are hospitalized usually have other medical problems, and if tested for COVID-19 antibodies they’ve shown a poor antibody response to the vaccine.”

In Florida, where about 48% of the population is fully vaccinated, officials say the Delta variant is a driving factor in the statewide increase in COVID-19 cases.

All Prevent COVID U participants will complete questionnaires using an eDiary app twice weekly, swab their nose daily for SARS-CoV-2 infection, and provide periodic blood samples. They will also be asked to identify their “close contacts,” such as family members, friends or roommates, who will then be invited to take part in the trial.

Credit: B.Stefanov- stock.adobe.com

At the end of the study, the Moderna vaccine will be offered to all those in the control group in case they change their minds about vaccination. All individuals who choose to be vaccinated will get their second mRNA vaccine dose one month after the first.

All study volunteers will be compensated for their time and participation, even if they never choose to get vaccinated.

For more information, please call (813) 974-4842 or email CRC@usf.edu, or visit PreventCovidU.org to sign up.

In the video above, USF Health leaders and frontline workers look back on the successes, challenges and emotions they experienced while dealing with an incredibly challenging year amid the COVID-19 pandemic. Their stories include developing testing supplies now used around the world, creating programs aimed at treating vulnerable populations and helping rapidly develop and roll out vaccines against the disease, which Dr. Charles Lockwood, MD, Dean of the USF Health Morsani College of Medicine said “rivals the moon landing.”

USF Health College of Nursing vice dean Denise Maguire, PhD, administers a vaccine shot.

USF Health virologist Michael Teng, PhD

The race for a COVID-19 vaccine began when Chinese scientists published the genetic sequence for the SARS-COV-2 virus on Jan. 11, 2020 – a full two months before the World Health Organization declared the novel coronavirus outbreak a global pandemic. Less than a year later, the U.S. Food and Drug Administration approved two vaccines for emergency use within a week of each other (Dec. 11, 2020 and Dec. 18, 2020). Shortly thereafter, the initial COVID-19 vaccine distributions began in the United States. Both these frontrunner vaccines – the first made by Pfizer and its partner BioNtech, and the second by Moderna – are based on new messenger RNA (mRNA) technology.

“As someone who has worked on vaccines for decades and studied RSV (respiratory syncytial virus), which still has no vaccine 60 years after its discovery, I’m excited about the tremendous achievement of this new mRNA technology,” said USF Health virologist Michael Teng, PhD. “It’s been an incredible story to watch unfold – just 11 months from identifying a new pandemic virus to actually getting a safe and effective frontline vaccine.”

We caught up with Dr. Teng recently to find out more about the science behind the mRNA vaccines, each requiring two doses several weeks apart.  He comments on some other vaccine issues as well. The following Q&A has been condensed and edited for clarity.

How do these mRNA vaccines work?

The Pfizer/BioNTech and Moderna mRNA vaccines are based on the same principle as other COVID-19 vaccines in advanced stages of development. These vaccines deliver genetic material that provides the instruction code for your body’s cells to produce a viral protein (antigen). Your immune system recognizes that viral protein as foreign to your body and mounts an immune response to protect against it.  For SARS CoV-2, the antigen is the viral spike (S) protein, which is located on the outside of the virus and allows the virus to enter a human cell in order to replicate.

The Pfizer/BioNTech and Moderna vaccines use messenger RNA (mRNA) as the genetic material and encase it in a protective lipid nanoparticle (small bubble of fat) for delivery.  Once inside your cells, the mRNA can be translated directly by your cells to make the crown-shaped SARS CoV-2 S. The first (priming) dose of the mRNA vaccine trains your immune system to recognize the viral protein and the second dose boosts your immunity. So, after vaccination, if you are exposed to the actual virus your immune system is ready to neutralize the virus quickly.

//www.youtube.com/watch?v=RQAko-C6mTw

In contrast, adenoviral vector vaccines, such as those developed by Oxford/AstraZeneca and Johnson & Johnson (Janssen), employ a DNA gene that encodes the SARS CoV-2 S protein as the genetic material and uses common cold virus particles (rendered harmless) as the delivery system. For these vaccines, the DNA first has to get into the cell nucleus where your cells can make the mRNA coding instructions, which must then be translated into production of the spike protein.

If the mRNA vaccine uses brand new technology, how could it be turned around so quickly?

While mRNA technology is relatively new and was never approved before COVID-19, the research on vaccines using a genetic approach is not.

Both companies (BioNTech and Moderna) have been testing the application of this platform against other infectious diseases and cancers for several years (i.e., Moderna has worked on mRNA vaccines for Zika and the flu). But, until now, none of the mRNA vaccines or therapeutics have made it through advanced clinical trials.

The challenge has been delivering the mRNA, which is very unstable, to its target human cells without the vaccine being degraded too quickly by the body’s naturally-occuring enzymes. You want to make sure the mRNA stays around long enough to make sufficient protein to stimulate an immune response, but not so long that it overstimulates the immune response… Both Pfizer and Moderna found a way to chemically hide the mRNA from the immune system so once it gets into your cells it has enough time to make the viral protein needed to trigger antibodies and activate T-cell production. The mRNA never enters the cell nucleus or alters a person’s genetic makeup.

What are the advantages of mRNA vaccines?

Well, we know they are relatively safe — and 90-plus percent efficacy for a vaccine (94-95%) is really very high. That level of protection rivals what we see with the measles and human papillomavirus (HPV) vaccines. Seasonal flu vaccines are only about 50 to 60 percent effective in a good year.

Another big advantage of this mRNA platform is that it’s easy to change (mRNA coding instructions) based on the disease you are targeting. You just need to swap in the gene sequence of the protein you want encoded to produce an immune response. So, theoretically, you can easily adapt the vaccine to respond to new viruses – or even mutations of the existing virus.

What are the drawbacks?

The major drawback of the mRNA vaccines is that we have not had yet fully marketed this particular type of vaccine. So, we still do not know the long-term effects of the vaccine, or how long immunity lasts.

The mRNA vaccines are significantly more expensive than the adenovirus vaccine and others in the pipeline for COVID-19.  And the cold-storage requirements (-94º F for the Pfizer vaccine and -4º F for the Moderna vaccine) may limit distribution.

SARS-CoV-2 variants recently emerged that may make the virus more contagious. Will current COVID-19 vaccines protect against the mutated virus, or will we need new ones?

It will take some time to get answers.  But, it’s important to know that RNA viruses like coronaviruses mutate, or change, quite frequently. Not every mutation makes the COVID-19 virus more dangerous or contagious; most have no effect, and others may even weaken the virus. Also, there are several sites (epitopes) on the SARS CoV-2 S protein that are recognized by antibodies. It is likely that multiple sites would have to mutate for the virus to escape the immune response from the vaccines. The current vaccines should cover the newly emerging 20B/501Y.V1 variant originally identified in the UK that has recently been found in Florida.

The bigger question is if we can vaccinate everyone within the next year, or year and a half. How much pressure will that put on SARS-CoV-2 to develop variants that escape immunity? It could happen; I don’t think this virus is going to magically disappear.

The most recent study I saw indicated that natural immunity to other coronaviruses seems to last about three years. The COVID-19 virus may become endemic like these other human coronaviruses that cause the common cold. That means you might need to return for a booster providing better immunity against new viral protein mutations — kind of like we do with the seasonal flu vaccine, which changes a little each year.

//www.youtube.com/watch?v=2BMzLBLOTGg

Would you get one of these first COVID-19 vaccines?

Absolutely, I’ll get vaccinated as soon as I can.

Most short-term side effects are in line with other established vaccines we’re familiar with – including injection site soreness, muscle stiffness, fever, headache, maybe some chills. These symptoms may occur more commonly with the second dose when your immune system is ramping up.  It’s not the vaccine itself causing the side effects, but rather the routine response of your immune system to a vaccine that’s working.

The risk-benefit calculation is simple for me. I’d rather take my chances of getting a headache than being on a ventilator with COVID-19.

Can people who get the vaccine return their pre-COVID lifestyle (meeting in groups, no masks, etc.)?

The Phase 3 clinical trials data showed that the mRNA vaccines are 90-plus percent effective at preventing you from getting symptomatic COVID-19. However, we do not know whether the vaccine blocks asymptomatic transmission of the virus – so, there is still a possibility vaccinated people can be reinfected or reinfect others without having apparent symptoms.

We really cannot lower our guard until we achieve herd immunity – that is, until 75 to 80% of the population obtains immunity to COVID-19 through vaccination, or immunity developed from from prior infection… Herd immunity by natural infection is a terrible experiment to do, because this virus can cause severe disease and death in up to 2% of the population, some people suffer long-term health consequences, and treating that many COVID-19 patients would overwhelm the health care system… So, until enough of us are vaccinated, we all need to continue following the public health measures that help prevent the spread of COVID-19 – wear masks, physically distance, avoid large gatherings and wash our hands.

I don’t think we’ll ever get completely back to our pre-COVID lifestyles, though.

COVID-19 has prevented access to many things, but voting in the General Election this November is not one of them.

From a medical perspective, there are a few important things to consider as you plan how you will cast your ballot. “First and foremost – wear your mask!” said Charles J. Lockwood, MD, senior vice president for USF Health and dean of the Morsani College of Medicine.

“Aside from planning how you will vote to avoid crowds, wearing your mask and remaining more than six feet from other people are the two strongest preventative measures you can take,” Dr. Lockwood said.

In Hillsborough County, election officials are taking steps to keep both voters and election officials and staff safe at all voting locations, including wearing masks and social distancing for any voter lines that form and from the voting booths. Here’s more information about those efforts in a video from the Supervisor of Elections.

“A degree of apprehension is understandable, but election officials have taken careful measures to protect voters and their poll workers,” Dr. Lockwood said.

In Hillsborough County, there are three ways to cast your vote: early voting, vote by mail, and in-person on election day (Nov. 3) at your polling place.

Mail-in voting is likely the least risky way to vote from an infectious disease perspective, Dr. Lockwood said.

“Simply drop it in your nearby secure U.S. Postal Service mailbox and your vote is on its way,” he said. “You can also take your mail-in ballot to the Supervisor of Elections locations and place it in the secure, designated curbside ballot boxes – so there is no real need to stand in line or even get out of your car.”

These locations and more information about voting by mail can be found here.

For early voting, many locations throughout Hillsborough County open Oct. 19 to Nov. 1 and could be an in-person option that has few crowds.

“If an early voting site looks busy, come back another time,” Dr. Lockwood said. “These sites are open for 13 calendar days from 7:00 a.m. to 7:00 p.m., so voters will have ample time and opportunity to visit these locations when there is plenty of spacing and limited crowding.”

More information about early voting and the many locations around Hillsborough County, including many public libraries, can be found here.

And for voting on Nov. 3 election day, Dr. Lockwood notes that this is more of an unknown. Polling places aim to have safety precautions in place, so even with crowds, lines and voting booths will be socially distanced.

Having an election during a pandemic is uncharted waters, Dr. Lockwood said.

“We are living through a generational event that has transformed in our country in ways previously unthinkable,” Dr. Lockwood said. “But how lucky we are to live in a nation where our voices are still heard and every vote still counts.”

Three ways to vote:

Early Voting: October 19 – November 1, 7 a.m. – 7 p.m.

Vote By Mail: We begin mailing out Vote By Mail ballots on September 24, and voted ballots must be in our office by 7 p.m. on November 3. For more info, including drop off locations, visit.

Election Day: November 3. For more info.

The COVID-19 pandemic is having a lasting impact on the way we live, work and interact. Watch Dr. Bryan Bognar, vice dean of the Morsani College of Medicine Department of Medical Education, discuss USF Health’s medical education successes and challenges due to the COVID-19 pandemic.

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The COVID-19 pandemic is having a lasting impact on the way we live, work and interact. Watch Dr. Terri Ashmeade, chief quality officer at USF Health, discuss patient safety in the clinics.

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The COVID-19 pandemic is having a lasting impact on the way we live, work and interact at USF Health. Watch Jacqueleen Reyes Hull, Ed.D, assistant vice president for administration at USF Health, discuss how daily life has changed for faculty and staff.

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USF Health medical student Tampa Hutchens discusses how the COVID-19 pandemic has affected medical education and what students and USF faculty have done to keep their medical training on track.

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USF Health Dean of the Taneja College of Pharmacy Dr. Kevin Sneed discusses the role pharmacists play in responding to the COVID-19 pandemic. Dr. Sneed stresses how pharmacists are helping find promising treatments, connecting with patients virtually to go over their medication regimens and further strengthening the healthcare sector’s approach to fighting the pandemic.

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USF Health Dean of Public Health, Dr. Donna Petersen, discusses the importance of public health especially during pandemics like COVID-19. Dean Petersen stresses the importance of following CDC guidelines — washing hands thoroughly, wearing a mask and maintaining social distance — to avoid contracting and spreading COVID-19. Dr. Petersen leads the COVID-19 Task Force and lays out plans to reopen USF to students, faculty and staff.

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Nurses protect the health and well-being of patients every day and play an integral role in our nation’s health care system. In the latest USF Health Brief, Dr. Usha Menon, interim dean of the USF Health College of Nursing, discusses the challenges and changes nurses and nurse training face during the COVID-19 pandemic.

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Dr. Stephen Liggett, USF Health associate vice president for research, discusses how COVID-19 has changed how research is conducted and the types of conditions researchers work.

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Dr. Deborah DeWaay, USF Health associate dean of undergraduate medical education, discusses the current and long-term changes in medical education due to the COVID-19 pandemic.

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Dr. Mark Moseley, USF Health’s Chief Clinical Officer, discusses how physicians and other health care providers are using telehealth services and technology to remotely care for patients, especially amid the COVID-19 pandemic.

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In the first USF Health Briefs, Dr. Charles Lockwood, Dean of the Morsani College of Medicine, talks about how the COVID-19 pandemic has changed our way of life and access to health care, the lessons the virus is teaching the medical community, and how long it may take before we can safely mingle in large groups again.

In the New Normal – physically distant and wearing masks – the Class of 2024 in the USF Health Morsani College of Medicine began classes this week, marking the start of their four-year medical school journey.

The MD program in the Morsani College of Medicine is one of first programs at USF to start face-to-face classes during the COVID-19 pandemic, an effort that took careful planning, said Bryan Bognar, MD, vice dean of the Morsani College of Medicine.

“We knew we only had one shot at setting this up right,” Dr. Bognar said. “And even with a successful launch, we must be constantly vigilant, all of us, in order to stay ahead of COVID.”

This MCOM Class of 2024, the largest in the college’s history with 190 students, filed into the new building July 27 in set arrival times to pace out screenings. This is the first class to start in the new MCOM facility, which opened in January 2020 in downtown Tampa. Sitting well apart from classmates, the 190 students filled the auditorium, which would typically seat 400 people.

Successfully re-opening for classes was complicated but careful attention to detail is paying off, Dr. Bognar said.

“It’s a marathon, of sorts, and it’s taking an incredible team effort from across USF Health,” he said. “Everyone’s excited about reentry. The key is for us all to stay disciplined to keep it up.”

Some of the main lessons the MCOM program has learned so far include:

• Allow a lot of extra time to stagger arrival times. You’ll be surprised how smooth it goes when entry is paced out.
• Frequently repeat the importance of following guidelines. It’s easy to forget so the reminders help prevent old habits from coming back.
• Lean on student leaders for sharing guidelines and new information to classmates.
• Tap into student creativity for ways to support the effort, offer reminders and provide supplies.
• To serve as reminders of how fast COVID-19 can take hold, share news stories about other schools, programs and businesses that experienced jumps in infections when guidelines weren’t followed.

Auditorium photo courtesy of Bryan Bognar. Other photos by Freddie Coleman

*This information was current on July 9, 2020. It is a rapidly moving pandemic thus this information could change.

There is currently no vaccine to prevent coronavirus disease 2019 (COVID-19), so the best way to prevent illness is to avoid being exposed to this virus. The virus is thought to spread mainly from person-to-person. The CDC recommends that you:

• Wash your hands often
  • Soap and water for at least 20 seconds.
  • Use a hand sanitizer that contains at least 60% alcohol if soap and water are not readily available.
• Avoid close contact
  • Inside your home: if possible, maintain 6 feet between the person who is sick and other household members.
  • Outside your home: put 6 feet of distance between yourself and people who don’t live in your household.
• Cover your mouth and nose with a cloth face cover when around others
  • You could spread COVID-19 to others even if you do not feel sick.
  • The cloth face cover is meant to protect other people in case you are infected.
  • The cloth face cover is especially important when other social distancing measures are difficult to maintain, but it is not a substitute for social distancing when it is possible.
  • Surgical masks and N95 respirators are critical supplies that should be reserved for healthcare workers and other first responders, but if you are wearing a disposable mask, please properly dispose of it in a trash can.
• Cover coughs and sneezes
  • Always cover your mouth and nose with a tissue when you cough or sneeze and then throw the used tissue away in the trash.
  • Use the inside of your elbow and do not spit if you do not have a tissue.
  • Immediately wash your hands with soap and water or clean your hands with hand sanitizer.
• Clean and disinfect
  • Clean and disinfect frequently touched surfaces daily. This includes tables, doorknobs, light switches, countertops, handles, desks, phones, keyboards, toilets, faucets and sinks.
• Monitor your health daily
  • Be alert for symptoms and take your temperature if symptoms develop.
  • Follow CDC guidance if symptoms develop.

• Direct exposure to a positive case: the CDC recommendation would be self-isolation for 14 days and testing only if symptoms develop.
• Indirect exposure to a positive case: in general, the recommendation would be self-monitoring. No need to isolate, but always wear a mask and social distance while being on the lookout for subtle symptoms.
• No knowledge of exposure: testing is not needed if you don’t have symptoms and you have no knowledge of an exposure to a positive case.

Symptoms can range from mild to severe illness, and appear 2-14 days after you are exposed to the virus. Be on the lookout for cough, fever, chills, muscle pain, shortness of breath or difficulty breathing, sore throat and new loss of taste or smell. Please do not go directly to the emergency room without contacting your healthcare provider first. Tampa General Hospital is NOT a COVID-19 testing site.

• For early detection, the FDA approved test is a nasal swab analyzed by PCR. The CDC recommends testing only if symptoms develop.
• There are a number of ways to receive a nasal swab test in your area:
  • Call USF Health at (813) 974-2201 to make an appointment. The volume of symptomatic patients is so high, we may not be able to test those without symptoms unless the patient’s doctor recommends the test because of significant risk factors.

• • Hillsborough County walk up or drive-thru testing sites, by appointment only. Insurance not required.
    • For more information or to make an appointment, CALL (888) 513-6321 or register online at HillsboroughCounty.org/Coronavirus

• • Pinellas County walk up testing sites, by appointment only. Insurance not required.
    • CALL (727) 824-6900 to make an appointment. Visit COVID19.PinellasCounty.org/testing/ for more information.
  • Pinellas County drive-thru testing sites, no appointment necessary. Insurance not required.
    • Visit COVID19.PinellasCounty.org/testing/ for testing location information.

• • Sarasota County testing sites, by appointment only. Insurance not required.
    • Testing is prioritized for anyone currently experiencing symptoms and individuals who work in a health care setting.
    • CALL (941) 861-2883 to make an appointment. Visit SCGov.net for testing location information.
  • Sarasota and Manatee County walk up or drive-thru testing sites, no appointment necessary. Insurance not required.
    • Visit SCGov.net for testing location information and requirements.

• An antibody blood test can tell you if you had a previous infection. It is not recommended for early detection because it can take 1-3 weeks after infection to make antibodies. It is unknown at this time if having antibodies to the virus can protect someone from getting infected with the virus again, or how long that protection might last.

• Positive with no symptoms: you should stay home for 10 days according to CDC guidelines. The course is unpredictable and within 5 days, many will develop symptoms. As much as possible, separate yourself from other people in your household.
• Positive with symptoms: you will need to isolate for a complete 10 days starting the first day of symptoms and 3 days of being fever-free without treating to suppress a fever. You need to meet both criteria to be able to stop quarantine. As much as possible, separate yourself from other people in your household.
• Notify anyone who may have been exposed to you within the last two weeks to let them know about your positive test result so they can self-monitor.
• Only go to the hospital or call 911 for help if your symptoms escalate into a medical emergency. Notify the operator that you have COVID-19. If possible, put on a cloth face covering before medical help arrives. Most people with COVID-19 have mild illness and can recover at home without medical care. Do not leave your home, except to get medical care.

• For information, visit USF Health’s COVID-19 patient resources page.
• Learn more about our Telehealth virtual appointments.
• This information was current on July 9, 2020. It is a rapidly moving pandemic thus this information could change.

USF Health medical student Tampa Hutchens discusses how the COVID-19 pandemic has affected medical education and what students and USF faculty have done to keep their medical training on track. This is the final episode in an eight-part series looking at the way COVID -19 is impacting the way we live, work and access health care.

A University of Arizona-University of South Florida team  identified and analyzed four promising antiviral drug candidates in the preclinical study

TAMPA, Fla. (July 6, 2020) — As the death toll from the COVID-19 pandemic mounts, scientists worldwide continue their push to develop effective treatments and a vaccine for the highly contagious respiratory virus.

University of South Florida Health (USF Health) Morsani College of Medicine scientists recently worked with colleagues at the University of Arizona College of Pharmacy to identify several existing compounds that block replication of the COVID-19 virus (SARS-CoV-2) within human cells grown in the laboratory. The inhibitors all demonstrated potent chemical and structural interactions with a viral protein critical to the virus’s ability to proliferate.

Yu Chen, PhD, an associate professor of molecular medicine with expertise in structure-based drug design, has turned toward looking for new or existing drugs to stop SARS-CoV-2.

The research team’s drug discovery study appeared June 15 in Cell Research, a high-impact Nature journal.

The most promising drug candidates – including the FDA-approved hepatitis C medication boceprevir and an investigational veterinary antiviral drug known as GC-376 – target the SARS-CoV-2 main protease (M^pro), an enzyme that cuts out proteins from a long strand that the virus produces when it invades a human cell. Without M^pro, the virus cannot replicate and infect new cells. This enzyme had already been validated as an antiviral drug target for the original SARS and MERS, both genetically similar to SARS-CoV-2.

“With a rapidly emerging infectious disease like COVID-19, we don’t have time to develop new antiviral drugs from scratch,” said Yu Chen, PhD, USF Health associate professor of molecular medicine and a coauthor of the Cell Research paper. “A lot of good drug candidates are already out there as a starting point. But, with new information from studies like ours and current technology, we can help design even better (repurposed) drugs much faster.”

Before the pandemic, Dr. Chen applied his expertise in structure-based drug design to help develop inhibitors (drug compounds) that target bacterial enzymes causing resistance to certain commonly prescribed antibiotics such as penicillin. Now his laboratory focuses its advanced techniques, including X-ray crystallography and molecular docking, on looking for ways to stop SARS-CoV-2.

Using 3D computer modeling, Michael Sacco (left), a doctoral student in the Department of Molecular Medicine, worked with Dr. Chen to determine the interactions between antiviral drug candidate GC-376 and COVID-19’s main protease.

M^pro represents an attractive target for drug development against COVID-19 because of the enzyme’s essential role in the life cycle of the coronavirus and the absence of a similar protease in humans, Dr. Chen said. Since people do not have the enzyme, drugs targeting this protein are less likely to cause side effects, he explained.

The four leading drug candidates identified by the University of Arizona-USF Health team as the best (most potent and specific) for fighting COVID-19 are described below. These inhibitors rose to the top after screening more than 50 existing protease compounds for potential repurposing:

• Boceprevir, a drug to treat Hepatitis C, is the only one of the four compounds already approved by the FDA. Its effective dose, safety profile, formulation and how the body processes the drug (pharmacokinetics) are already known, which would greatly speed up the steps needed to get boceprevir to clinical trials for COVID-19, Dr. Chen said.
• GC-376, an investigational veterinary drug for a deadly strain of coronavirus in cats, which causes feline infectious peritonitis. This agent was the most potent inhibitor of the M^pro enzyme in biochemical tests, Dr. Chen said, but before human trials could begin it would need to be tested in animal models of SARS-CoV-2. Dr. Chen and his doctoral student Michael Sacco determined the X-ray crystal structure of GC-376 bound by M^pro, and characterized molecular interactions between the compound and viral enzyme using 3D computer modeling. 

• Calpain inhibitors II and XII, cysteine inhibitors investigated in the past for cancer, neurodegenerative diseases and other conditions, also showed strong antiviral activity. Their ability to dually inhibit both M^pro and calpain/cathepsin protease suggests these compounds may include the added benefit of suppressing drug resistance, the researchers report.

All four compounds were superior to other M^pro inhibitors previously identified as suitable to clinically evaluate for treating SARS-CoV-2, Dr. Chen said.

Michael Sacco looks at COVID-19 viral protein crystals under a microscope.

A promising drug candidate – one that kills or impairs the virus without destroying healthy cells — fits snugly, into the unique shape of viral protein receptor’s “binding pocket.” GC-376 worked particularly well at conforming to (complementing) the shape of targeted M^pro enzyme binding sites, Dr. Chen said. Using a lock (binding pocket, or receptor) and key (drug) analogy, “GC-376 was by far the key with the best, or tightest, fit,” he added. “Our modeling shows how the inhibitor can mimic the original peptide substrate when it binds to the active site on the surface of the SARS-CoV-2 main protease.”

Instead of promoting the activity of viral enzyme, like the substrate normally does, the inhibitor significantly decreases the activity of the enzyme that helps SARS-CoV-2 make copies of itself.

Visualizing 3-D interactions between the antiviral compounds and the viral protein provides a clearer understanding of how the M^pro complex works and, in the long-term, can lead to the design of new COVID-19 drugs, Dr. Chen said. In the meantime, he added, researchers focus on getting targeted antiviral treatments to the frontlines more quickly by tweaking existing coronavirus drug candidates to improve their stability and performance.

Two viral protein images generated by Yu Chen, University of South Florida Health, using X-ray crystallography. Above: The protein dimer (one molecule is blue and the other orange) shows the overall structure of the COVID-19 virus’s main protease (M^pro), the researchers’ drug target. Below: Three configurations of active sites where inhibitor GC-376 binds with the M^pro viral enzyme, as depicted by 3D computer modeling.

Dr. Chen worked with lead investigator Jun Wang, PhD, UA assistant professor of pharmacology and toxicology, on the study. The work was supported in part by grants from the National Institutes of Health.

-Photos by Torie Doll, USF Health Communications and Marketing

USF Health Dean of the Taneja College of Pharmacy Dr. Kevin Sneed discusses the role pharmacists play in responding to the COVID-19 pandemic. Dr. Sneed stresses how pharmacists are helping find promising treatments, connecting with patients virtually to go over their medication regimens and further strengthening the healthcare sector’s approach to fighting the pandemic. This is the seventh in an eight-part series looking at the way COVID -19 is impacting the way we live, work and access health care.