Tag: Infectious Disease Research

Southern Research team targets new, safer drugs for malaria

Posted on May 21, 2019

Scientists at Southern Research’s Drug Discovery division have joined the fight against malaria through efforts aimed at discovering new drugs and improving the safety and efficacy of current antimalarial medicines.

A research team lead by Babu Tekwani, Ph.D., distinguished fellow and chair of the Department of Infectious Diseases at Southern Research, is working on the development of nano-formulations of drugs that prevent relapse of the illness.

This project, funded by the NIH’s National Institute of Allergy and Infectious Diseases (NIAID), targets malaria caused by Plasmodium vivax, one of the five plasmodium parasites responsible for the serious and sometimes fatal disease in humans.

Vivax malaria is notorious for causing relapses, even after treatment with commonly used antimalarial drugs.

Southern Research Tekwani
A Southern Research team led by Dr. Babu Tekwani, center, is seeking to discover new therapeutics for malaria and to make existing medicines for the disease safer.

Today, Primaquine is the only FDA-approved drug available to prevent relapses in malaria patients, eliminating all malaria parasites from the body in what is referred to as radical cure.

The medicine, however, causes severe destruction of red blood cells, a condition known as hemolysis, in individuals with the genetic deficiency of glucose 6-phosphate dehydrogenase (G6PD).

This side effect prevents the use of Primaquine in a substantial proportion of malaria-infected individuals.

Tekwani’s team at Birmingham-based Southern Research has established specific experimental models and bioassays to evaluate the safety and efficacy of drugs in G6PD deficiency. These models are being employed to test new antimalarial drugs and formulations.

Tekwani’s team is also working on a research project to better understand the molecular basis of antimalarial drugs’ action. The goal of the project is to develop new antimalarial drugs with better safety profiles and activity against drug-resistant cases of malaria.

This project is funded by the U.S. Department of Defense in collaboration with the University of Mississippi and the Walter Reed Army Institute of Research.

“The continuous emergence of drug-resistant cases of malaria underscores the need for the identification of new drugs,” Tekwani said. “Indeed, the building and continuous augmentation of an armamentarium of multiple drugs is necessary to cope with the growing problem of drug-resistance”.

“The experimental models we’ve developed for evaluation of the safety and efficacy of antimalarial drugs have provided better tools for new antimalarial drug discovery,” he added.

BATTLING MALARIA

Malaria continues to be a global health challenge despite extensive efforts initiated by global and public health agencies for malaria control. The mosquito-borne disease claimed the lives of 435,000 people in 2017, of which included mostly children in Africa. There were 219 million cases reported worldwide that year. In addition, an estimated 1,700 cases of malaria are reported in the U.S. each year.

More than 3.3 billion people in 106 countries continue to be at risk for contracting malaria, according to a 2018 world malaria report published by the World Health Organization (WHO).

Extensive efforts initiated in 2000 by malaria-affected countries and global health agencies have led to remarkable progress in reducing malaria-related deaths from more than one million to less than 500,000 per year. However, progress has been stagnant since 2015, and malaria is even re-emerging in some countries.

“Southern Research is looking forward to making important new contributions to malaria drug discovery with the extensive experience of Dr. Tekwani in this area and funding from the NIH-NIAID and the U.S. Department of Defense,” said Mark Suto, Ph.D., vice president of Drug Discovery at Southern Research.

The Department of Infectious Diseases in Southern Research’s Drug Discovery division focuses on a diverse array of infectious disease pathogens, with the objective of identifying novel mechanisms, targets and strategies for the prevention and treatment of protozoal, bacterial and viral infectious diseases throughout the world.

Tekwani has spent more than 30 years researching tropical parasitic diseases such as malaria, leishmaniasis and human African trypanosomiasis, vector-borne infectious diseases and major global health threats. His work on new drug discovery for infectious diseases has identified potential new targets and sources for therapies.

 

 

Southern Research teams with UAB to launch 3 pilot studies

Posted on February 20, 2019

How certain bacteria may make people more prone to asthma is one topic of three research grants jointly funded by Southern Research and the UAB School of Medicine.

These new research pilots are the latest effort to harness synergies between researchers at the University of Alabama at Birmingham and Southern Research, a Birmingham-based nonprofit research institute with nearly 400 scientists and engineers.

The two other pilots seek an improved way to develop new vaccines and a new mouse model for a potentially dangerous, hereditary deficiency shared by 400 million people worldwide.

The cooperation began with a July 2018 research retreat, sponsored by Art Tipton, Ph.D., president and chief executive officer of Southern Research, and Etty “Tika” Benveniste, Ph.D., senior vice dean for Basic Sciences in the UAB School of Medicine.

“While our researchers work together in many areas, we strongly suspected there would be additional ones that would be possible if both sides knew the research capabilities of each side better,” Tipton said. “And we were correct.”

“We announced at the end of it that we would fund some joint pilot programs,” Benveniste said. “Proposals were submitted and reviewed, and now three programs have been funded.”

This program parallels one held for the UAB School of Engineering, the College of Arts and Sciences, and Southern Research that was announced last July. That symposium was so successful it was repeated this month, and it will have additional funded programs to be announced later this year.

The one-year, $25,000 pilots were selected for intellectual merit, originality, potential to win major research funding and ability to foster collaborations between Southern Research and UAB.

Here are brief descriptions of the three pilots.

UAB
Javier Campos-Gómez of Southern Research and Beatriz León of UAB (Image: UAB)

ASTHMA STUDY

This study is based on the observation that human lung infections with the bacterium Pseudomonas aeruginosa are associated with more severe chronic cases of asthma and allergic sinusitis.

This suggests that the bacteria make people more susceptible to allergic airway inflammation, and that treating the lung infection could prevent severe asthma attacks. However, P.aeruginosa is often resistant to antibiotics.

The study is led by Southern Research principal investigator Javier Campos-Gómez, Ph.D., research associate biologist in the Department of Infectious Diseases, Drug Discovery Division, and UAB principal investigator Beatriz León, Ph.D., assistant professor in the Department of Microbiology

Campos-Gómez and León will investigate a different way to stymie P.aeruginosa, by probing the molecular basis for increased susceptibility to allergic inflammation and asthma in infected patients. They have preliminary evidence that a certain metabolite of P.aeruginosa may affect the immune response to allergens, and this could offer a new path to treatment therapies.

VACCINE DEVELOPMENT

UAB
Braden McFarland of UAB and Raj Kalkeri of Southern Research (Image: UAB)

This study starts with the understanding that the bacteria found in the human gastrointestinal track are necessary for the development of our immune system. However, 85 percent of bacteria found in the guts of laboratory mice are not found in the guts of humans, implying that vaccine efficacy evaluation with regular laboratory mice might not translate to humans.

The study is led by Southern Research principal investigator Raj Kalkeri, Ph.D., MBA, subject matter expert for infectious disease research in the Drug Development division, and UAB principal investigator Braden McFarland, Ph.D., instructor in the Department of Cell, Developmental and Integrative Biology.

Kalkeri and McFarland hope to bridge the knowledge gap through vaccine evaluation in humanized microbiome mice — mice that have human donor bacteria in their gastrointestinal tracts. This might be a better model to test potential human vaccine efficacy, as well as help reveal how gut microbes affect vaccine protection.

SAFETY OF THERAPEUTIC DRUGS

UAB
Babu L. Tekwani of Southern Research and Robert P. Kimberly of UAB (Image: UAB)

This study involves the hereditary condition called glucose 6-phosphate dehydrogenase, or G6PD, enzyme deficiency that affects more than 400 million people worldwide.

This enzyme deficiency can make people susceptible to drug-induced hemolytic anemia, and it can also limit use of several important drugs in public health. Yet development of safer drugs for these 400 million people has been hampered by lack of suitable experimental models for the enzyme deficiency.

The study is led by Southern Research principal investigator Babu L. Tekwani Ph.D., distinguished fellow and chair of infectious diseases in the Drug Discovery division, and UAB researchers in the Center for Clinical and Translational Science, Jennifer A. Croker, Ph.D., director of Administration, and Robert P. Kimberly, M.D., director.

Tekwani and colleagues will establish a model for the enzyme deficiency in humanized-immunocompromised mice, and then investigate the mechanism of drug-induced hemolytic anemia. This mouse model also should be useful to develop safer drug alternatives. Tekwani and his group are working on improving the safety of antimalarial drugs in populations with G6PD deficiency.

 

 

New bacterial signaling language offers pathway to treat infections

Posted on February 19, 2019

Scientists at the microbiology lab led by Javier Campos-Gómez, Ph.D., in Drug Discovery at Southern Research discovered that Pseudomonas aeruginosa, a bacterium responsible for severe, drug-resistant infections in humans, uses a family of fatty acids, known as “oxylipins,” in a cell-to-cell signaling language critical for its virulence.

The Campos-Gómez team was established to explore novel ways to fight infectious disease, so when Campos-Gómez’s long-standing colleague and team member, Eriel Martínez, Ph.D., suggested that oxylipin molecules could represent the “words” of a new type of P. aeruginosa bacterial language, the laboratory immediately began investigating that hypothesis.

While bacteria use other chemical molecules in signaling systems, the scientists say this is the first time that oxylipins, which are commonly recognized signaling factors in animals, plants and even fungi, have been shown to play a part in cell-to-cell communication in any bacterium.

Pseudomonas Southern Research
Southern Research scientists Eriel Martinez, left, and Javier Campos-Gómez have discovered a new cell-to-cell signaling language in a bacterium blamed for dangerous infections.

“Bacteria talk to each other using chemical signaling molecules,” Martinez said. “This allows bacteria to work together to achieve functions that couldn’t be achieved as individuals. Our study reports a new bacterial language that uses oxylipins as words.”

The researcher’s findings suggest that disrupting oxylipin production by P. aeruginosa will defend against a bacterial infection the World Health Organization (WHO) has named a serious threat to human health.

“This is important because we can design a new generation of antibiotics that target this oxylipin pathway,” Campos-Gómez said.

A paper titled “Oxylipins mediate cell-to-cell communication in Pseudomonas aeruginosa,” published this month in Communications Biology, a new peer-reviewed, open-access journal of the Nature group, outlines the new findings.

Read the paper published by Communications Biology.

BIOFILM FORMATION

Bacteria mainly communicate via what’s called “quorum sensing,” which involves the production of various small molecules that function as “words” of the bacterial language. In P. aeruginosa, oxylipins function as new “words” in a novel quorum sensing system, the Southern Research scientists found.

This system controls the changing roles of genes in a bacteria community, turning some on and others off. In P. aeruginosa, the oxylipins are synthesized from oleic acid, a specific fatty acid, which is abundant in the tissue of a host organism, including humans.

The scientists previously found that these oxylipin molecules play a key role in the formation of the biofilm that acts as a shield to protect P. aeruginosa from attack by the human immune system and from antibiotics. (See original publication here).

“This is a step forward. Now, we know more about how oxylipins function in P. aeruginosa. They are signaling molecules involved in regulating biofilm formation and virulence,” Campos-Gómez said.

‘DISARMING THE BACTERIA’

Southern Research pseudomonas
Eriel Martinez is a research scientist in the Campos-Gómez lab at Southern Research.

In 2017, the WHO included P. aeruginosa in its first-ever list of antibiotic-resistant bacteria that pose the greatest threat to human health. P. aeruginosa was listed in the most critical group of multidrug resistant bacteria in need of a new therapeutic treatment option.

The WHO has warned the bacteria in this group pose a particular threat in hospitals, nursing homes, and among patients whose care requires devices such as ventilators and blood catheters. They can cause severe and often deadly conditions such as bloodstream infections and pneumonia.

The Centers for Disease Control and Prevention (CDC) estimates that 51,000 health-care associated P. aeruginosa infections occur in the United States each year. More than 6,000 of these, around 13 percent of the total, are multidrug resistant, with roughly 400 deaths, according to the CDC.

“P. aeruginosa is one of the toughest bacterial infections to cure because it is able to form this biofilm that makes it very resilient against antibiotics,” Campos-Gómez said.

The Southern Research scientists have already developed a high throughput assay to identify small molecules that block the production of oxylipins in P. aeruginosa and have identified a couple of promising compounds.

“We are trying to develop a new generation of antibiotics that do not directly kill the bacteria, reducing the odds that it will develop resistance to the drug,” Campos-Gómez said. “We want to disarm the bacteria, so that the immune system takes care of the bacteria itself.”

 

SR researcher Susan Schader discusses the future of HIV treatment

Posted on August 29, 2018

Prolific, dedicated HIV researcher Susan Schader, Ph.D., believes that a cure for HIV cannot be pursued without first defining the concept of “cure.”

“There are many things that go into ‘curing,’” she said. “Are we curing the world, or are we curing the human? And that’s where I challenge the scientists I work with. You’re telling me that you’re working toward a cure? How are you curing HIV? In an individual, let’s just start there, or even a cell. Tell me how you’re curing it.”

That big-picture view—what are you working toward? What are you working for?—has largely defined Susan M. Schader’s career as a scientist. Recently promoted to principle investigator, she guides a project focused on new viral targets and novel therapeutics in the face of this constantly mutating virus. When she joined Southern Research three years ago, she immediately felt at home at the institution that has touched nearly every HIV drug that’s come to market since the epidemic began in the 1980s, turning a death sentence into a treatable disease.

Susan Schader is SR's primary investigator for HIV/AIDS.
Susan Schader is SR’s primary investigator for HIV/AIDS.

RETROSPECTIVE

Schader’s mindset goes back to her early work in the lab of Dr. Robin Shattock at St. George’s Hospital Medical School, studying the effect of TMC120 (later dapivirine) and tenofovir on HIV replication. “He was the perfect mentor. We called him the Prince of Microbicides,” Schader said. “He was always big picture-focused. Although he didn’t say, ‘Susan, you must be big picture-focused,’ he was. And you saw this side of humanity, and what you were doing in the lab meant something.”

That broad perspective would prove to be a common thread among the other mentors who had the most impact on her during her early career. Dr. John Moore, who reminded her, when she got caught up in the technical details, to “keep the big picture in mind.” Dr. Mark Wainberg, under whom she received her doctorate and who recognized her knowledge and experience and gave her the freedom to work, to lead, even to sit in his place on steering committees and at conferences—gave her a new perspective on where her work fit into the global effort against HIV.

Schader recounts a story from a visit to the International AIDS Symposium after she’d left Shattock’s lab. The TMC120 she’d been studying was in testing as part of a silicone vaginal ring that women would be able to use for protection from HIV—an important advancement for women in developing countries who might have neither access to medical treatment nor the personal agency to negotiate sexual contact.

Both researchers and workers on the front line of the AIDS epidemic attended the symposium, and it was a group of the latter, healthcare workers in Africa, who approached Schader. “They said, ‘We’ve heard about this ring. Can we see it? Can we touch it?’” she said. “And it was an aha moment for me. It’s the human connection— this is a good concept, but if you really want to get it adopted, you have to be able to say, ‘Here. Touch it. Feel it. What are your thoughts on it?’ We could have done a better job as scientists to help the people on the front lines understand where we were going. And it was those women who brought it to my attention, who said, ‘We really want this product.’”

SMALL SCALE, BIG DISCOVERIES

Over a decade later, Schader is working in a world facing a $7 billion funding gap, per the UN, between our current reality and the goal of eradicating HIV by 2030. “That to me just says, it’s got to stop being about a country,” she said. “It’s got to stop being about the person. You can treat an individual, but we also have to look longer term.”

“What I can do in the lab is on a very small scale,” Schader said. “But I know by bringing everyone together at Southern Research, it’s the biggest
gift I’ve ever been given in my career, because the scientists I work with have the capacity to do what no other research lab can do or would attempt. The scientists here are dedicated, and they want to stay here. I learn something new every day here, and we’ve already discovered things that, hopefully by the end of the year, we can get some funding to help us carry on research.”

Schader believes the biggest thing standing between science and a cure—a cure by any definition—is funding. A constant struggle for a share of limited grant money pits scientists against each other, she said, and impedes collaboration. That, combined with lack of access to new technology, resources and brainpower, hinders potential advances.

Teams have had to innovate new technology using their own research funds, or just go without. “Struggling for two days with something when you can buy a piece of equipment that will let you do it in 30 seconds or less—just those processes can make us less frustrated and more productive,” she said. “What we’ve accomplished over the past year, we could have accomplished a lot faster.”

Those accomplishments are significant. What other labs are unable to do, Schader’s team specializes in doing—developing ways to detect HIV in active replication, to test drugs, to design novel, clinically relevant assays. Her lab is the first in the world to produce protein from HIV in a particular bacteria. That discovery can mean the difference between the therapies that were effective decades ago and the ones that are changing the world now. “We just need the funding to be able to sit down and say, ‘OK, let’s work together.’”

THE BIG PICTURE, FULL CIRCLE

While her team works toward the future, a project from Schader’s past has reappeared. While pursuing her doctorate, Schader was awarded nearly a quarter of a million dollars from the International Partnership of Microbicides to study the drugs they wanted to test in combination—research that led to the silicone ring that had made waves at the IAS. Now, she’s been approached directly—this time to supply preclinical data because the dapivirine ring is a reality, has been tested in Africa and is up for regulatory approval in Europe. “I was involved at the beginning, and now I get to see and help bring it to people under the European regulatory agency,” she said. “And it’s at Southern Research that we’re doing it.”

Seeing it come full circle isn’t just a thrill for Schader—it’s also educational and encouraging for her team, she said. “To actually say we’re helping women on a worldwide scale, it really makes people look up from their bench and go, ‘Yeah, what I do means something.’”

“I think we can do it,” Schader said. “I think we can cure HIV. We just need to know what a cure looks like.”

Southern Research adds veteran researcher as infectious diseases chair

Posted on July 17, 2018

Southern Research announced today that accomplished researcher Babu L. Tekwani, Ph.D., has joined the Birmingham-based organization as Distinguished Fellow and Chair of the Infectious Disease Department in Drug Discovery.

Babu L. Tekwani, Ph.D.

Tekwani has spent more than 30 years researching tropical parasitic diseases such as malaria and leishmaniasis, vector-borne infectious diseases, and major global health threats. His work has identified potential new targets and sources for therapies against these diseases.

In his new role within Southern Research Drug Discovery, Tekwani will direct a department that focuses on the disease-causing mechanisms and novel therapeutic and vaccine approaches for a diverse array of pathogens.

The department’s objective is to identify novel mechanisms, targets and strategies for the prevention and treatment of both bacterial and viral infectious diseases throughout the world.

Tekwani plans to strengthen Southern Research’s current drug discovery research program for global health and tropical infectious diseases.

“Because infectious diseases represent a major global health problem, there are critical unmet needs for novel, safe and effective therapies,” said Mark J. Suto, Ph.D., vice president of Drug Discovery. “The urgency is made greater by the emergence of drug-resistant and continually increasingly virulent strains of these pathogens. Tekwani brings a wealth of experience and adds a new dimension to Southern Research’s infectious diseases drug discovery program.”

COMBATTING DISEASES

Some of Tekwani’s most recent work focuses on developing a targeted drug delivery approach for a safer and more effective antimalarial therapeutic relative to currently used strategies against the disease for U.S. troops and global travelers.

Tekwani’s research has been funded by the National Institute of Allergy and Infectious Diseases, which leads research to understand, treat, and prevent infectious, immunologic, and allergic diseases, in addition to the U.S. Department of Defense and the U.S. Army Medical Research and Material Command, which play a leading role in the advancement of military medicine, among other sources.

“Infectious diseases kill millions of people across the world every year, and there is a vital need for new drug discoveries that can impact global health,” Tekwani said. “With a long history of exploring how to combat infectious diseases, Southern Research is positioned to make significant contributions in drug discovery, and I am excited lead that effort.”

Tekwani previously worked at the University of Mississippi, where he served as principal scientist and professor of pharmacology at the School of Pharmacy’s National Center for Natural Products Research. While there, he directed a group that developed in vitro assays to screen compounds for biological activity. Tekwani has established extensive collaborative research with several laboratories within U.S. and around the world.

Before joining the University of Mississippi in 2001, Tekwani worked as a scientist in the Biochemistry Division at the Central Drug Research Institute in Lucknow, India. He was awarded an international fellowship by the Fogarty International Center National Institute of Health and completed post-doctoral research training at the Milton S. Hershey Medical Center Penn State College of Medicine.

Tekwani received a doctorate in biochemistry from Lucknow University, a master’s degree in biochemistry from G.B. Pant University in Pantnagar, India, and a bachelor’s degree in biology from Rajasthan University in Jaipur, India. He has published more than 225 peer-reviewed manuscripts and has been issued two patents.

Tekwani’s research has been recognized with several awards, including a career development award of UNDP/WHO Tropical Diseases Research, University of Mississippi School of Pharmacy Faculty Research Award, Distinguished Scientist Award, and a Global Health Drug Discovery award entitled “Global Challenges in Neglected Tropical Diseases.” 

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Southern Research programs aim to shield against pandemic flu dangers

Posted on January 23, 2018

With experts predicting another deadly influenza pandemic in the future, Southern Research scientists are working on several fronts to help limit the death toll from a catastrophic flu outbreak that one day slams the nation.

Birmingham-based Southern Research conducts tests on emerging pandemic strains and participates in strategic government vaccine programs focusing on highly pathogenic avian influenza (HPAI) strains that pose potentially grave public health risks.

In addition, Southern Research has performed toxicology studies for flu vaccine platforms and provided pre-clinical studies on vaccine candidates, along with clinical trial support for vaccine makers. The non-profit organization has also researched antiviral treatment approaches that could protect people after infection.

“Scientists will tell you it’s not if, it’s when we have a pandemic. That’s the way the flu virus works,” said Landon Westfall, Ph.D., a senior project manager and infectious disease scientist at Southern Research. “It’s like the San Andreas fault – the big one is coming one day. The idea is since we can’t prevent it, we should prepare for it. That’s the goal.”

pandemic influenza Southern Research
The last global flu pandemic, the 2009 H1N1 swine flu outbreak, killed as many as 575,000 people across the globe.

Pandemic influenza strains pose much a greater threat than even the nastiest strains of seasonal flu. The dominant seasonal strain this year, H3N2*, fits that description, causing an above-average rate of hospitalizations and prompting Alabama to declare a public health emergency.

The current flu season’s misery is worsened by the fact that the available vaccine is only moderately effective.

“That’s the challenge with flu. Vaccines don’t always work,” Westfall said. “Most of the time, they protect 55 to 60 percent of the population. That’s kind of the goal of influenza vaccines. But there will always be subsets of the population that won’t be protected.”

ELEVATED DANGERS

Novel avian or swine flu strains, however, have the potential to cause lethal damage on a global scale. Because these dreaded strains are new, very few people have immunity against them, so they can spread widely and rapidly, sickening a large segment of the population, Westfall said.

When pandemics emerge, more than half of an affected population can be infected in a single year, while the number of deaths stemming from the flu outbreak can sharply exceed normal levels.

That’s why the work being conducted by Southern Research and other organizations as part of the U.S. government’s influenza preparedness programs is critically important, Westfall said.

The goal is to prevent a global calamity like the 1918 Spanish flu pandemic, which killed more than 50 million people, and outbreaks in 1957 and 1968 that each killed at least 1 million people worldwide. The last pandemic, the 2009 H1N1 swine flu outbreak, killed as many as 575,000 people. More information on pandemics.

pandemic flu Southern Research
Landon Westfall is a senior project manager and infectious disease scientist at Southern Research.

For more than a decade, pandemic fears have centered on the highly lethal H5N1 avian influenza, despite the fact that the so-called “bird flu” virus does not infect humans easily. If a mutated form of the H5N1 virus became easily transmissible from person to person while retaining its severe effects, the public health consequences could be very serious, the World Health Organization warns.

“For the most part, avian influenza affects birds. When the virus makes a jump for one species to another, say from bird to human, that’s a big thing,” said Westfall, who oversees the influenza virology program for Southern Research’s Drug Development division. “That’s a rapid evolution for a virus that will likely cause major problems. In cases, where the avian flu has infected humans, the mortality rate has been around 60 percent.”

Southern Research scientists have worked on influenza projects for government agencies including the National Institutes of Health, the National Institute of Allergies and Infectious Diseases, and the Biomedical Advanced Research and Development Authority. The organization has also worked with a number of commercial clients.

“We’re recognized as one of the leading supporters for clinical vaccine research, especially for flu,” Westfall said. “That is partly because of our history in the field but also because of our capabilities to test a large volume of samples in a relatively short time.”

THE NEXT PANDEMIC

Southern Research flu pandemic
The H1N1 virus triggered a global influenza pandemic in 2009.

Although most experts believe another influenza pandemic is inevitable, Westfall said it is impossible to predict when or where it will occur, or how severe its impact will be. It’s almost impossible to predict with certainty the subtype of influenza virus most likely to cause the next worldwide outbreak.

Late in 2017, scientists reported that a new strain of H7N9 avian flu circulating in China showed the ability to transmit easily among animals with highly lethal results, raising alarm about its potential to trigger a global human pandemic.

While the Centers for Disease Control and Prevention says the risk of H7N9 is currently low because human-to-human transmission is rare, the CDC still rates the strain as having the greatest potential to cause a pandemic.

Westfall said the evolving nature of influenza viruses presents tough challenges to the research community.

“Flu is like a malleable pathogen that can change from week to week, from month to month, and from region to region,” he said. “Every person who gets infected with the flu basically creates a small change in that virus that’s then passed on to multiple people. Flu constantly changes that way.”

*In the designation of influenza subtypes, the H refers to hemagglutinin, a protein found on the surface of flu viruses, while the N refers to viral neuraminidase, another protein present on the surface of the virus.

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Southern Research targets bio-threats under BARDA contracts

Posted on August 8, 2017

Southern Research has been awarded two contracts from the Biomedical Advanced Research and Development Authority (BARDA), which is a division of the U.S. Department of Health and Human Services’ Office of the Assistant Secretary for Preparedness and Response, for nonclinical research services advancing the agency’s work to protect the U.S. against infectious disease and bio-terror threats.

The BARDA contracts have a minimum value of $45 million and a maximum value of $90 million and a base term of five years.

Southern Research, which has considerable experience in infectious disease research, has long been a leader in the evaluation of vaccine candidates and possible therapeutics for influenza and emerging biological threats.

Southern Research bio-threats
Southern Research has won two contracts from BARDA for work to protect the U.S. from infectious diseases and bio-terror threats.

“This work positions Southern Research to play a key role in protecting against potentially serious public health issues,” said Tim McGrath, vice president, Drug Development.

“We have the expertise and capabilities to accelerate the development of vaccines and therapeutics that are effective against biological threat agents.”

PORTFOLIO OF COUNTERMEASURES

BARDA’s mission includes developing medical countermeasures our nation needs to protect public health against emerging infectious diseases, pandemic influenza, and chemical, biological, radiological, and nuclear threats.

Under one of the BARDA contracts, Southern Research will develop and utilize novel animal models used in the testing of potential vaccines and therapeutics against biological threat agents.

The development of animal models is considered a key element in the evaluation of medical countermeasures for this broad range of threats because the efficacy of these products cannot be verified using traditional clinical studies.

“Southern Research is pleased to continue this relationship with BARDA and support this critically important initiative,” said Michelle Wright Valderas, director of project management and principal investigator on this contract.

The second BARDA-supported project is focused on developing the reagents and assays that would be used to support the animal model testing and later human clinical trials.

“I am excited to contribute to this important research supporting vaccine development to protect public health,” said John Farmer, a project leader responsible for immunology research at Southern Research and principal investigator on this contract.

IDIQ CONTRACTS

Task orders issued under these contracts will be funded in whole or in part with federal funds from the Department of Health and Human Services Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority, under Contract Nos. HHSO100201700017I and HHSO100201700018I.

Both are Indefinite Delivery Indefinite Quantity (IDIQ) contracts, meaning Southern Research is positioned to bid on task orders once they are issued by BARDA. All work will be conducted using quality standards consistent with Good Laboratory Practices (GLP) guidelines.

Southern Research worked previously with BARDA under a 2011 IDIQ contract to develop animal models. In addition, Southern Research has worked as a subcontractor with other organizations on BARDA contracts.

Southern Research ready to assist new hepatitis B treatment approaches

Posted on July 28, 2017

A Southern Research scientist says a new generation of antiviral therapies is urgently needed against hepatitis B, a chronic disease affecting 240 million people whose cure has proved elusive.

Raj Kalkeri, Ph.D., a project leader and subject matter expert in infectious disease for Southern Research’s Drug Development division, added that the stubborn characteristics of the hepatitis B virus (HBV) have thrown up significant hurdles slowing the discovery and development of a cure for this persistent viral infection.

“Because of its role in at least 650,000 deaths each year, hepatitis B constitutes a major international public health problem,” Kalkeri said. “HBV persistence can lead to cirrhosis, liver failure and the primary form of liver cancer, hepatocellular carcinoma. This places a major burden on health care costs.”

Southern Research hepatitis B
Raj Kalkeri, standing at right, works with a HBV team in a Southern Research laboratory.

Birmingham-based Southern Research has been active in the effort to advance new treatments by developing comprehensive hepatitis B capabilities for researchers. This includes in vitro assays to monitor different phases of the HBV life cycle, along with a mouse model for persistent HBV infection that could be useful in testing a new generation of HBV therapies.

What’s needed now, Kalkeri said, is greater cooperation within the scientific community and additional support for research that targets the infection’s most challenging aspects, including its persistence and ability to suppress an immune system response.

“Concerted efforts across academia, industry and government are needed,” he said. “Collaborations across these groups with additional research funding will facilitate better understanding of HBV persistence and the development of effective strategies to advance a functional cure.”

COMBATTING PERSISTENCE

While there is a safe and effective vaccine for hepatitis B, it fails in 5 to 15 percent of persons receiving the vaccine. Smoking, obesity, other chronic illnesses and advanced age are some of the factors associated with vaccine failure.

Current antiviral therapies can halt the progress of the infection in some patients, but they don’t wipe out all traces of the virus. That allows HBV to hide out for some time, before reappearing once therapy is completed.

Hepatitis B’s persistence, which can turn the disease into a lifelong struggle for many sufferers, is a complex phenomenon, Kalkeri said.

For starters, the human immune system has a hard time clearing out hepatitis B. It begins when T-lymphocytes, a key component of the immune system that combats microbial intruders, fail to do their job because of disruption caused by the virus.

Reversing this defective T-cell response could be helpful in the development of new hepatitis B treatments, though it’s probably not sufficient alone to play a starring role in a cure, Kalkeri said.

The major challenge with hepatitis B persistence is known as cccDNA, short for covalently closed circular DNA. This is a special DNA structure that’s deposited in the nucleus of HBV infected cells in the form of minichromosome. Its strategic location makes it a difficult target for antivirals and for the immune system.

Present in low levels, the seemingly untouchable cccDNA continues to produce the virus even in patients being actively treated.

“As a result of the persistence of cccDNA, antiviral therapies now have to administered lifelong for a majority of HBV patients in order to avoid a reactivation of the virus,” Kalkeri said.

“The bottom line is that long-term therapy is ineffective in eliminating HBV from infected patients and results in drug toxicity issues, as well as the emergence of viral resistance,” he added.

REASONS FOR OPTIMISM

While there are promising signs that hepatitis B research is making progress, the persistence problem may ultimately put a final cure out of reach, Kalkeri said. What could emerge, however, is a way to control the disease’s persistence, resulting a functional cure, he added.

“It’s more realistic to hope for a functional cure for HBV, which means viral replication would be suppressed and other functions would be restored to a normal level,” Kalkeri added.

One source of optimism revolves around the discovery that a cell surface protein known as NTCP acts a receptor for hepatitis B. In essence, NTCP opens the door for the virus to enter into healthy cells.

“With the discovery of NTCP, we could potentially use it as a tool in the laboratory to understand the mechanisms of HBV infection, cccDNA formation, and more,” Kalkeri said.

“At a minimum, this kind of infectious cell culture model would enable identification of HBV entry inhibitors and pave the way for combination studies along with other antiviral agents against this infection.”

Kalkeri said Southern Research’s HBV cure assay capabilities are available to advance research. These testing platforms are:

IN VITRO

Virus yield assay (HepG2.2.2.15 cells)

Infectious virus assay (HepG2-NTCP)

HBV core promoter assay

Inducible HBV cccDNA model (HepDE19)

IN VIVO

Adeno-Associated Virus-HBV mouse model (C57BL/6)

Using the tools developed for the HBV program and in collaboration with Southern Research’s Drug Discovery division, Kalkeri and his team have demonstrated the inhibition of HBV core promoter by a repurposed anti-cancer clinical candidate SRI-032007. The research shows that it is feasible to reduce the production of the viral genetic material in an in vitro laboratory setting. This work is being presented as a poster in September at the 2017 International HBV meeting in Washington, D.C. Additional testing in animal models of this compound is being planned. Finding new antivirals for HBV could complement the anti-HBV activity of current and help in the development of effective curative strategies.

Read an article on HBV by Kalkeri in Future Virology.

Southern Research probe of Zika looks into ‘rebound virus’

Posted on June 21, 2017

Southern Research scientists are investigating how the Zika virus is able to find a safe harbor in an infected host’s tissue and stage a rebound weeks after the virus was seemingly cleared by the immune system.

Evidence of a Zika virus rebound, called a “secondary peak” following an initial infection, emerged during a Southern Research-funded project to determine how the virus progresses in infected cynomolgus macaques.

In that study, researchers found an ever increasing presence of viral RNA, a scientific marker for the presence of the virus itself, in the testes of monkeys. Prolonged shedding of the virus was also detected in urine.

“We hypothesized that the Zika virus is using the immune privileged tissue as a reservoir and going dormant, or in low replication mode, just hiding there,” said Fusataka Koide, associate director of infectious disease research at Southern Research.

Koide and fellow SR staff, Laurie Queen and Priscilla Williams, view a viral titer plate to determine if a drug presents the growth of Zika virus.
Koide and fellow SR staff, Laurie Queen and Priscilla Williams, view a viral titer plate to determine if a drug prevents the growth of Zika virus.

“When the immune status changes in the host, the virus could surge again,” he added. “An adaptive mutation and selection process post-infection could also contribute to successful establishment of Zika virus in a host.”

While a deeper understanding of this Zika virus rebound is needed, a possible mutation-driven secondary peak of the virus could pose new challenges for companies attempting to develop anti-viral therapeutics for post-infection treatment.

“They’ll need to study the mechanism of how the infection occurs to come up with an effective strategy for the drug,” Koide said. “Maybe it will prevent the initial viremia, but it could come back later on. They’ll need to know the drug can penetrate those tissues that may be harboring Zika virus.”

MEETING AN URGENT NEED

Zika virus infection exploded as a global health threat in early 2016. Since then, Southern Research has been heavily involved in the scientific community’s efforts to better understand the virus’s pathogenicity and has assumed a leadership role in providing efficacy models for evaluation of potential vaccines and anti-viral treatments.

Last year, the National Institute for Allergies and Infectious Diseases (NIAID), a division of the National Institutes of Health (NIH), contracted Southern Research to develop a non-human primate model for evaluation of candidate novel therapeutics and vaccines for protection and control of Zika virus infection.

Koide said potential vaccines are now being tested in macaques, with promising results in a proof-of-concept study that demonstrated that an immune system response had been triggered against the virus. In August, he said, efficacy studies will begin with potential new anti-viral compounds.

In addition to non-clinical research, Southern Research is now providing Phase-I clinical trial support for pharmaceutical companies that are working to develop vaccines against the Zika virus, Koide said.

While fears about Zika virus infection have somewhat faded since last summer, Koide said that it remains a threat and there is still an urgent need for both an effective vaccine and anti-viral treatments.

Last year’s outbreak of the virus in Brazil and South and Central America led to a significant increase in the number of children born with microcephaly, or an unusually small head. Cases of Guillain-Barré Syndrome and other neurological disorders were also reported.

“Vaccines are a preventative measure, which is probably the most effective strategy to fight Zika virus infection,” Koide said. “But some populations — pregnant women, the elderly, and immune-compromised individuals — may not be able to receive a vaccine and will need to rely on anti-viral drugs for protection.

“That’s important. You need both arms – vaccines and anti-viral drugs to fight the virus,” he added.

What you need to know about Zika virus transmission.

 

Researchers viewing the device counting the number of areas on the plate where the Zika virus is replicating.
Researchers viewing the device counting the number of areas on the plate where the Zika virus is replicating.

REBOUND RISKS

Meanwhile, Southern Research scientists are also working to completely understand the Zika virus’s ability to stage a rebound. Just how does the virus manage to survive in a host after an initial onslaught by the immune system appears to eliminate it?

To study the escape process, they’ve isolated the virus from the first acute infection phase, and later, from the secondary peak, so they can examine genetic differences between the two viral populations in order to determine if specific changes in RNA sequence might be associated with the rebound.

This kind of rebound is not seen in similar viral diseases such as Dengue fever, making Zika virus unique, Koide said.

“We just don’t know what triggers the rebound,” he added. “That is something we need to tease out because it’s RNA we’re detecting, not an infectious particle per se. Studying Zika virus’s ability to persist in immune privileged tissues (such as testes) could have important implications for non-vector mediated transmission of Zika virus.”

And while the rebound virus is eventually cleared by the macaques, Koide said revealing the Zika virus’s safe harbors is critical to evaluating whether there’s a risk that the rebound could change how the infection progresses in humans, either through enhanced transmission or potentially escalating clinical complications.

“Understanding the role viral reservoirs play in Zika virus’s immune escape should provide strategic insights for the development of new vaccines and therapeutics,” Koide said.

NIH orders High Throughput Screening for Zika

Posted on November 7, 2016
High Throughput Screening for Zika
Working with assays in Sourthern Research’s High Throughput Screening lab.

In 2014, Southern Research received funding from the National Institute of Allergies and Infectious Diseases (NIAID) through a multi-center U19 grant (U19AI109680) administered by the University of Alabama at Birmingham to conduct high throughput screening (HTS) against six disease-causing viruses: dengue, West Nile, SARS, influenza, Venezuela equine encephalitis complex, and chikungunya. With the program in place, and as Southern Research has completed screening the viruses, the National Institutes of Health (NIH) issued a supplementary $650,000 award for the Birmingham-organization to expand its program to include high throughput screening for Zika.

“Southern Research has a long history in antiviral research, including screening viruses in the same flavivirus genus as Zika, so we’re pleased the NIH saw fit to expand the U19 program to include screening on Zika,” said Bob Bostwick, Ph.D., director of the High-Throughput Screening Center at Southern Research. “For drug discovery purposes, we hope to identify compounds that work well across this entire genus.”

According to the supplemental grant, Southern Research will construct an assay for Zika that can be conducted in HTS, and test over 300,000 compounds against the virus, a process that will take nine months.

Developing robust screening capabilities

For Southern Research, compound screening has been a part of the organization’s efforts since the mid-1950s, when researchers began manually screening anticancer drugs under a contract with the National Cancer Institute (NCI). Around this same period, the Virus Research Division began evaluating antiviral agents against a wide range of pathogenic viruses, including the herpesviruses, poxviruses, acute upper respiratory disease viruses, and mosquito-borne viruses, such as Yellow Fever virus.

By the 1960s, the early work had already shown promise. Manual screenings conducted by the viral research team had identified the compounds that led to the discovery of Ara-A, an antiviral used to treat human herpesviruses, chicken pox, shingles, human cytomegalovirus — a cause of childhood hearing loss — and a lethal encephalitis.

In the 1980s, following the emergence of the AIDS epidemic in the United States, Southern Research expanded into HIV antiviral research through a series of contracts and grants with the United States Army and the NIH. This effort involved screening compound collections consisting of approximately 20,000 samples, and developing a staff of scientists proficient in working with many infectious diseases. By the following decade, the organization’s anti-HIV screening program had become the largest in the country.

While earning a global reputation for producing high quality antiviral research, Southern Research’s screening capabilities were expanding far beyond antivirals to include screening of other infectious diseases and cancer. In the late 1990s, the organization invested in emerging HTS technologies to maintain a prominent role at the forefront of drug discovery. This involved assembling a large compound collection — consisting of over 1 million samples — and acquiring robotic platforms for automated screening, thus enabling the organization to test hundreds of thousands of compounds for each new target. Eventually, the program would become involved in the NIH Roadmap Molecular Libraries initiative, and serve as one of twelve centers in the NCI Chemical Biology Consortium.

“Southern Research’s in-house screening capabilities are unmatched by most universities and private research organizations across the globe,” said Art Tipton, Ph.D., president and CEO of Southern Research. “With our Biosafety Level 3 (BSL3) facility, an active in-house library of over one million compounds, and a wealth of institutional knowledge, our researchers pride themselves on finding chemical structures needed to develop drugs against some of the greatest global health threats.”

High Throughput Screening and drug discovery

Zika Virus
Zika Virus under high magnification.

Today, HTS is an automated process that allows researchers to rapidly test a large number of compounds in order to determine their potential use as starting points for the invention of new drugs. With time and advances in technology, the process of screening compounds has evolved significantly from the early days. However, despite these advances, some things remain the same.

“Whether you are working on an antiviral or an anti-cancer medication, the drug discovery process is incredibly complex and often starts with screening,” said Bostwick. “HTS usually requires screening hundreds of thousands of compounds to find three or four good chemical starting points for medicinal chemistry.”

With the recent expansion of its U19 program to include screening of the Zika virus, Southern Research maintains a prominent global position in antiviral research. Its work has led to the fight against HIV/AIDS — supporting the United States government and numerous drug companies in the production of many of the FDA-approved antiviral drugs currently on the market — and screening of compounds that allowed for numerous other drug breakthroughs, including several against previously drug resistant strains of tuberculosis and malaria. Yet, despite this record of success, researchers admit a cure for Zika will still take time.

“Even though we know a lot about flaviviruses, discovering and developing effective therapeutic agents may take several years,” Bostwick continued. “Just like any other project we’ve undertaken, we will use data as our guide and hope our efforts will yield results which can be helpful to the scientific community.”

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