The preclinical study, in fruit flies and mice, also identified ways to block this process, which could have implications for treating or preventing the muscle wasting sometimes associated with inflammatory diseases—including bacterial infections—Alzheimer’s disease and long COVID.

“We are interested in understanding the very deep muscle fatigue that is associated with some common illnesses,” said senior author Aaron Johnson, PhD, an associate professor of developmental biology. “Our study suggests that when we get sick, messenger proteins from the brain travel through the bloodstream and reduce energy levels in skeletal muscle. This is more than a lack of motivation to move because we don’t feel well. These processes reduce energy levels in skeletal muscle, decreasing the capacity to move and function normally.”

Johnson and colleagues reported on their findings in Science Immunology, in a paper titled “Infection and chronic disease activate a systemic brain-muscle signaling axis.” In their report the team concluded, “Our study argues that infections and chronic diseases activate a conserved IL-6–mediated systemic brain-muscle signaling axis, which could be a therapeutic target to improve muscle outcomes in affected patients.”

“Infections and neurodegenerative diseases induce neuroinflammation, but affected individuals often show non-neural symptoms including muscle pain and muscle fatigue,” the authors wrote. “The molecular pathways by which neuroinflammation causes pathologies outside the central nervous system (CNS) are poorly understood.”

To investigate the effects of brain inflammation on muscle function, the researchers modeled three different types of diseases—an E. coli bacterial infection, a SARS-CoV-2 viral infection and Alzheimer’s. When the brain is exposed to inflammatory proteins characteristic of these diseases, damaging chemicals called reactive oxygen species (ROS) build up. The reactive oxygen species cause brain cells to produce an immune-related molecule called interleukin-6 (IL-6), which travels throughout the body via the bloodstream.

Johnson added, “Flies and mice that had COVID-associated proteins in the brain showed reduced motor function—the flies didn’t climb as well as they should have, and the mice didn’t run as well or as much as control mice.” We saw similar effects on muscle function when the brain was exposed to bacterial-associated proteins and the Alzheimer’s protein amyloid beta. We also see evidence that this effect can become chronic. Even if an infection is cleared quickly, the reduced muscle performance remains many days longer in our experiments.” Reporting on their experiments, the team further stated, “Using genetic rescue experiments and pharmacological treatments, we conclude cytokine signaling from the CNS is sufficient to impair motor function and that IL-6 could be a therapeutic target to treat muscle dysfunction in response to infections and chronic disease. Brain muscle-communication is thus a central regulator of muscle performance.”

Johnson, along with collaborators at the University of Florida and first author Shuo Yang, PhD—who did this work as a postdoctoral researcher in Johnson’s lab—make the case that the same processes are likely relevant in people. The bacterial brain infection meningitis is known to increase IL-6 levels and can be associated with muscle issues in some patients, for instance. Among COVID-19 patients, inflammatory SARS-CoV-2 proteins have been found in the brain during autopsy, and many long COVID patients report extreme fatigue and muscle weakness even long after the initial infection has cleared. Patients with Alzheimer’s disease also show increased levels of IL-6 in the blood as well as muscle weakness.

The study pinpoints potential targets for preventing or treating muscle weakness related to brain inflammation. Several therapeutics already approved by the Food and Drug Administration for other diseases can block this JAK-STAT pathway, the team pointed out. JAK inhibitors as well as several monoclonal antibodies against IL-6 are approved to treat various types of arthritis and manage other inflammatory conditions. “IL-6 inhibitors have been used to treat autoimmune diseases such as rheumatoid arthritis, and clinical trials are ongoing to expand the inflammatory disorders that can be targeted with IL-6 inhibitors,” the researchers stated.

“We’re not sure why the brain produces a protein signal that is so damaging to muscle function across so many different disease categories,” Johnson said. “If we want to speculate about possible reasons this process has stayed with us over the course of human evolution, despite the damage it does, it could be a way for the brain to reallocate resources to itself as it fights off disease. We need more research to better understand this process and its consequences throughout the body.

“In the meantime, we hope our study encourages more clinical research into this pathway and whether existing treatments that block various parts of it can help the many patients who experience this type of debilitating muscle fatigue,” he said. Acknowledging limitations of their study, and noting results from previous clinical studies using IL-6 inhibitors or JAK inhibitors, the team further concluded, “These clinical results argue that systemic treatment with IL-6 and JAK inhibitors could inhibit changes to muscle performance induced by the brain-muscle signaling axis and prevent muscle dysfunction associated with chronic and infectious diseases.”

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Kappler said the bacterium had a unique ability to “talk” to and deactivate the immune system, convincing it there was no threat. “These bacteria are especially damaging to vulnerable groups, such as those with cystic fibrosis, asthma, the elderly, and Indigenous communities,” Kappler said. “In some conditions, such as asthma and chronic obstructive pulmonary disease, they can drastically worsen symptoms. Our research shows the bacterium persists by essentially turning off the body’s immune responses, inducing a state of tolerance in human respiratory tissues.”

The researchers reported on their studies, and results, in PLOS Pathogens, in a paper titled “Tolerance to Haemophilus influenzae infection in human epithelial cells: Insights from a primary cell-based model.”

Respiratory tract infections are highly debilitating, and Haemophilus influenzae is a bacterial pathogen that is associated with persistent acute and chronic respiratory tract infections, particularly among vulnerable individuals, the authors explained. “Haemophilus influenzae is a human-adapted pathobiont that inhabits the nasopharynx as a commensal but causes disease in other parts of the respiratory tract.” What are classed as nontypeable strains of H. influenzae (NTHi) are the most common type of clinical isolate, the team continued. In addition to causing acute diseases such as pneumonia, these strains are a major cause of exacerbations of chronic lung diseases, including in patients recovering from COVID-19. Interactions between the bacteria and the respiratory epithelia represent a key factor in NTHi virulence,” the team continued. “Despite this, insights into the molecular interactions that allow NTHi to persist in contact with human epithelia are lacking, but likely hold the key to uncovering both bacterial and host processes that are crucial for infection.”

For their newly reported studies the team generated primary normal human nasal epithelia (NHNE), derived from cells from five healthy donors, and monitored the effects on tissue gene expression of NTHi infection. They first prepared the human nasal tissue in the lab, growing it to resemble the surfaces of the human respiratory tract. They then monitored post infection (p.i.) gene expression changes over a 14-day period of “infection” with the NTHi. “Persistent infections rely on close molecular interactions between the human respiratory cells and the bacterial pathogen,” the team noted, “… and here we have investigated changes in host and bacterial cells during persistent, long-term infections with H. influenzae.”

Their found very limited production of inflammation molecules over time, which normally would be produced within hours of bacteria infecting human cells. “We then applied both live and dead Haemophilus influenzae, showing the dead bacteria caused a fast production of the inflammation makers, while live bacteria prevented this,” professor Kappler said.  “This proved that the bacteria can actively reduce the human immune response.”

In their paper the authors wrote, “… Physiological assays combined with dualRNAseq revealed that NHNE from five healthy donors all responded to H. influenzae infection with an initial, ‘unproductive’ inflammatory response that included a strong hypoxia signature but did not produce pro-inflammatory cytokines. Subsequently, an apparent tolerance to large extracellular and intraepithelial burdens of H. influenzae developed, with NHNE transcriptional profiles resembling the pre-infection state.”

This is the first time that large-scale, persistence-promoting immunomodulatory effects of H. influenzae during infection have been observed, they stated. “In addition to providing first molecular insights into mechanisms enabling persistence of H. influenzae in the host, our data further indicate the presence of infection stage-specific gene expression modules, highlighting fundamental similarities between immune responses in NHNE and canonical immune cells, which merit further investigation.”

Co-author and pediatric respiratory physician emeritus professor Peter Sly, MD, at UQ’s Faculty of Medicine, said the results show how Haemophilus influenzae can cause chronic infections, essentially living in the cells that form the surface of the respiratory tract.

“This is a rare behavior that many other bacteria don’t possess,” professor Sly said.
“If local immunity drops, for example during a viral infection, the bacteria may be able to ‘take over’ and cause a more severe infection.” The findings will lead to future work towards new treatments to prevent these infections by helping the immune system to recognize and kill these bacteria. “We’ll look at ways of developing treatments that enhance the immune system’s ability to detect and eliminate the pathogen before it can cause further damage,” Kappler added.

In their paper the authors concluded, “… our data provide first evidence that NTHi infections can delay strong inflammatory responses in human epithelia and induce an apparent tolerance of NTHi infection that had not been previously observed, but could be a driver of NTHi persistence in the human respiratory tract. This state of ‘peaceful’ coexistence of NHNE and NTHi required infection with live NTHi, which indicates an active immunomodulatory role for NTHi.”

They pointed out that further research is needed to investigate whether bacterial effector proteins or metabolites are involved in triggering NHNE tolerance of NTHi infection, and what mechanisms within human epithelia cause differences in tolerance of NTHi infections.

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The findings are published in PLOS Biology in an article titled, “The evolution of antimicrobial peptide resistance in Pseudomonas aeruginosa is severely constrained by random peptide mixtures.”

“The prevalence of antibiotic-resistant pathogens has become a major threat to public health, requiring swift initiatives for discovering new strategies to control bacterial infections,” the researchers wrote. “Hence, antibiotic stewardship and rapid diagnostics, but also the development, and prudent use, of novel effective antimicrobial agents are paramount. Ideally, these agents should be less likely to select for resistance in pathogens than currently available conventional antimicrobials. The usage of antimicrobial peptides (AMPs), key components of the innate immune response, and combination therapies, have been proposed as strategies to diminish the emergence of resistance.”

A recent GEN article highlighted antibiotic-resistant bacteria and a weakness to help overcome antibiotic resistance.

In the new study, researchers investigated whether antimicrobial peptide mixtures synthesized in the lab could reduce the risk of the pathogen P. aeruginosa from evolving antimicrobial resistance, compared to exposure to a single antimicrobial peptide. They found that using antimicrobial peptide mixtures carried a much lower risk of the bacteria developing resistance. The mixtures also helped prevent the bacteria from developing cross-resistance to other antimicrobial drugs, while maintaining—or even improving—drug sensitivity.

Overall, the findings suggest that the use of antimicrobial peptide mixtures is a strategy worth pursuing in the search for new, longer-lasting treatments for bacteria. The researchers suspect that using a cocktail of multiple antimicrobial peptides creates a larger set of challenges for bacteria to overcome, which can potentially delay the evolution of resistance, compared to traditional antibiotics. Furthermore, these cocktails can be synthesized affordably, and previous studies have shown them to be nontoxic in mice.

“Even after four weeks of exposure, a usual treatment duration for Pseudomonas infections, we could not find resistance against our new random peptide, but against other antimicrobials,” added lead author Bernardo Antunes.

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“You could say that we are adding a piece of the puzzle to the understanding of how antibiotic resistance spreads between bacteria,” says Ronnie Berntsson, PhD, associate professor at Umeå University and one of the authors behind the study.

The team has studied Enterococcus faecalis, which is a bacterium that often causes hospital infections, where in many cases treatment with antibiotics no longer works because the bacteria have developed resistance.

These bacteria can also spread the resistance further via the type 4 secretion systems, T4SS. It is a kind of protein complex that acts as a copying device, allowing properties in the form of genetic material to be spread to other bacteria. Resistance to antibiotics is one such trait that can be moved between bacteria with the help of T4SS.

Role of PrgK

An important part of T4SS is the enzyme PrgK, which breaks down the bacterial cell wall and thus facilitates the transfer of properties between bacteria. This enzyme has three parts or domains, LytM, SLT, and CHAP.

PrgK works like scissors that cut into the bacterial cell wall. Contrary to what the researchers previously thought, it turned out that only the SLT domain was active, but in a different way than expected. The other two domains instead turned out to have an important role in the regulation of the enzyme. The researchers also identified that another T4SS protein, PrgL, binds to PrgK and ensures that it ends up in the right place in the protein machinery.

“The findings are important for continued research into how to prevent T4SS from transferring properties such as resistance to antibiotics to other bacteria,” says Josy ter Beek, PhD, staff scientist at Umeå University.

The study has been conducted through a combination of biochemical analyses of the protein linked to functional studies in vivo and supplemented with structural studies of PrgK using both X-ray crystallography and AlphaFold modeling.

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The findings are published in Microbiology Spectrum in the article titled, “The uncharacterized PA3040-3042 operon is part of the cell envelope stress response and a tobramycin determinant in a clinical isolate of Pseudomonas aeruginosa.”

The team discovered a mechanism, that reduces the formation of biofilm on the surface of P. aeruginosa. The formation of a sticky, slimy biofilm is a powerful tool used by bacteria to protect themselves against antibiotics—a trick also used by P. aeruginosa.

“This biofilm can be so thick and gooey that an antibiotic cannot penetrate the cell surface and reach its target inside the cell,” explained Clare Kirkpatrick, head of research at department of biochemistry and molecular biology, adding: “Maybe one day, we could pharmacologically stimulate this mechanism to reduce biofilm development on the surface of P. aeruginosa.”

Specifically, the researchers worked with three newly discovered genes in a lab-grown strain of P. aeruginosa. When they overexpressed these genes, they saw a strong reduction of biofilm. They also observed the system affected by the genes is part of the P. aeruginosa core genome.

“Being part of P. aeruginosa’s core genome, this system has been found in all investigated strains of P. aeruginosa, including a large variety of strains isolated from patients. So, there is reason to believe that reduction of biofilm via this system should be effective in all known strains of P. aeruginosa,” said Kirkpatrick.

It is not uncommon for patients infected with a P. aeruginosa strain to initially respond well to antibiotic treatment but then become resistant as the strain evolves resistance during treatment. Strains mutate, but their common core genome does not change.

The researchers activated the biofilm-reducing system by overexpressing genes. But they also discovered that the system is naturally stimulated by cell wall stress.

“So, if we stress the cell wall, it may naturally lead to a reduction in biofilm, making it easier for an antibiotic to penetrate the cell wall,” said Kirkpatrick, adding: “Currently, cell wall-targeted drugs are not widely used against P. aeruginosa, but perhaps, they could start to be used as additives to help reduce biofilm production and improve access of the existing antibiotics to the cells.”

The new findings could lead to novel strategies for not only P. aeruginosa, and may also help against other antibiotic-resistant bacteria.

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The findings are published in Science in an article titled, “A neutralizing antibody prevents post-fusion transition of measles virus fusion protein.”

To better understand how the measles virus fuses with cells, the LJI team turned to an antibody called mAb 77. They found that mAb 77 targets the measles fusion glycoprotein, the piece of viral machinery measles uses to enter human cells via a specialized process called fusion.

“What’s exciting about this study is that we’ve captured snapshots of the fusion process in action,” explained LJI professor, president, and CEO Erica Ollmann Saphire, PhD, who co-led the study with Matteo Porotto, PhD, professor of viral molecular pathogenesis (in pediatrics) at Columbia University. “The series of images is like a flip book where we see snapshots along the way of the fusion protein unfolding, but then we see the antibody locking it together before it can complete the last stage in the fusion process. We think other antibodies against other viruses will do the same thing but have not been imaged like this before.”

The measles virus is just one member of the larger paramyxovirus family, which also includes the deadly Nipah virus.

“What we learn about the fusion process can be medically relevant for Nipah, parainfluenza viruses, and Hendra virus,” said study first author and LJI postdoctoral researcher Dawid Zyla, PhD. “These are all viruses with pandemic potential.”

“Measles causes more childhood deaths than any other vaccine-preventable disease, and it’s also one of the most infectious viruses known,” added Saphire.

It’s not just young children at risk, explained Zyla. “The current vaccine works well, but it cannot be taken by pregnant people or people with compromised immune systems,” Zyla said.

The LJI team needed to engineer a version of the measles fusion glycoprotein—a harmless fragment of the virus—stable enough to image with a cryo-electron microscope. To do this, Zyla worked closely with scientists in Porotto’s laboratory at Columbia University.

Porotto’s group had uncovered some strange mutations in a measles variant that attacked peoples’ central nervous systems. This mutated variant had some weak points in its fusion glycoprotein structure. To compensate, the virus had evolved special stabilizing mutations. “The virus has to mutate to go into the brain, but then it needs these stabilizing mutations to compensate,” said Porotto.

Thanks to these discoveries at Columbia, Zyla had a strategy for engineering a fusion glycoprotein with these same stabilizing mutations. This new fusion glycoprotein could be mass produced in cell culture, and it was sturdy enough for structural investigations.

“We got extremely good yields for the glycoprotein, which also enabled us to do structural biology and biochemical and biophysical studies,” said Zyla.

The scientists then captured images with the help of the LJI Cryoelectron Microscopy Core. The new images showed the fusion glycoprotein together “in complex” with mAb 77.

The scientists observed how mAb 77 arrests the virus in the middle of the fusion process—when fusion glycoprotein is already part way done “folding” into the right conformation to complete membrane fusion.

“It was striking to see what this intermediate step in the fusion process actually looks like,” said Zyla.

Looking toward the future, the scientists hope the antibody could be used as part of a treatment cocktail to protect people against measles or to treat people with active measles infection.

In a follow-up experiment, the scientists showed that mAb 77 provided significant protection against measles in cotton rat models of measles virus infection. Cotton rats pretreated with mAb 77 prior to measles virus exposure showed either no infection or reduced signs of infection in their lung tissue.

Going forward, Saphire and Zyla are interested in studying different antibodies against measles. “We’d like to stop fusion at different points in the process and investigate other therapeutic opportunities,” Zyla said.

Zyla also plans to continue working closely with measles researchers at Columbia University. “The combination of structural biology expertise from LJI and cell biology and virology expertise from Columbia was key to pushing this project forward,” said Zyla.

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The team, from the Rosalind Franklin Institute, the Universities of Oxford and Pittsburgh, and the National Institutes of Health, developed a new PET radiotracer, called FDT ([¹⁸F]FDT), that is taken up by live TB bacteria in the body. (Radiotracers are radioactive compounds which give off radiation that can be detected by scanners and turned into a 3D image.) Development of the new Mtb-specific radiotracer means that PET can be used for the first time to accurately pinpoint where and when there is active disease in a patient’s lungs.

The researchers reported on studies evaluating the radiotracer in multiple preclinical models with no adverse effects, and say it is now ready to progress into early clinical studies in humans.

Clifton Barry III, PhD, from the National Institute of Allergy and Infectious Diseases, said: “FDT will enable us to assess in real time whether the TB bacteria remains viable in patients who are receiving treatment, rather than having to wait to see whether or not they relapse with active disease. This means FDT could add significant value to clinical trials of new drugs, transforming the way they are tested for use in the clinic.”

Barry is co-corresponding author of the team’s published paper in Nature Communications, titled “Distributable, metabolic PET reporting of tuberculosis,” in which they say that the combined results of their preclinical assessment and other evaluations “… now suggest [¹⁸F]FDT as a new, viable radiotracer for TB, suitable for Phase I trials.”

Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains a serious global health challenge causing an estimated 1.3 million deaths worldwide in 2022, the authors wrote. “Prompt, short-term diagnoses of TB are crucial for public health infection control measures, as well as for ensuring appropriate treatment for infected patients and controls.”

Professor Ben Davis, PhD, science director of the Franklin’s Next Generation Chemistry group, led the research. He explained, “Finding an accurate way to identify when TB is still active in the body is not only important for initial diagnosis, but to ensure patients are receiving antibiotics long enough to kill the disease, and no longer.”

Two methods currently exist for TB diagnosis, either testing for the TB bacteria in a patient’s sputum, or carrying out a PET scan to look for signs of inflammation in the lung, using the common radiotracer FDG ([¹⁸F]FDG).

However, a sputum test can show a negative long before the disease has been fully treated in the lungs, which could result in patients finishing treatment too early. And while scanning for inflammation can be helpful in seeing the extent of the disease, the current radiotracer is not specific to TB, and inflammation can be caused by other conditions. Inflammation can also persist in the lung after the TB bacteria has been eliminated, leading to treatment continuing longer than necessary.

“Existing detection methods rely almost exclusively on bacterial culture from sputum which limits sampling to organisms on the pulmonary surface,” the team noted. And while advances in monitoring tuberculous lesions have utilized the common glucoside [¹⁸F]FDG, these methods also lack specificity to the causative pathogen Mycobacterium tuberculosis so do not directly correlate with pathogen viability. “… [¹⁸F]FDG is also taken up and retained by any metabolically active tissue and so, as a generic marker of more active metabolism, has a limitation in its lack of specificity and inability to clearly distinguish granulomatous TB disease from other inflammatory conditions, including cancer,” the investigators stated.

Other radiotracers have been developed, the authors further pointed out, but their specificity and sensitivity may be only similar, or even worse than that of FDG, and they can be complex to produce. Their new approach is more specific as its focus is on a carbohydrate, trehalose, that is only processed by the TB bacteria. “The lack of naturally occurring trehalose in mammalian hosts as well as the uptake of exogenous trehalose by Mtb has suggested that trehalose-based probes could function as both highly specific and sensitive reporters,” they stated noted.

The new radiotracer, [¹⁸F]FDT, is what they described as one of the simplest ¹⁸F-analogs of trehalose. It is created from FDG using a relatively simple process involving enzymes developed by the research team. This means it can be produced without specialist expertise or laboratories and so would be a viable option in low- and middle-income countries with less developed healthcare systems. These countries currently see over 80% of global TB cases and deaths from the disease. “… we show that one of the simplest ¹⁸F-analogs of trehalose, 2-[¹⁸F]fluoro-2-deoxytrehalose [¹⁸F]FDT can be generated as an in vivo TB-reporter using one-pot, automatable, pyrogen-free, chemoenzymatic synthesis from readily-available [¹⁸F]FDG in a validated manner that does not require specialist expertise,” they wrote.

In their published paper the team reported on tests with the PET radiotracer in multiple preclinical models, including non-human primates. “Toxicological and preclinical testing in diverse species shows that this now creates access to a safe probe that is effective and selective in multiple preclinical models both to visualize TB lesions and to monitor their treatment non-invasively,” they stated.

A key advantage of the new approach is that it only requires a hospital to have standard radiation control and PET scanners, which are becoming more widely available throughout the world. Davis further commented, “The common radiotracer FDG and the enzymes we’ve developed to turn it into FDT can all be sent by post. With a minimum of additional training, this effective diagnostic in essence could be rolled out into most healthcare systems around the world—and most importantly, in the places where this disease is still taking its greatest toll.”

The authors concluded, “We anticipate that this distributable technology to generate clinical-grade [¹⁸F]FDT directly from the widely-available clinical reagent [¹⁸F]FDG, without need for either custom-made radioisotope generation or specialist chemical methods and/or facilities, could now usher in global, democratized access to a TB-specific PET tracer … Together therefore our results suggest that disease-selectivity demonstrated by [¹⁸F]FDT will allow effective monitoring of disease and its treatment. This is likely to be invaluable for clinical evaluation of not only effectiveness in the development of new therapies but also in longitudinal monitoring and hence compliance.”

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Uduak Thomas | Senior Editor

Katalin Karikó was thrust into the limelight during the COVID-19 pandemic for her pioneering work that led to key advances in mRNA vaccination—work that was awarded the Nobel Prize in Physiology or Medicine last year. During that time, the world learned some of Karikó’s story, marked by challenges, determination, and a love of science. Now, Uduak is eager to read Karikó’s story told in her own words. Breaking Through is “a testament to one woman’s commitment to laboring intensely in obscurity—knowing she might never be recognized in a culture that is more driven by prestige, power, and privilege—because she believed her work would save lives.”

Christina Jackson | Associate Editor

A new book can be seen on Christina’s desk, in her bag, or in her hand, on a weekly basis. When asked what book she plans to pick up this summer, she pointed to The Gene by Siddhartha Mukherjee. The Gene is described as offering “a definitive account of the fundamental unit of heredity—and a vision of both humanity’s past and future.” With a history marked by a cast of characters including Darwin, Mendel, Crick, Watson, and Franklin, Mukherjee also injects the story of his own family and their mental illness. Undoubtedly, we’ll see the 600-page book on Christina’s desk for another week or so, before she devours it and moves onto something else. 

Corinna Singleman, PhD | Managing Editor 

Ben Goldfarb, an environmental journalist, traveled throughout the United States and the world to analyze how roads have transformed our planet. Corinna used to study the impacts of human contamination on fish, and maintains her passion for learning about ecology and conservation in her post-research life. In Crossings, she is eager to read about the impacts of human roadways on animal commuting strategies and how we can address these issues. The book has been described as an “eye-opening account of the global ecological transformations wrought by roads” and was a New York Times Notable Book of 2023 and an Editors’ Choice. 

John Sterling | Editor in Chief 

As a journalist and biotech expert, John loves nothing more than a good story about science. For that reason, he is looking forward to digging into Kira Peikoff’s latest book, Baby X, a fictional thriller set in a world where a person can have a baby with anyone else—using just a biological sample. In it, a black market operation (called The Vault) steals cells from people (imagine a used napkin or fork) to convert them into sperm and egg. The “thought-provoking look into the near future” raises questions about the progress of technology and the impacts it has on the world.

James Lambo | Art Director 

If you ever wanted to know about how CRISPR works from a layperson’s perspective, James says “The Code Breaker is the book for you.” James (who got a jump start on his summer reading and is already deep into the book) says that biography veteran Walter Isaacson weaves a fascinating tale about how—over billions of years—bacteria have outwitted viruses. The story describes how modern-day researchers have seized this new technology to overcome modern-day diseases, including cancer and SARS-CoV-2. Doudna’s story, Isaacson writes, “is a thrilling detective tale that involves the world’s most profound mysteries, from the origins of life to the future of our species.”

Katherine Vuksanaj | Online Editorial Manager

Women in Science Now shares stories and insights of “women from a range of backgrounds working in various disciplines, illustrating the journeys that brought them to the sciences, the challenges they faced along the way, and the important contributions they have made to their fields.” This is a fitting choice for Kathy who found her own way into science publishing and makes important contributions at GEN every day. In her book, Munoz combines stories with data to illuminate the challenges women scientists face, while “highlighting research-based solutions to help overcome these obstacles.”

Alex Philippidis | Senior Business Editor

It comes as no surprise that Alex chose one of the leading books on the COVID-19 pandemic for his summer read. For two years, Alex led COVID-19 coverage for GEN, covering the latest drugs, vaccines, and other SARS-CoV-2 research on a daily basis throughout 2020 and 2021. Gottlieb’s book, which was released in the fall of 2021, is “an intense ride through the pandemic with chilling details of what really happened. It is also sprinkled with notes of true wisdom that may help all of us better prepare for the future,” notes Sanjay Gupta, MD, CNN chief medical correspondent.  

Kevin Mayer | Senior Editor

While some of us are delving into modern questions about COVID-19 and CRISPR, Kevin chose to read about questions that have been around a bit longer. Kevin plans to read “Sky In A Bottle” this summer. In his book, Pesic introduces us to chemistry, optics, and atomic physics and describes the polarization of light, Rayleigh scattering, and connections between the appearance of the sky and Avogadro’s number. He discusses changing representations of the sky in art, from new styles of painting to new pigments that created new colors for paint.

Julianna LeMieux, PhD | Deputy Editor in Chief 

As a microbiologist, I have always been a fan of Dr. Fauci’s research on HIV and his work as NIAID director to lead the nation through several viral outbreaks including Ebola, SARS, West Nile, and anthrax. I cannot wait to dive into his new memoir that “reaches back to his boyhood in Brooklyn, NY” and “carries through decades of caring for critically ill patients, navigating the whirlpools of Washington politics, and behind-the-scenes advising and negotiating with seven presidents on key issues from global AIDS relief to infectious disease preparedness at home.”

Rob Reis | Production Editor

Not all science summer reads need to be about science, per se. When GEN‘s production editor, Rob, first started reading the medical thrillers written by doctor and author Robin Cook more than 40 years ago, the main appeal was the interesting characters and compelling stories, but as Cook continues to keep abreast of the changes affecting the world of medicine, Rob increasingly sees connections between the topics covered in GEN and the stories crafted by Cook. He will not only re-read Cook’s 2023 novel, Manner of Death, this summer, but he also looks forward to Cook’s 2024 novel, Bellevue, when it gets published in December. 

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Can GeoVax Labs’ dual-antigen COVID-19 vaccine succeed where leading messenger RNA (mRNA)-based jabs developed during the pandemic have faded, clinically and commercially?

The company will begin to find out as it launches a 10,000-participant Phase IIb trial comparing the efficacy, safety, and immunogenicity of its next-generation, dual-antigen COVID-19 vaccine GEO-CM04S1 to one of the current FDA-approved COVID vaccines—a study being funded by the Biomedical Advanced Research and Development Authority (BARDA).

BARDA has awarded GeoVax approximately $24.3 million through its Rapid Response Partnership Vehicle (RRPV) to fund the manufacturing of clinical materials for the randomized, double-blinded Phase IIb trial, as well as regulatory and other support activities for the study. GeoVax could receive up to $45 million through RRPV based on meeting technical and scientific milestones.

Through its Clinical Studies Network, BARDA will also award approximately $343 million from its Project NextGen program to fully fund an as-yet-undisclosed contract research organization (CRO) that will carry out the Phase IIb trial. The Network offers services for Phase I through IV clinical trials of medical countermeasure candidates such as vaccines and treatments.

Investors responded to the BARDA award announcement June 18 by sending GeoVax shares rocketing 71% from $1.11 to $1.90. Those shares have fluctuated early this week, surging another 30% to $3.03 on Monday before dipping 27% to $2.20 on Tuesday.

GeoVax Chairman, President, and CEO David A. Dodd told GEN his company and the CRO have worked for over a year in preparation for the start of the Phase IIb trial.

GEO-CM04S1 is based on GeoVax’s MVA viral vector platform, which supports the presentation of multiple vaccine antigens to the immune system in a single dose.

Two-prong attack

While current COVID-19 vaccines such as Pfizer/BioNTech’s Comirnaty and Moderna’s Spikevax are mRNA vaccines targeting the Spike protein, GeoVax’s GEO-CM04S1 mounts a two-prong attack on SARS-CoV-2 by encoding for both the spike (S) and nucleocapsid (N) antigens of the virus. The vaccine is designed to induce both durable neutralizing antibody and T-cell-based immunity against current and future variants of SARS-CoV-2 by attacking parts of the virus that are less likely to mutate over time.

By pursuing a more broadly functional engagement of the immune system, GEO-CM04S1 is designed to protect against severe disease caused by continually emerging variants of COVID-19—and thus should not require frequent and repeated modification or updating, according to GeoVax.

GEO-CM04S1 is already under study in three Phase II trials. One trial is assessing GEO-CM04S1 as a primary vaccine in immunocompromised blood cancer patients who have received cell transplants or CAR-T therapy (NCT04977024). The study’s open-label portion has generated data showing GEO-CM04S1 to be highly immunogenic in these patients, inducing both antibody responses, including neutralizing antibodies, and T-cell responses.

“We expect that this year there will be another update. We also expect that as we go into early 2025, we anticipate expanding that trial to additional sites in North America as well as in the U.K.,” Dodd said.

The other two trials are evaluating GEO-CM04S1 as a:

• Booster vaccine for healthy adults who have previously received the Pfizer or Moderna mRNA vaccines (NCT04639466). The trial was fully enrolled in September 2023 and final results are expected in the fourth quarter, reflecting a 12-month tracking of study patients.
• Booster vaccine in immunocompromised patients with chronic lymphocytic leukemia (CLL), a high-risk population for which current mRNA vaccines and monoclonal antibody (MAb) therapies have been shown to offer inadequate protective immunity (NCT05672355). GeoVax expects to read out data in the fourth quarter.

‘The reason why that becomes important to us is, if the data looks good, we may very well initiate our own company sponsored CLL trial,” Dodd said. “The various discussions we’ve been having with regulatory authorities indicate that there may be an expedited pathway for registration by focusing on such a high-risk group that is recognized as not being satisfied or addressed adequately by what is out there right now.”

GeoVax says its COVID-19 vaccine is potentially more durable than current FDA-approved COVID-19 jabs, which have been shown to lose effectiveness within two to six months.

“We’re showing protective immunity from the original Wuhan through the Omicron XBB1.5 variant, so it offers breadth of protection across the variants as well as durability,” Dodd said.

Longer durability

GeoVax says its studies to date have shown the effectiveness of GEO-CM04S1 to last twice as long as the two to six month range of current COVID-19 vaccines: “Our durability currently is coming in from our clinical trials at 8 to 12 months,” Dodd added.

And where Pfizer/BioNTech and Moderna developed COVID-19 vaccines aimed at protecting the general population from the virus, GeoVax says its COVID-19 jab is intended for immunocompromised adults who are more likely to potentially experience severe COVID-19 symptoms, hospitalization, and increased risk of death, yet are less likely to respond adequately to current COVID-19 vaccines.

The number of immunocompromised adults is estimated at between 50 million and 70 million people in the U.S. and up to 300 million worldwide.

“We’re not planning on going toe to toe with the current vaccines,” Dodd said. “From day one of moving forward with our vaccine, we have focused on going after the populations for whom the pandemic has never ended, the immunocompromised populations who have medical conditions that have depleted their body’s ability to respond to COVID or SARS-CoV-2.”

“These patients remain at risk of severe disease, hospitalization, and risk of death. They’re under active medical care they’re being managed by hematological oncologists, or they might be managed by the nephrologist, or by the endocrinologist if they have diabetes. They have medical conditions in which they are under active medical care. That’s different than the general population,” Dodd explained.

By focusing on immunocompromised patients, GeoVax reasons it can maximize potential revenue for its vaccine as revenues for the approved COVID-19 jabs has plunged with the pandemic evolving into an endemic.

$7.4B U.S. revenue potential

In its corporate overview presentation to investors this past spring, GeoVax estimated the market revenue potential for GEO-CM04S1 in the  U.S. alone at $7.4 billion—just below the combined $8 billion in combined 2024 global sales that Pfizer has projected for both its COVID-19 vaccine Comirnaty^® (co-marketed with BioNTech) and its COVID-19 drug Paxlovid^®.

Dodd says GeoVax is updating its revenue projection because the spring forecast was based on an older estimate of just 20 to 25 million immunocompromised Americans—while the National Health Interview Survey of the U.S. Centers for Disease Control and Prevention cites between 50 million to 70 million Americans with compromised immune systems.

“From a business standpoint, we believe that we have the opportunity with our vaccine to be the lead vaccine to be used among people with compromised immune systems, because they’re not benefiting from what is currently out there,” Dodd said.

GeoVax has not furnished a peak annual sales estimate for GEO-CM04S1

Last year, Comirnaty generated $11.220 billion in direct sales and alliance revenues, down 70% from $37.806 billion in 2022, while Paxlovid generated only $1.279 billion in 2023, down 93% from $18.933 billion a year earlier.

Moderna’s COVID-19 vaccine Spikevax racked up $6.7 billion in 2023 sales, a 64% plunge from $18.4 billion in 2022. For this year, Moderna has only disclosed a $4 billion combined sales projection for its respiratory vaccine franchise, which includes Spikevax as well as its respiratory syncytial virus (RSV) vaccine mRESVIA (mRNA-1345), approved by the FDA on May 31.

The BARDA award marks a milestone for GeoVax. Based in the Atlanta suburb of Smyrna, GA, GeoVax was founded in 2001 with the initial focus of developing an HIV vaccine, based on research by Harriet Latham Robinson, the company’s founder and chief scientific officer emeritus.

Pivot from HIV

Dodd joined GeoVax’s board in 2010, and the following year was first elected chairman. As chairman, Dodd oversaw the company’s pivot away from HIV in 2014 after it failed to attract funding from investors or the NIH to advance its vaccine past Phase IIa.

The company began pursuing vaccine development based on its MVA platform, with early signs of success. GeoVax’s Ebola Zaire vaccine, for example, showed 100% protection in non-human primates given a single dose without any adjuvants, while the company also developed vaccines for Ebola Sudan and Marburg virus.

“We’re not planning on carrying those forward on our own funding, but we’re in discussions right now” with potential partners to move toward Phase I studies, Dodd said. Should those talks yield one or more agreements, he said, the resulting studies “will be done through funding by non-dilutive means.”

Dodd took on the additional roles of president and CEO in 2018, intent on enabling GeoVax to develop its pipeline by growing and broadening the company’s financing.

As COVID-19 began to wreak havoc on the world, GeoVax began a program to develop a vaccine for the virus. That sent the company’s stock, then trading Over the Counter, zooming from 13 to 50 cents a share. But by June 2020, with the world upended by the pandemic, GeoVax was down to five employees and $100,000 in available cash.

Three months later, GeoVax closed on a $12.8 million public offering and up-listed its publicly traded shares and warrants from the Over the Counter market to Nasdaq.

In 2021, GeoVax acquired its two main pipeline programs, shelling out undisclosed sums for an exclusive license from City of Hope to develop GEO-CM04S1 two months after the company bought exclusive rights to the cancer drug Gedeptin^® from PNP Therapeutics.

Gedeptin is now in a Phase I/II trial (NCT03754933) in patients with advanced head and neck cancer. Initial study results from the first trial of the Phase II portion are expected to be announced within the next two to three weeks, Dodd said, to be followed by plans for an expanded Phase II study of Gedeptin, then a combination study evaluating Gedeptin with an immune checkpoint inhibitor.

The FDA has granted Gedeptin orphan drug status for the intra-tumoral treatment of anatomically accessible oral and pharyngeal cancers, including cancers of the lip, tongue, gum, floor of mouth, salivary gland and other oral cavities.

Also in GeoVax’s pipeline is GEO-MVA, a vaccine for smallpox and Mpox being developed for adult men at high risk of Mpox. GeoVax aims to become the first U.S. based supplier of a vaccine for Mpox and smallpox (Copenhagen-based Bavarian Nordic began commercial launch of the currently sole FDA-approved Mpox vaccine, Jynneos^® [MVA-BN] in April), plus satisfy interest from the federal government in replenishing and re-stocking the Strategic National Stockpile with a domestic-sourced smallpox vaccine.

Progress report

GeoVax plans later this year to disclose its progress toward an expedited regulatory registration pathway. “Frankly, we believe that our first product to be registered and commercialized could very easily be GEO-MVA as a standalone vaccine,” Dodd said. “I’m not saying it will be commercialized. But we’ll have updates on that, because development is being driven by a heavy regulatory strategy, as you might imagine.”

GeoVax’s pipeline also includes a half dozen preclinical programs—including a treatment for solid tumor cancers, and vaccines for pan-coronavirus, Ebola Zaire, Ebola Sudan, Marburg virus, and Zika.

“Those products will advance to the degree that there is non-dilutive, let’s say external collaboration, business development, or co-development funding. We’re not allocating a lot of time to those if any,” Dodd said.

Despite data showing 100% protection in a single dose for its Zika virus candidate, Dodd said, “it has not been a priority, because there are others out there that are going after it.”

“That’s one program that is held in discussions if there are potential partners, and whatever form of a transaction they may end up thinking about,” Dodd added. “Our focus is, number one, the [BARDA-funded] Project NextGen program for GEO-CM04S1, then number two, both the GEO-CM04S1 Phase II programs and the Gedeptin program.”

Project NextGen is a $5 billion program designed to speed up development of next-generation COVID-19 vaccines, drugs, and enabling technologies that lower costs, speed production, increase efficacy, and improve access to those vaccines and drugs. Project NextGen is led by BARDA and the NIH’s National Institute of Allergy and Infectious Diseases (NIAID).

To date, BARDA says, it has spent more than $2 billion in Project NextGen funding to support development of next generation vaccines, treatments, and enabling technologies. BARDA is part of the U.S. Department of Health and Human Services (HHS)’s Administration for Strategic Preparedness and Response (ASPR).

GeoVax finished the first quarter with a $5.58 million net loss, up from a $4.038 million net loss in Q1 2023, and no grant revenue either quarter. The company reported a $26 million net loss in 2023, nearly double its $14 million net loss the previous year.

GeoVax has grown its workforce to about 25 people, Dodd said, up from the 17 the company reported in its Form 10-K annual report for 2023. That workforce is expected to grow over time through a combination of full-time and contracted employees: “We’re actually going through all that planning right now of what our timing will be and our options for staffing up.”

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Just – Evotec Biologics will focus on project activities and technologies designed to significantly decrease the time for development, manufacturing, and CMC-focused regulatory efforts. These innovations will significantly increase the speed to first clinical doses while maintaining high mAb quality, productivity, and safety criterion, said Matthias Evers, PhD, CBO of Evotec.

Activities include developing and testing process development optimization, improving efficiencies in cGMP manufacturing and drug product release, and enhancing operational and resource workflows. The program will culminate in testing the optimized system components through rapid response exercises, starting with a DOD-identified MCM antibody sequence, and ending with the manufacturing of clinical doses.

Emergency response system 

The Just – Evotec Biologics’ optimized manufacturing solution will seamlessly integrate into the U.S. Government’s rapid emergency response system spanning the entire drug development lifecycle, with an overall 100-calendar day target timeline for advancing drug development from pathogen identification through fielding of doses, added Linda Zuckerman, PhD, executive vice president, global head of therapeutics, Just – Evotec Biologics.

“We are proud to be selected to provide our expertise and technologies in support of this important program. We are excited to push our current end-to-end biologics development platform and partner with the DOD to bring ‘next level’ development of fast, high quality, cost efficient mAbs to the clinic,” she continued.

“The Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense (JPEO-CBRND) is thrilled to reinforce its collaboration with Just – Evotec Biologics in the context of an innovative program.

“This strategic alliance enables us to harness the power of advancements in manufacturing as part of our readiness and agile reaction approach, ensuring that we are prepared to swiftly develop medical countermeasures in response to a diverse array of biologic threats,” noted Bruce Goodwin, joint project lead at JPEO-CBRND (JPL for CBRND Enabling Biotechnologies).

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