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.

A USF-Health led study analyzing plasma cell-free DNA indicates host inflammation is as important as damage inflicted by the parasite in cerebral malaria

A mother and her comatose child with cerebral malaria on the Malaria Research Ward at Queen Elizabeth Central Hospital, Blantyre, Malawi. [Photo by Jim Peck, Blantyre Malaria Project/Michigan State University]

Even with good antimalarial treatment, about one in five children diagnosed with cerebral malaria (CM) dies — and those who survive often have long-lasting neuropsychiatric complications such as learning disabilities, hyperactivity and behavioral problems.

It remains challenging for doctors to predict which particular pediatric patients are at highest risk for potentially fatal CM; the vast majority of children contract uncomplicated malaria with flu-like symptoms that typically resolve.  Current tools to help identify and triage those with the severest forms of malaria — including a specialized ophthalmic examination to pinpoint abnormalities in retinal blood vessels, brain imaging, blood work requiring a phlebotomist, and immunology laboratory testing — are cost-prohibitive in developing countries where malaria is most common.

A retrospective study led by researchers at the University of South Florida Health (USF Health) Morsani College of Medicine suggests that measuring cell-free DNA in plasma (cfDNA) offers a simple, rapid way to identify severe and potentially deadly cases of malaria.  The team’s findings were published recently in in JCI Insight, a journal of the American Society for Clinical Investigation.

Kami Kim, MD, (above) and Iset Vera, PhD (below), of the USF Health Division of Infectious Disease and International Medicine, led this study. They conduct malaria research with the Blantyre Malaria Project in Malawi, Africa, and other collaborators.

DNA is normally contained inside cells. Cell-free DNA circulates freely in plasma or other bodily fluids and often indicates the destruction of cells, including immune cells (neutrophils) that play a role in clearing malaria parasites.

A simple biological molecule (biomarker) like cfDNA that correlates with disease severity and risk of death can help guide clinical decisions, such as whether to admit a child with malaria into the intensive care unit, or start adjuvant treatments (in addition to antimalarial drugs) to decrease brain swelling or control platelet counts, said the paper’s senior author Kami Kim, MD, professor and director of the USF Health Morsani College of Medicine’s Division of Infectious Disease & International Medicine.  While uncomplicated malaria can be treated with oral antiparasitic drugs, treating severe malaria requires IV medications in a hospital setting.

“Plasma cell-free DNA offers a clinical tool to help (health providers) target specific treatments and more effectively use medical resources, especially in rural settings where specialized equipment and therapies are limited or unavailable,” Dr. Kim said. “That can end up benefiting more patients.”

The USF Health study compared the plasma of Malawian children with cerebral malaria, uncomplicated malaria (symptomatic but no severe illness) and no malaria (healthy controls).

Blood smear from a patient with cerebral malaria depicts red blood cells infected by the malaria parasite Plasmodium falciparum. At the center of the image is a DNA neutrophil extracellular trap, or NET, near the infected cells.

The researchers measured levels of total cfDNA in the children’s plasma by streamlining a test employing an easy-to-use, portable device to detect cellular genetic material with fluorescent molecules. They used laboratory-based polymerase chain reaction (PCR) technology to specifically measure each of the two types of cfDNA that make up total cfDNA — the host (patient) cfDNA and the parasite cfDNA.  The bedside test required just a finger prick of blood to provide results in about 5 minutes, versus the 5-hour turnaround time of the more technologically-advanced PCR test. Both tests performed comparably in detecting total cfDNA levels, Dr. Kim said.

Other research groups previously linked the concentration of parasite cfDNA in human plasma to malaria severity in children and adults.  But this new study was the first to show that total plasma cfDNA is predominantly made up of host cfDNA, rather than cfDNA derived from the malaria parasite.

The higher that levels of total cfDNA (and major contributor host cfDNA) rise, the sicker children with malaria get, said first author Iset M. Vera, PhD, a research instructor in the USF Health Department of Internal Medicine. Both were better indicators of disease severity than parasite cfDNA alone, Dr. Vera added.

“Host inflammation promoted by the immune response of white blood cells (neutrophils) contributed to disease progression, and therefore the total cfDNA in plasma correlated with severity of malaria infection, including deaths from cerebral malaria,” Dr. Kim said.  “The cfDNA marker gave us insight into what may be causing inflammation in the super sick kids. The study  substantiated our hypothesis that host inflammation is as much a critical part of cerebral malaria as the damage done by the parasite.”

Dr. Karl Seydel (MSU and Blantyre Malaria Project) about to examine a young patient recovering from cerebral malaria on the Malaria Research Ward at Queen Elizabeth Central Hospital, Blantyre, Malawi. [Photo by Jim Peck, BMP/MSU]

That’s important because malaria exacts disproportionate human and economic costs on the world’s poorer countries, Dr. Vera said.  “Malaria burdens the mothers who travel to urban hospitals and spend days there so their sick children can get the advanced care unavailable in their communities. And, it burdens developing countries when children die from malaria or develop long-term complications so they cannot grow up to be productive adults.”

The study was supported in part by grants from the National Institutes of Health’s Center for Advancing Translational Science, the Burroughs Welcome Fund, and the National Health and Medical Research Council of Australia.

The female Anopheles mosquito transmits the malaria parasite to humans through its bite. P. falciparum malaria—the most deadly type—is most common in sub-Saharan Africa, where it causes more than 400 000 deaths a year, mostly in young children.

The device invented by USF Health doctors, teaming with Tampa General Hospital, Northwell Health and Formlabs, has been used worldwide to address critical shortages of test kit swabs

Tens of millions of the USF Health-invented 3D printed nasal swabs have been mass produced for use by health care providers worldwide. [Allison Long, USF Health Communications]

Now, a multisite clinical trial led by the University of South Florida Health (USF Health) Morsani College of Medicine provides the first evidence that 3D-printed alternative nasal swabs work as well, and safely, as the standard synthetic flocked nasal swabs.

The results were published online Sept. 10 in Clinical Infectious Diseases. A commentary accompanying the paper cites the authors’ timely, collaborative response to supply chain disruptions affecting testing capacity early in the pandemic.

Seeking a solution to an unprecedented demand for nasal swabs at their own institution and others, USF Health researchers in the Departments of Radiology and Infectious Diseases reached out to colleagues at Northwell Health, New York’s largest health care provider, and leading 3D-printer manufacturer Formlabs. Working around the clock, this multidisciplinary team rapidly designed, tested and produced a 3D printed nasal swab prototype as a replacement for commercially-made flocked nasal swabs. Bench testing (24-hour, 3-day, and leeching) using respiratory syncytial virus as a proxy for SARS-CoV-2, as well as local clinical validation of the final prototype (fabricated with FDA-approved nontoxic, surgical grade materials), was successfully completed in mid-March 2020.

The larger-scale clinical trial began in late March at three sites: Tampa General Hospital (TGH), Northwell Health, and Philadelphia-based Thomas Jefferson University Hospital.  (Other sites joined later.)

The paper’s first author Summer Decker, PhD, directs the USF Health Radiology-TGH Division of 3D Clinical Applications, which creates and prints 3D anatomical models for surgeons and other clinicians and designs medical devices. [Allison Long, USF Health Communications]

“In the midst of a pandemic, our team of experts representing academic medicine, health care delivery systems, and the medical device industry put aside boundaries to quickly work together toward a common purpose,” Dr. Decker said. “It’s rewarding that the novel design for a 3D swab we created has been adopted around the world, equipping more providers to diagnose COVID-19 and hopefully help prevent its spread.”

The gold standard for diagnosing respiratory infections is to look for viral genetic material found in mucosal fluid collected with a long, slender swab inserted into the patient’s nose and back of the throat. The nasal swab is put into a plastic tube with chemicals that stabilize the sample until the virus-specific genetic material can be extracted and amplified by polymerase chain reaction (PCR) in a diagnostics laboratory. Conventional swabs feature a bushy tip coated with nylon flock; the USF Health doctors designed a tip with a 3D printed textured pattern able to capture a sufficient sample for COVID testing while keeping patient safety and comfort in mind.

Kami Kim, MD, infectious diseases division director at USF Health Morsani College of Medicine, led the multisite clinical trial comparing the performance of commercial nasal swabs with the 3D-printed alternative.

The clinical trial fully tested the safety and effectiveness of this 3D printed swab in 291 symptomatic adults undergoing COVID-19 screening at the TGH, Northwell Health and Thomas Jefferson University Hospital sites. The 3D printed nasal swab was compared to the standard synthetic nasal swab across three SARS-CoV-2 testing platforms FDA-authorized for emergency use — a modified version of the Center for Disease Control and Prevention’s real-time reverse transcriptase PCR diagnostic panel, and two commercial molecular diagnostic tests.

“This trial provided the first rigorous head-to-head comparison to make sure that the 3D swab performed as well as the standard,” said principal investigator Kami Kim, MD, professor and division director for infectious disease at the USF Health Morsani College of Medicine. “Across all three platforms used in our study, we demonstrated that the commercial swab and the 3D printed swab were comparable for accurate detection of COVID-19 infection.”

For both swabs, the only adverse patient reaction documented during the trial was a few instances of slight nasal bleeding. The cost of materials per 3D printed nasal swab ranges from 26-to 46-cents, while commercial swabs cost about $1 each, the authors reported.

Given the ongoing need for widespread COVID-19 testing, the study authors concluded that 3D printing technology offers a viable, cost-efficient option to address swab supply shortages, particularly when local hospitals or other clinical sites already have 3D printing labs equipped to print and process the devices.

The 3D printed nasal swabs were specifically designed for patients using FDA-approved surgical grade material. [Allison Long, USF Health Communications]

“Among all parts 3D printed during COVID-19, nasopharyngeal swabs have received the most attention, with participants ranging from humanitarians to charlatans,” Dr. Rybicki wrote in his summary. “The authors should be congratulated for staying on the right side of the curve, and for their perseverance, leadership, scientific rigor, and good will.”

From designing 3D printed test swabs, to researching antibody responses and engaging in leading clinical trials, USF Health scientists rapidly team up to help fight COVID-19

While the world waits for therapies to reduce death rates and a widely available vaccine to prevent COVID 19, team science at USF Health and other academic medical centers continues to take on an unprecedented sense of urgency.

Globally, scientists across disciplines are publicly sharing their ideas, expertise and data like never before – all singularly focused on finding solutions to a highly contagious and potentially life-threatening new virus known as severe acute respiratory syndrome coronavirus 2, or SARS-CoV-2.

Since the pandemic began, the number of studies posted by researchers worldwide to open-access repositories like bioRxiv and medRxiv has skyrocketed. These preprints – papers written after a study concludes but made available before peer review – let scientists disseminate their findings more quickly and obtain instant feedback on their work. Researchers also continue to identify and share viral genome sequences, protein structures, and COVID-19 related epidemiological and clinical data through online databases.

Meanwhile, thousands of clinical trials have been launched as academic medical centers, hospitals and laboratories join forces with government and industry in the search for optimal diagnostics and therapies. At USF Health, more than 65 COVID-19 related laboratory, clinical and epidemiological projects are underway or in final stages of the approval process. These represent unique research efforts by the faculty of all four USF Health colleges, as well as joint efforts with pharmaceutical firms and biotechnical and software companies. Many of the patient-related studies are conducted by USF Health faculty physicians at Tampa General Hospital.  USF Health is also working with Tampa General to create a biorepository that collects, processes and stores health data and residual specimens from patients who test positive or negative for COVID-19 to use in future biomedical research.

“The need for rapid and accurate basic and clinical results has never been greater. The scientific community has risen to the challenge of a lifetime and continues to push forward,” said Stephen Liggett, MD, associate vice president for USF Health Research and vice dean for research in the Morsani College of Medicine. “Without a doubt we are still in the early stages of understanding this new coronavirus – in knowing who should be tested and how often, and which tests work best; in knowing how to treat patients and how effective vaccines will be in conferring immunity.”

//www.youtube.com/watch?v=8LWaITfItQA

View the interview with Stephen Liggett, MD, associate vice president for research at USF Health, who discusses how the COVID-19 pandemic has changed research here.

USF faculty and student researchers have been quick to mobilize their talent and resources, Dr. Liggett said. “They want to do whatever they can to find answers — both to help fight this pandemic and to prepare for future outbreaks.”

How are some key scientific areas contributing to the pandemic response?  Below are just a few examples provided by USF Health scientists:

Epidemiology:  Containing the spread of the virus

From the start, epidemiologists have been at the forefront of efforts to understand how fast and why SARS-CoV-2 is spreading. Also known as disease detectives or virus hunters, epidemiologists and the models using data they gather are instrumental in tracking and predicting the patterns of disease transmission in populations, said Thomas Unnasch, PhD, distinguished professor in the USF College of Public Health and codirector of the Center for Global Health Infectious Disease Research. Their work had been critical for both guiding policymakers’ plans to curb the pandemic and helping evaluate whether countermeasures to contain the virus are working.

“We’ve been hunkered down in the midst of a pandemic wildfire and testing only the symptomatic people most likely to be infected” — largely to prevent surges of sick patients from overwhelming the health care system, Dr. Unnasch said. “We’re still missing about 90 percent of the population with COVID-19 infections exhibiting mild or no symptoms.”

USF College of Public Health’s Thomas Unnasch, PhD, oversees the COVID-19 symptom surveillance network for Tampa Bay.

Dr. Unnasch oversees a symptom-based surveillance network launched in mid-April to help identify and map COVID-19 hotspots across the Tampa Bay region. USF College of Public Health researchers worked with the Hillsborough, Pinellas, Pasco and Polk County Health Departments to create the Tampa Bay symptom surveillance survey, adapting existing COVID-19 surveillance technology developed by the Puerto Rico Sciences Trust and deployed in Puerto Rico and, more recently, the Boston area through Harvard University.

The anonymous survey asks Tampa Bay residents questions about potential exposure and symptoms consistent with COVID-19. The information collected, which drills down to the zip code level, is provided to the local health departments and hospital groups.

Surveillance – a tool commonly used by public health agencies to identify and prevent the spread of HIV, tuberculosis, anthrax and other infectious diseases – can help fill in the gaps created by limitations inherent in a complex society, such as a lack of uniform testing, Dr. Unnasch said.

COVID-19 cases in Pinellas and Hillsborough County broken down by zip code, as tracked and entered by the Hillsborough County Health Department on April 16, 2020. Pasco and Polk counties have since been added to the symptom surveillance system.

“So far the only way to prevent the disease is to prevent transmission of the virus. That has meant everyone doing the right thing — staying at home, social distancing face masks, and hygiene,” Dr. Unnasch said.  “As we reopen our communities, surveillance can help us do that safely by detecting clusters of new cases early at a very targeted level, so we can stomp out the embers before they reignite COVID-19 outbreaks.”

Real-time mapping of suspected COVID-19 hotspots can be used to strategically direct Tampa Bay’s public health resources to specific areas where testing, contact tracing and isolation are most likely needed, he said.

“The more data we get and the more accurate the information, the more powerful the tool will be.”

Biostatisticians: Keeping the bias at bay

The data collected by epidemiologists or other health researchers can be fed into mathematical models that predict how fast COVID-19 infections may spread or the number of deaths expected in an overall population. At the community/clinical level, predictive models can help hospitals and medical staff triage patients and allocate limited health care resources (like ICU beds or ventilators) by estimating the risk of people being infected or having a poor disease outcome.

While they can be useful to prepare for worst-case scenarios, predictive models have differed widely in their forecasts – and sometimes they can cause more harm than benefit in guiding policy or clinical decisions, said Ambuj Kumar, MD, MPH, director of the Research Methodology and Biostatistics Core, USF Health Office of Research.

Dr. Kumar, a biostatistician and associate professor of internal medicine, points to a recently published systematic review analyzing studies of prediction models for the diagnosis and prognosis of patients with COVID-19. This review concluded that all 31 clinical models were poor quality, at high risk of bias, and their reported performance was likely overly optimistic.

Ambuj Kumar, MD, MPH, directs USF Health’s Research Methodology and Biostatistics Core.

Methodologist/biostatisticians like Dr. Kumar are trained to recognize the issues and complications arising from the analysis of human health data. They play a key role in any team designing and executing a model, providing the statistical methodology needed to draw meaningful conclusions or make predictions. These data scientists help reduce bias in selecting sample populations, observing or reporting findings, and measurement. They are attuned to factors that can interfere with an accurate estimate of cause-and-effect.

Requiring frequent updates, projections are only as good as the model’s underlying assumptions and the reliability and standardization of the data applied to the model, Dr. Kumar said.

For instance, the commonly cited Institute for Health Metrics and Evaluation model assumes social distancing and other strong voluntary measures to control viral spread will stay in place, but predicting how people will behave as the U.S. reopens in phases is tricky. And, the death data relied upon by many models may be confounded a lack of consistency in the way COVID-19 deaths are reported and counted by hospitals and health departments. (Public health experts have suggested that deaths are undercounted.)

Predictive modeling uses existing data and reasonable assumptions to forecast how an infectious disease spreads in the real world. As more data becomes available, it triggers adjustment of the model, resulting in different outcomes.

Many people understandably want to know now what to expect during this pandemic: How many more cases? How long will it last? When can I safely return to work, or school? Will there be a second wave?

But, many uncertainties about testing, immunity, susceptibility and treatments still influence the variables that make up the algorithms forecasting COVID-19 outcomes, Dr. Kumar said. As the reliability and accuracy of rapidly accumulating data improves, so should the models, he added.

“Predicting the future is particularly challenging when we’re dealing with a virus new to the entire world,” Dr. Kumar said.  “Whether you’re battling COVID-19 or another crisis, you can’t compromise on the systematic, standardized approach needed to create a useful model, or study. If you want accurate results, there’s no substitute for good, rigorous science.”

Virology:  Studying how SARS-CoV-2 works

To develop effective therapies and vaccines to combat COVID-19, scientists need to understand how the virus functions, including its interaction with human immune response. That’s the role of virologists like Michael Teng, PhD, associate professor of internal medicine in the USF Health Morsani College of Medicine.

Dr. Teng has spent many years working with the National Institutes of Health and other groups on research and development of a vaccine for respiratory syncytial virus, or RSV. While RSV was discovered over 60 years ago, researchers continue to work on a vaccine for this common respiratory virus that infects virtually every child by age 2.

Like many other scientists, USF Health virologist Michael Teng, PhD, quickly pivoted from his usual research activities to respond to the new global health threat.

Scientists and companies now testing a myriad of SARS-CoV-2 vaccines in the pipeline have benefited from the extensive RSV research, Dr. Teng said. “They’ve learned a lot from RSV about what works and what pitfalls to avoid in vaccine development.”

Like many other scientists, Dr. Teng quickly pivoted from his usual research activities to respond to the new global health threat. In mid-March his laboratory studied the durability and effectiveness of the 3D-printed nasal swabs successfully created for COVID-19 testing by a team at USF Health Radiology and its innovative 3D Clinical Applications Division, directed by  associate professor Summer Decker, PhD.  Faculty with expertise  in anatomy and infectious diseases as well as radiology contributed to the effort. The ambitious 3D design, modeling and printing project teamed USF Health with Formlabs, a 3D printer manufacturer, and Northwell Health, the largest hospital system in New York, the pandemic’s U.S. epicenter.

An integral part of coronavirus test kits that detect the RNA virus’s genetic code, swabs were in extremely short supply as the pandemic escalated. The slender, flexible device collects a sample from the nasal passages or throat, and that sample goes into a test tube containing transport media for preservation until the specimen is processed by a hospital or commercial laboratory. Using RSV as a proxy for a SARS-CoV-2, synthetic respiratory tract mucous (made by USF Health’s Sophie Darch, PhD), and a World Health Organization recipe for transport media, Dr. Teng demonstrated that the 3D-printed alternative swabs worked as well as conventional commercial swabs to safely collect enough of the sample, without leeching into transport media or interfering with the nucleic acid test’s ability to detect virus particles.

Top:  A USF Health Radiology-led team successfully designed, tested and produced a prototype 3D printed nasopharyngeal swab in record time. As of late May, more than 50,000 of the nasal swabs had been mass produced and were being used worldwide by health care providers to alleviate bottlenecks in COVID-19 testing. Bottom: Jonathan Ford, PhD, a biomedical engineer in USF Health Radiology, holds a cube of the 3D diagnostic nasal swabs.

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The 3D printed swabs, fabricated with FDA-approved, nontoxic materials, also passed performance benchmarks when clinically validated in hospitalized patients undergoing COVID-19 screening at Tampa General Hospital and Northwell Health sites. (A larger-scale multisite clinical trial, led by USF Health Infectious Disease Division Director Kami Kim, MD, is further evaluating the performance of the investigational 3D swabs for diagnostic testing.) Meanwhile, several hundred hospitals and academic medical centers across the country, many state governments, and international agencies and health care facilities are already using the USF-patented swabs to alleviate bottlenecks in COVID-19 testing.

The team worked late nights, taking only about a week from swab prototype design and bench testing to the start of clinical validation. “That’s an incredibly fast turnaround time,” Dr. Teng said.

Dr. Teng is also a coinvestigator for a Morsani College of Medicine-College of Public Health project led by Dr. Kim, which is working to find and map epitopes, the parts of SARS-CoV-2 proteins recognized by the immune system. Antibodies are made by the immune system in response to a threat from a specific virus, bacteria and other harmful pathogen. Some epitopes are associated with protective antibody responses that neutralize (inactivate) a virus when that pathogen is recognized by the immune system again. Others may actually lead to a harmful immune response when a person is exposed to the same virus a second time. The USF Health team wants to identify specific epitopes triggering strong protective antibodies to help researchers design vaccines that mimic a beneficial immune response against COVID-19.

“The data we gather may also be useful in screening (convalescent) plasma for specific antibodies that may best be used to treat critically ill COVID-19 patients,” Dr. Teng said.

Thomas McDonald, MD, USF Health professor of cardiovascular sciences, is investigating whether genetic, physiological or medication-interaction factors may contribute to racial and ethnic disparities in COVID-19 infection rates and cardiovascular complications.

A coronavirus “pseudotype” created by Dr. Teng’s laboratory is being used by the team working on finding neutralizing antibodies and a second USF Health team investigating what factors may affect who suffers worse COVID outcomes.

The second team, led by Thomas McDonald, MD, professor of cardiovascular sciences at the USF Health Heart Institute, wants to know if socioeconomic differences alone account for racial and ethnic disparities in who gets sicker and dies from COVID-19, or if genetic, physiological, or even medication-interaction factors contribute to disproportionate infection rates and cardiovascular complications.

Human pluripotent stem cells grown in Dr. McDonald’s laboratory are prodded to become lung, immune, and heart cells in a petri dish. The stem cells come from blood samples donated by many patient volunteers of different ages, genders and races, as well as various pre-existing cardiovascular conditions. These tissue samples will be infected with the COVID-19 proxy virus engineered by Dr. Teng.

The substitute virus combines the well-studied vesicular stomatitis virus (VSV) with an outer shell containing the spike protein on the surface of SARS-CoV-2 that allows the coronavirus to enter human cells. This non-replicating virus is “a sheep in wolf’s clothing,” invading cells like the COVID-19 virus without harming scientists working with the pathogen, Dr. McDonald said. VSV also expresses the same enzyme, luciferase, that gives fireflies their glow. When hit with a chemical, this “firefly luciferase” lights up the virus so researchers can trace how much invades cells and which cell types are vulnerable.

“With a machine we can image the range of light, which is the level of infection coming out of the cells,” Dr. Teng said.

For the Dr. Kim-led study evaluating the ability of different serum antibodies to block the virus from entering human cells, less light would indicate that the antibodies protected against infection, he added.

Luciferase, the same enzyme that gives fireflies their glow, is helping USF Health researchers track how much proxy COVID-virus invades human cells and which cells are most vulnerable.

Structural biology: A key to drug discovery

Unraveling the structure of viral proteins and identifying the receptors they use to enter cells can help guide discovery and design of potential antiviral treatments.

Yu Chen, PhD, is a USF Health associate professor of molecular medicine with a background in structural biology and biochemistry. Dr. Chen applies his expertise in structure-based drug design using advanced techniques — including X-ray crystallography and molecular docking — to help develop inhibitors (drug compounds) that target bacterial enzymes causing resistance to certain commonly prescribed antibiotics such as penicillin.

Now he’s turned his attention toward looking for new or existing drugs to stop SARS-CoV-2.

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

One way to do this would be to block the virus’s main protease, known as M^pro, an enzyme that cuts out proteins from a long strand that the virus produces when it invades a cell. Without it, the virus cannot replicate. Dr. Chen works with colleagues at the University of Arizona College of Pharmacy (Jun Wang, PhD) and the USF Department of Chemistry (James Leahy, PhD) on this project.

“M^pro represents a promising target for drug development against COVID-19 because of the enzyme’s essential role in viral replication 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.

This winter, an international team of scientists shared their description of the complex crystal structure of M^pro and in April published their discovery of its inhibitors, a half-dozen leading drug candidates identified by targeting the viral enzyme. Taking advantage of the breakthrough, Dr. Chen and other scientists worldwide hope to add more candidates to the drug discovery pipeline soon.

Together with the scientists from University of Arizona, Dr. Chen has found that several known protease inhibitors, including an FDA-approved hepatitis C (HCV) drug boceprevir and an investigational veterinary antiviral drug GC376, showed potent inhibition of the viral protein, and were more active than the previously identified inhibitors. Dr. Chen and his doctoral student, Michael Sacco, have recently determined the first structure of GC376 bound by M^pro, and characterized the molecular interactions between the compound and the viral enzyme.  Their paper describing these results will soon be published in the prestigious scientific journal Cell Research.

Generated by X-ray crystallograhy, this image depicts the overall structure of the COVID-19 virus’s main protease (Mpro), which plays a key role in viral replication. Dr. Chen and colleagues recently found two new protease inhibitors that offer promise in blocking the drug target. –Photo courtesy of Yu Chen.

Dr. Chen and colleagues are also looking for small molecules that can effectively stop the M^pro enzyme from working or last long enough in the body to kill the COVID-19 virus.

The researchers use the latest computer software to visualize and predict how different drug candidates (M^pro inhibitors) bind with the viral proteins. This 3D structural analysis of “binding hotspots” can help in designing and chemically modifying other types of protease inhibiting-drugs with improved activity against SARS-CoV-2, Dr. Chen said.

The most potent antiviral compounds would be tested in human respiratory cell cultures growing the virus. Only then can a drug candidate move to animal models, and, eventually, human trials.

Genomics: Linking genetic variations to outcomes

Why do some individuals get so ill from the COVID-19 virus, while others barely notice symptoms? Why do certain countries and populations have higher death rates than others? Age, underlying medical conditions, socioeconomic and environmental factors play a role – but genetic variation, both in the virus itself and the humans it invades, are likely part of the equation.

“This virus has swept across the world, and some differences in immune response, virulence and disease outcomes of people infected with SARS-CoV-2 could be due to various strains of the virus yet to be defined,” USF Health’s Dr. Liggett said.

Differences in immune response, virulence and disease outcomes of people infected with SARS-CoV-2 could be due to various strains of the virus not yet defined, Dr.  Liggett says.

Sequencing all genes that make up the COVID-19 virus — not just certain sections of the virus’s genome — will be key to uncovering genetic changes that could make a difference in patient susceptibility and outcomes, Dr. Liggett said. More than a decade ago, a team led by Dr. Liggett sequenced for the first time all known genomes of the human rhinovirus, providing a framework for antiviral treatments or vaccine development for this common respiratory virus implicated in asthma flare-ups.

“All parts of a virus’s genome work together for its existence, reproduction and infectivity,” he said. “So, to sequence only one part would be like looking at just the spark plugs, instead of the whole engine, when your car is not running well.”

The data gathered so far indicates that SARS-CoV-2 mutates slowly in the population. Most people have only 10 or so genetic variations in the 30,0000 nucleotide viral genome compared to the reference standard, Dr. Liggett said. “This may be a good sign that antibodies developed from an infection, a vaccine, or derived from an infusion, will provide long-lived immunity. This lower level of mutations also allows us to track a viral strain, potentially knowing how a community became infected.”

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Noting where genetic variation does not occur is also important, since this may represent a “soft-spot” in the virus’s genome that cannot tolerate change because it is so vital, he added. “That might offer a clue about where to target a vaccine or therapy.”

As for human genetic variations that might influence whether certain individuals or subgroups of patients with COVID-19 fare better or worse, Dr. Liggett says the scientific community understands many human genes responsible for mounting an immune defense against this SARS-CoV-2 virus, and other respiratory viruses.

“With enough samples and epidemiology, we may be able to identify patients at genetic risk for serious, life-threatening outcomes,” he said. “However, it will be extremely challenging to find those needles in this big haystack.”

Clinical Trials: Testing treatments that attack on several fronts

As clinicians cared for more patients, one thing became increasingly clear – COVID-19 is more than a respiratory disease that injures the lungs.

It can strike many cell types and organs throughout the body including the brain, heart, blood vessels and kidneys; destroy taste and smell; cause life-threatening blood clots; and trigger a dangerous inflammatory cytokine storm. People with weakened immune systems are more vulnerable to severe illness – including the elderly and those with heart or lung diseases, diabetes, obesity or other underlying medical conditions. Black and Latino populations are disproportionately more likely to die from the virus. And while children are largely spared, a rare inflammatory pediatric syndrome with cardiac complications has been associated with COVID-19.

USF Health, working with Tampa General Hospital, had been at the forefront of a wide range of COVID-19 clinical trials in the Tampa Bay region.

Physicians and scientists are exploring many possible treatments to increase survival and improve prognoses for critically ill patients. Some target the virus itself or human cellular pathways that the virus exploits to replicate. Others aim to prevent collateral inflammatory damage in the human host. A disease affecting so many parts of the body will need drugs, or combinations of drugs, to attack on several fronts, said USF Health infectious disease physician-scientist Dr. Kim.

In the Tampa Bay region, USF Health, working with Tampa General Hospital, is at the forefront of a wide range of COVID-19 clinical trials. Creating drugs from scratch can take years, so several trials are investigating medications already prescribed for other infectious or inflammatory diseases to determine their effectiveness against SARS-CoV-2. For instance, Dr. Kim is local lead investigator for a multisite randomized controlled trial testing the safety and effectiveness of sarilumab in blocking acute lung damage in hospitalized COVID-19 patients. Sarilumab, approved for treating rheumatoid arthritis, is a monoclonal antibody targeting the proinflammatory cytokine receptor interleukin 6. Another trial will evaluate the ability of nitazoxanide, originally developed as an antiparasitic drug for gastrointestinal infections, to prevent respiratory virus replication in health care workers.

Dr. Kim is also working with Tampa General’s laboratory to analyze and validate the reliability of commercial tests that test patient blood samples for antibodies, proteins that provide evidence of past COVID-19 infection and recovery.

Kami Kim, MD, director of the Division of Infectious Disease and International Medicine at USF Health, leads a study evaluating the accuracy of antibody testing.

The accuracy of the antibody testing – different from the nasopharynx swab or saliva tests used to diagnose a current active infections – is important because it can give health officials a clearer picture of how widely COVID-19 has spread in the community and the extent of asymptomatic cases. Based on past experience with other coronaviruses like SARS and MERS, a positive SARS-CoV-2 antibody test would typically indicate some level of immunity. Researchers like Dr. Kim want to confirm that and hope to define the concentration of antibodies needed to confer immunity as well as how long that immunity lasts.

(In late May, the Centers for Disease Control and Prevention released new guidelines cautioning that some antibody tests have high false positive rates, and more definitive data is needed before they can be used to make decisions about returning to work, school or other public places.)

“We need to know if people who have the antibodies are actually protected against another infection,” Dr. Kim said. “It’s not yet clear… but, preliminary data indicates that a fairly large proportion of those people who recover from COVID-19 infection will have what are the protective (neutralizing) antibodies.”

SARS-CoV-2 shares genetic and some clinical similarities with the first SARS virus (SARS-CoV) — which caused a smaller scale global outbreak and has not re-emerged since the last reported case in 2004. But the new coronavirus is both more highly contagious and more apt to spread asymptomatically.

Based on past experience with other coronaviruses like SARS and MERS, a positive SARS-CoV-2 antibody test would typically indicate some level of immunity. Scientists are working to figure out how much immunity and how long it lasts.

“It’s the thing that has kept all of us in public health and infectious diseases up at night – a completely new pathogen that explodes before we had a real chance to get a handle on what was happening,” Dr. Kim said. “We’re learning more as we go, but teamwork is essential. No one will be able to solve all the pieces of this pandemic puzzle by themselves,” she added.

It will take time for scientists to fully understand the COVID-19 virus and how genetics, the environment, medications, lifestyle and public health measures impact the course of the disease.

“COVID-19 has essentially shut down the entire world,” added Dr. Kim, who as a clinical infectious diseases fellow at the University of California San Francisco in the 1980s witnessed firsthand the devastating consequences of the domestic HIV/AIDS epidemic. “A lesson we need to learn is the importance of maintaining preventive public health infrastructures — not only in our local communities, but globally, so that we can efficiently combat any future pandemics.”

USF Health’s Dr. Kami Kim probes the epigenetics of two global parasitic infections, malaria and toxoplasmosis

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While an undergraduate at Harvard University, Kami Kim, MD, participated in a research thesis project exploring leukemia’s resistance to chemotherapy and the effectiveness of combination drugs in combatting it.  While she was excited to help figure out (and publish) a mechanism, she recalls that she signed on for this laboratory research primarily “to help in get into medical school.”

Her interest in research intensified in medical school in early 1980s at the beginning of the domestic AIDS era, about the same time tuberculosis cases were exploding and malaria, once considered virtually eliminated as a major public health threat, began to re-emerge globally.

“It was clear that there was much to be done in infectious diseases research — a lot of interesting problems that needed to be solved,” said Dr. Kim, who joined the USF Health Morsani College of Medicine last year as a professor in the Department of Internal Medicine’s Division of Infectious Disease and International Medicine.

Kami Kim, MD, a USF Health professor of infectious disease, with her multidisciplinary laboratory research team, which includes expertise from the medicine, public health, mathematics and statistics

 Undergraduate laboratory work that sparked a lifelong passion for research

Basic science and clinical infectious diseases expertise

After clinical training as an infectious diseases fellow at the University of California San Francisco (UCSF) – and witnessing firsthand the devastating consequences of acquired immunodeficiency syndrome – Dr. Kim returned to laboratory research, with an emphasis on parasitic infectious diseases.  Meanwhile, she continued to see patients as an attending academic physician at some of the nation’s best hospitals in San Francisco and New York City.

That blend of rigorous clinical and basic science expertise makes Dr. Kim one of the first of several high-profile, energetic recruits who will help take USF Health’s global infectious disease research to the next level.

Dr. Kim came to USF Health in November 2017 from Albert Einstein College of Medicine in New York City, where she was a professor of medicine, microbiology and immunology, and pathology.  In addition to her laboratory research at USF, she consults monthly on infectious diseases cases at Tampa General Hospital. At Einstein, she directed the infectious diseases section of the Center for Epigenomics and helped launch and led the National Institutes of Health-funded Geographic Medicine and Emerging Infections Training Program, which supports interdisciplinary training in translational research for pre-doctoral students, post-doctoral research fellows and clinical fellows.

A plaque formation of the intracellular parasite Toxoplasma gondii

Seeking solutions to life-threatening global parasitic diseases

Dr. Kim’s USF Health research team, working out of a laboratory in the university’s research park, focuses on two major areas — malaria and toxoplasmosis.  The world’s most dangerous parasitic disease, malaria claims more than 2 million victims and 445,000 deaths yearly, primarily in sub-Saharan Africa. Toxoplasmosis, often asymptomatic, can be life-threatening to babies born to women infected during pregnancy and people with weakened immune systems.

• Toxoplasmosis project: Combining advanced techniques from genetics, cell biology and proteomics, the researchers investigate the ways that epigenetics – the interface of genetics and environmental factors – regulate development of chronic infection by the cat-borne gondii parasite. They seek to understand how this pervasive parasite switches back and forth between a rapidly dividing acute stage destructive to healthy tissue (tachyzoite) and a chronic, or dormant, stage, where bradyzoite forms within pseudocysts remain invisible to the immune system. Dr. Kim collaborates with other leading Toxoplasma experts: Distinguished USF Health Professor Michael White, PhD, a long-time colleague, as well as investigators at Indiana University, Pennsylvania State University and Albert Einstein College of Medicine.
• Malaria project: In the hot, wet regions of Africa, mosquitoes are ubiquitous and children exposed to malaria from birth may contract the infection several time a year. The overwhelming majority of clinical cases are uncomplicated, with flu-like symptoms of fever and malaise that typically resolve. Researchers are trying to determine why a small percentage of individuals, in particular certain children, are more likely to develop severe malaria with coma and death (cerebral malaria) or long-term neurological complications such as seizures and cognitive and behavioral problems. In particular, the USF team is assessing specific biomarkers, or genetic predispositions, and parasite or host factors that may help predict disease development or its outcomes.

 Dr. Kim discusses research correlating HIV co-infection with cerebral malaria.

Research instructor Iset Vera

Both research initiatives harness the latest genomic technology to better understand how immunity works within the framework of host-parasite interactions – all with the aim of devising better or first-time treatments.

Valuable insights into cerebral malaria, future therapies

With collaborators from the Blantyre Malaria Project, based in Malawi, Africa, Dr. Kim published a high-profile paper in mBIO in 2015 reporting for the first time that children co-infected with HIV were much more likely than those who were not to die from severe malaria. Autopsies of the children who died from cerebral malaria indicated that those with HIV had brain blood vessels more clogged with white blood cells and platelets than those of children with malaria alone.  HIV appeared to rev up brain inflammation that could lead to death.

In another study, published in Cell Host & Microbe in 2017, Dr. Kim and colleagues used neuroimaging, parasite transcript profiling and laboratory blood profiles to develop machine-learning models of malarial retinopathy and brain swelling. The researchers found that the interaction of high parasite biomass, low platelet levels and certain parasite protein variants that bind to the endothelial protein C receptor (EPCR) play a pivotal role in fatal cases of malaria. Their findings added strength to the rationale that anti-inflammatory and anticoagulant treatments counteracting the breakdown of endothelium may benefit those with severe malaria.

“We still don’t entirely know why some of these kids get super sick and have complications requiring hospitalization,” Dr. Kim said. “If we could figure that out we could save lives, reduce complications and use limited healthcare dollars more effectively in these under-resourced countries.”

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 The “Goldilocks” theory of immunity

When it comes to infectious diseases, too much of a good thing may make you sick.  Dr. Kim calls it the “Goldilocks” theory of immunity – not too much (overactive immune system) and not too little (under-responsive immune system).

For instance, “for someone with malaria the right amount of immunity might not be just the right amount if they already also have tuberculosis,” Dr. Kim said. “What we’re realizing now with the human immune response to parasites or other foreign invaders (pathogens) is that you have to get the balance just right, so you get rid of the pathogen without damaging the human host.”

Otherwise, she added, even after the pathogen is eliminated, long-term complications like a damaging autoimmune inflammatory condition may linger.

Rigorously studying the dynamics of host-parasite interaction – including how parasites hijack the epigenome, which adjusts specific genes in response to signals from the outside world such as diet and stress — is critical to bridging the gap between discovery and effective treatments for different subgroups of infected patients.

“Both the pathogen and the infected host are duking it out to see which one wins, so figuring out what’s happening on both sides is really important to understanding immunity – how our body fights off disease,” Dr. Kim said. “Using genomic information to tell us who’s most susceptible to certain conditions will likely help us to tailor therapies to the individual, or perhaps to know who needs to be vaccinated.”

Dr. Kim with Li-Min Ting, PhD, an assistant professor in the Department of Internal Medicine’s Division of Infectious Disease

 Striking the right balance of immunity

Potential applications for other diseases

Within their complex life cycles, both malaria and toxoplasma parasites have dormant forms that the human immune system can’t identify and kill, and antimicrobial drugs can’t touch.  For malaria, this silent form lurks in the liver. For Toxoplasma, cysts can settle quietly into the infected person’s brain and muscle tissue without replicating, sometimes for years, until weakened immunity reactivates the disease.

Dr. Kim and other researchers continue to look for new ways to combat chronic infection by parasites.

“Normally when treating a disease you think of killing the form that makes a person clinically symptomatic,” she said, “but with both malaria and Toxoplasma if you can kill the biologically silent form, which is absolutely essential for the disease to continue, you’re accomplishing the same thing.”

Although Dr. Kim’s group targets specific problems underlying malaria and toxoplasmosis, such immune research may have broad applications for understanding and treating other conditions.  For instance, atherosclerosis has been linked to the release of molecules from the immune system that can cause inflammation, blood vessel injury and plaque instability leading to heart attacks and stroke.

A T. gondii plaque assay

“Even though drug companies, because of financial return on investment, aren’t necessarily willing to invest in research on malaria host factors,” Dr. Kim said, “they are really interested in stroke and cardiovascular disease.  And the big players in the kind of inflammation seen in these two major diseases are platelets and monocytes” – the same inflammatory culprits implicated in cerebral malaria.

While more research is needed, perhaps statin and antiplatelet drugs already approved for another indication could be effective in helping combat malaria,” she said. “It’s entirely possible by better understanding what’s a good immune response to malaria in one situation and bad in another will lead to insights that can be used to develop treatments for other diseases, or insight into what’s protective in another disease.”

Pursuing new approaches to outsmart elusive pathogens

Dr. Kim received her MD degree from the Columbia College of Physicians and Surgeons in New York City. She completed her residency in medicine at Columbia-Presbyterian Medical Center, a clinical fellowship in infectious diseases at UC San Francisco, and two postdoctoral research fellowships – one in parasitology at San Francisco General Hospital and a second in microbiology and immunology at Stanford University.

Dr. Kim is a fellow of the Infectious Diseases Society of America and the American Academy of Microbiology. She is also an elected member of American Society for Clinical Investigation and the Association of American Physicians, national honor societies for physician-scientists. A recipient of the Burroughs Wellcome Fund (BWF) New Investigator Award in Molecular Parasitology early in her career, she has served on the BWF Postdoctoral Research Enrichment Program’s scientific advisory board since 2014.  She is a member of the NIH Pathogenic Eukaryotes Study Section.

The cutting-edge tools of computational genomics contribute to Dr. Kim’s work.

Throughout much of her career, Dr. Kim’s research has been funded by the National Institute of Allergy and Infectious Diseases.  She holds several patents, and was one of the first investigators to develop techniques to genetically manipulate T. gondii. She is the co-editor and currently preparing the third edition of Toxoplasma gondii, the Model Apicomplexan: Perspectives and Methods, a textbook widely considered the seminal source for scientists and physicians working with this parasite.

Dr. Kim said she was attracted to USF because of the university’s upward national trajectory and USF Health leadership’s commitment to building translational research and pursuing innovative approaches and excellence in all its academic missions. She is a member of the USF-wide Genomics Program.

“I enjoy being part of a USF clinical community that excels in the treatment of infectious diseases and working with physicians and scientists who do parasitology research,” she said.  “You constantly have to think outside the box and come up with clever strategies – because we’re dealing with pathogens that do not behave like they are supposed to.”

 Toxplasma parasite strategy for survival

Dr. Kim, one of the first investigators to develop techniques to genetically manipulate Toxoplasma gondii, co-edits a textbook widely considered the seminal source for scientists and physicians working with this parasite.

Some things you might not know about Dr. Kim

• Korean was her first language, and she also speaks Spanish.
• She enjoys food, arts and crafts, and travel. Countries she has visited include Korea, Malawi, South Africa, France, Japan, and Brazil.
• Kim is married to Thomas McDonald, MD, USF Health professor of cardiovascular sciences and director of the new Cardiogenetics Clinic. They have two sons who are both mathematicians, one in a mathematics PhD program and the other in college. They met in the cardiac intensive care unit at Columbia Presbyterian Medical Center when Dr. McDonald was a resident and Dr. Kim was rounding as a medical student.

Dr. Kim’s career as an infectious disease physician-scientist bridges basic research and clinical practice.

-Video and photos by Torie M. Doll, USF Health Communications and Marketing