Posts tagged with "clinical trial"

Green covid by Mina Tocalini for 360 Magazine

Tuberculosis Bacteria Paradox

TB-causing bacteria remember prior stress, react quickly to new stress

Tuberculosis bacteria have evolved to remember stressful encounters and react quickly to future stress, according to a study by computational bioengineers at Rice University and infectious disease experts at Rutgers New Jersey Medical School (NJMS).

Published online in the open-access journal mSystems, the research identifies a genetic mechanism that allows the TB-causing bacterium, Mycobacterium tuberculosis, to respond to stress rapidly and in manner that is “history-dependent,” said corresponding author Oleg Igoshin, a professor of bioengineering at Rice.

Researchers have long suspected that the ability of TB bacteria to remain dormant, sometimes for decades, stems from their ability to behave based upon past experience.

Latent TB is an enormous global problem. While TB kills about 1.5 million people each year, the World Health Organization estimates that 2-3 billion people are infected with a dormant form of the TB bacterium.

“There’s some sort of peace treaty between the immune system and bacteria,” Igoshin said. “The bacteria don’t grow, and the immune system doesn’t kill them. But if people get immunocompromised due to malnutrition or AIDS, the bacteria can be reactivated.”

One of the most likely candidates for a genetic switch that can toggle TB bacteria into a dormant state is a regulatory network that is activated by the stress caused by immune cell attacks. The network responds by activating several dozen genes the bacteria use to survive the stress. Based on a Rice computational model, Igoshin and his longtime Rutgers NJMS collaborator Maria Laura Gennaro and colleagues predicted just such a switch in 2010. According to the theory, the switch contained an ultrasensitive control mechanism that worked in combination with multiple feedback loops to allow hysteresis, or history-dependent behavior.

“The idea is that if we expose cells to intermediate values of stress, starting from their happy state, they don’t have that much of a response,” Igoshin explained. “But if you stress them enough to stop their growth, and then reduce the stress level back to an intermediate level, they remain stressed. And even if you fully remove the stress, the gene expression pathway stays active, maintaining a base level of activity in case the stress comes back.”

In later experiments, Gennaro’s team found no evidence of the predicted control mechanism in Mycobacterium smegmatis, a close relative of the TB bacterium. Since both organisms use the same regulatory network, it looked like the prediction was wrong. Finding out why took years of follow-up studies. Gennaro and Igoshin’s teams found that the TB bacterium, unlike their noninfectious cousins, had the hysteresis control mechanism, but it didn’t behave as expected.

“Hysteretic switches are known to be very slow, and this wasn’t,” Igoshin said. “There was hysteresis, a history-dependent response, to intermediate levels of stress. But when stress went from low to high or from high to low, the response was relatively fast. For this paper, we were trying to understand these somewhat contradictory results. ”

Igoshin and study co-author Satyajit Rao, a Rice doctoral student who graduated last year, revisited the 2010 model and considered how it might be modified to explain the paradox. Studies within the past decade had found a protein called DnaK played a role in activating the stress-response network. Based on what was known about DnaK, Igoshin and Rao added it to their model of the dormant-active switch.

“We didn’t discover it, but we proposed a particular mechanism for it that could explain the rapid, history-dependent switching we’d observed,” Igoshin said. “What happens is, when cells are stressed, their membranes get damaged, and they start accumulating unfolded proteins. Those unfolded proteins start competing for DnaK.”

DnaK was known to play the role of chaperone in helping rid cells of unfolded proteins, but it plays an additional role in the stress-response network by keeping its sensor protein in an inactive state.

“When there are too many unfolded proteins, DnaK has to let go of the sensor protein, which is an activation input for our network,” Igoshin said. “So once there are enough unfolded proteins to ‘distract’ DnaK, the organism responds to the stress.”

Gennaro and co-author Pratik Datta conducted experiments at NJMS to confirm DnaK behaved as predicted. But Igoshin said it is not clear how the findings might impact TB treatment or control strategies. For example, the switch responds to short-term biochemical changes inside the cell, and it’s unclear what connection, if any, it may have with long-term behaviors like TB latency, he said.

“The immediate first step is to really try and see whether this hysteresis is important during the infection,” Igoshin said. “Is it just a peculiar thing we see in our experiments, or is it really important for patient outcomes? Given that it is not seen in the noninfectious cousin of the TB bacterium, it is tempting to speculate it is related to survival inside the host.”

Gennaro is a professor of medicine and epidemiology at Rutgers Biomedical and Health Sciences. Igoshin is a senior investigator at Rice’s Center for Theoretical Biological Physics.

The research was supported by the Welch Foundation (C-1995) and the National Institutes of Health (GM096189, AI122309, AI104615, HL149450).

AC_LatinoCovid by Allison Christensen for 360 Magazine

Antibody Cocktail May Prevent Symptomatic COVID-19 Infections

An antibody cocktail being tested at UVA Health and other sites was able to block 100% of symptomatic COVID-19 infections among people exposed to the virus, early results from the clinical trial suggest.

In addition, those who developed asymptomatic infections accumulated far less virus in their bodies than usual and saw their infections resolve within a week, according to interim data released by the cocktail’s manufacturer, Regeneron Pharmaceuticals.

“This is the first treatment shown to prevent COVID-19 after a known exposure, and offers protection for unvaccinated individuals caring for a family member with COVID-19,” said UVA Health’s William Petri Jr., MD, PhD, one of the leaders of the trial at UVA. “We expect that Regeneron will file for Emergency Use Authorization from the FDA so that this drug can be used outside of the context of a clinical trial.”

Antibodies for COVID-19

The phase 3 clinical trial aims to determine if the antibodies will prevent COVID-19 infection in people who have been exposed but not yet developed the disease. This is known as “passive immunization.”

Regeneron’s new analysis, which has not yet been published in a scientific journal, looked at outcomes in approximately 400 trial participants. Of 186 people who received the antibodies, none developed symptomatic COVID-19. Of the 223 who received a placebo, eight developed symptomatic COVID-19, the company reports.

Asymptomatic infections occurred in 15 of the antibody recipients and in 23 of the placebo recipients. Overall rates of infection, including both symptomatic and asymptomatic infections, were approximately 50% lower in the antibody group.

Among those who developed infections, placebo recipients had, on average, a peak viral load (the amount of virus in the body) that was more than 100 times greater than antibody recipients. The antibody group also recovered more quickly–all the infections resolved within seven days, while 40 percent of infections in the placebo group lasted three to four weeks, Regeneron said.

The cocktail also appears to shorten the duration of viral shedding, the time when the virus is being manufactured in the body. The viral shedding period was nine weeks among antibody recipients and 44 weeks among the placebo recipients. While people with COVID-19 are not infectious for this entire time, reducing the duration of viral shedding may shorten the period when they can spread the disease.

There were more adverse events reported among placebo recipients than among antibody recipients – 18 percent and 12 percent, respectively. Regeneron attributed this to the larger number of COVID-19 infections in the placebo group.

There was one death and one COVID-19-related hospitalization in the placebo group and none in the antibody group. Injection-site reactions were reported among 2 percent of both groups.

“We are profoundly grateful to the nurses and staff of the UVA COVID-19 clinic, led by Dr. Debbie-Anne Shirley,” Petri said. “Their day-to-day support made our participation in this trial possible.”

About the Clinical Trial

Phase 3 clinical trials, such as the one under way at UVA, examine the safety and effectiveness of new drugs and treatments in large numbers of people. Positive results in the phase 3 trial could spur the federal Food and Drug Administration to make the antibody cocktail available for post-exposure COVID-19 prevention.

The antibody cocktail is not a vaccine and is not expected to provide permanent immunity to COVID-19.

The team conducting the study at UVA is led by Petri and Shirley and includes Gregory Madden, MD; Chelsea Marie, PhD; Jennifer Sasson, MD; Jae Shin, MD; Cirle Warren, MD; Clinical Research Coordinator Igor Shumilin; assistant Rebecca Carpenter; and COVID-19 Clinic nurses Michelle Sutton, Elizabeth Brooks, Danielle Donigan, Cynthia Edwards, Jennifer Pinnata, Samantha Simmons and Rebecca Wade.

To keep up with the latest medical research news from UVA, subscribe to the Making of Medicine blog.

COVID-19 Trial Tests if Common Drug Can Keep Patients Out of Hospital

At-risk people diagnosed with COVID-19 across the United States and Canada can participate in a clinical trial testing whether a common drug can keep them from getting sicker and keep them out of the hospital.­­

The trial, conducted by Washington University School of Medicine in St. Louis, is based on a discovery by the University of Virginia School of Medicine’s Alban Gaultier, PhD, and a former graduate student, Dorian A Rosen, PhD.

Gaultier and Rosen found last year that the antidepressant fluvoxamine may stop the deadly inflammation known as sepsis, in which the immune response spirals out of control. The drug’s apparent benefit for dampening dangerous inflammation prompted the Washington University researchers to begin investigating its potential benefit for COVID-19, which can also cause dangerous overreactions of the immune system.

“If this clinical trial is proven successful, fluvoxamine could become a standard treatment for patients newly diagnosed with COVID-19, especially patients at risk,” Gaultier said. “Even the best vaccines do not protect 100% of the population, and discovery of safe and affordable treatments to prevent COVID-19-associated complications is critical.”

Fluvoxamine and COVID-19

Earlier this year, the Washington University researchers launched their first clinical trial of the drug in patients with COVID-19. That trial compared fluvoxamine with a harmless placebo in 152 adult outpatients. None of the 80 participants who received fluvoxamine became seriously ill after 15 days, while six patients who received placebo did. Of those six, four were hospitalized, for periods ranging from four to 21 days. One was on a ventilator for 10 days.

Based on those initial results, Washington University is now launching a much larger trial open to residents across the United States and Canada. The trial is seeking approximately 880 at-risk participants, age 18 and older, who have tested positive for COVID-19 and are experiencing mild symptoms.

Participants will be provided with either fluvoxamine or a placebo for approximately 15 days. No face-to-face contact is required; everything necessary will be sent to the participants’ doorsteps.

Contactless Check-Ins

The researchers will track the patients by videochat, email or telephone to determine if fluvoxamine provides a benefit and helps keep participants out of the hospital. During brief daily check-ins, trial participants will report their oxygen levels, blood pressure and temperature, along with whether they are feeling shortness of breath or have had any other problems.

The study team will continue to follow the participants for approximately 90 days after they have finished taking fluvoxamine or the placebo.

The trial is open to people who have at least one risk factor for severe COVID-19, such as being 40 or older, being part of a high-risk racial/ethnic group (such as African-American, Hispanic, Native American or biracial), or having one or more medical conditions such as obesity, diabetes, high blood pressure, heart disease, a lung disease or an immune disorder such as rheumatoid arthritis.

For more information about the trial, visit this website.

Hiccup in COVID-19 Vaccine Development

By Althea Champion

In a statement from AstraZeneca, reported by STAT News, the biopharmaceutical company reported a halt in their global research trial. The company, which is working with the University of Oxford and is one of the few waist-deep in the process of developing a COVID-19 vaccination, reported that the halt is a “routine action which has to happen whenever there is a potentially unexplained illness in one of the trials.”

The company is in Phase 3 of their clinical trial in the U.S., as well as Brazil and South Africa, according to the New York Times, and in Phase 2/3 in England and India. AstraZeneca began the third phase of its clinical trial not much longer than a week ago, on Aug. 31.

Phase 3 efficacy trials involve thousands of volunteers, some of which are administered the vaccine in question, and others the placebo.

AstraZeneca and its most close competitors, Moderna and Pfizer, which have each been in phase 3 of their clinical trials since July 27, are backed by the Trump administration’s Operation Warp Speed, a targeted allocation of resources meant to hasten the development of a COVID-19 vaccine. 

The halt of AstraZeneca’s COVID-19 vaccine—AZD1222—is the first made public by its drug maker, and will allow a safety review to take place. 

“A volunteer in the U.K. trial [of AZD1222] had been found to have transverse myelitis, an inflammatory syndrome that affects the spinal cord and is often sparked by viral infections,” reported the New York Times. “However, the timing of this diagnosis, and whether it was directly linked to AstraZeneca’s vaccine, is unclear.”

The vaccine was first developed by Oxford University’s Jenner Institute and Oxford Vaccine Group, according to nih.gov, and was then “licensed to AstraZeneca for further development.” Oxford-Astrazeneca began the third phase of its clinical trial not much longer than a week ago, on Aug. 31

The company stressed in its statement that the safety of their participants is a priority.

“We are working to expedite the review of the single event to minimize any potential impact on the trial timeline,” said the company in their statement. “We are committed to the safety of our participants and the highest standards of conduct in our trials.”

Genetic Immunity Presents at First Russian-Chinese HIV Congress in Moscow

Peter Boros, Genetic Immunity’s President presented the Company’s pDNA-based platform technology and clinical trial data relating to HIV in front of an esteemed gathering of HIV experts.

As part of the presentation, Genetic Immunity announced the launch of a Phase III clinical trial for the company’s lead product candidate, a therapeutic HIV vaccine, to be conducted at the Moscow City Center for the Prevention and Control of AIDS, with the planned enrollment of up to 200 patients. Upon successful completion, Genetic Immunity plans to apply for marketing approval in the Commonwealth of Independent States (CIS) region.

“It was an honor to have been invited and to present in front of such a highly regarded group of HIV experts from Russia, China and the United States. I believe our presentation was well-received and we are all looking forward to a successful trial completion. If marketing approval is granted, our therapeutic HIV vaccine could introduce a paradigm shift in treating HIV,” stated Boros.

The DermaVir platform contains a novel plasmid DNA that encodes most HIV genes. The vaccine is administered topically using the DermaPrep medical device.

“Mr. Boros gave an excellent presentation about Genetic Immunity’s therapeutic vaccine platform with a special emphasis on the company’s HIV results to date. I look forward to completing the planned Phase III trial, and – upon a successful result – to treating patients with a very promising new vaccine product,” added Professor Alexey Mazus, Head of the Moscow City Center for the Prevention and Control of AIDS.