It’s possible that I shall make an ass of myself. But in that case one can always get out of it with a little dialectic. I have, of course, so worded my proposition as to be right either way (K.Marx, Letter to F.Engels on the Indian Mutiny)
A recent review explores the innovative use of self-assembled protein nanoparticles (SAPNs) and virus-like particles (VLPs) in veterinary vaccine development. The research highlights the superior safety and efficacy of these nanovaccines over traditional formulations, offering a promising future for animal health and disease prevention.
Classical vaccines often rely on traditional technologies, such as live attenuated or inactivated pathogens, which carry inherent risks including reduced immunogenicity under certain conditions and potential safety concerns. This has spurred the need for innovative approaches that can provide safer and more effective prophylactic solutions in veterinary medicine. SAPNs emerge as a cutting-edge solution, harnessing the power of nanotechnology to revolutionize vaccine design and implementation.
The article (DOI: 10.1186/s44149-024-00119-w), published on 10 May 2024, in the Animal Diseasesjournal, researchers at Zhejiang University's Institute of Preventive Veterinary Medicine, delve into the development and application of SAPNs and VLPs, offering a detailed discussion of their potential in veterinary medicine.
The article focuses on various types of SAPNs, including natural and synthetically designed nanoparticles. These nanoparticles are tailored to enhance the immune system's ability to recognize and respond to pathogens more effectively. Key highlights include the use of animal virus-derived nanoparticles and bacteriophage-derived nanoparticles, which have shown the potential to elicit strong cellular and humoral responses. The nanoparticles' ability to mimic pathogen structures enables them to trigger a more substantial immune reaction, potentially leading to long-lasting immunity. Researchers have documented successes in using these nanoparticles to protect against diseases like foot-and-mouth disease and swine fever, showcasing their broad applicability and effectiveness.
Dr.Fang He, a principal investigator of the article, expressed the significance of this review, " Nanoparticle vaccines have demonstrated enormous promise and should be considered promising techniques in veterinary vaccine development."
Veterinary nanoparticle vaccines have broad implications, with the potential to extend the benefits beyond veterinary applications into human health. The enhanced safety and immunogenicity of these vaccines could lead to the development of advanced vaccines for human use. Additionally, by reducing the environmental impact of livestock diseases, this technology may contribute to more sustainable agricultural practices globally.
Animal Diseases（ISSN 2731-0442, CN 42-1946/S）is a peer-reviewed, free open access academic journal sponsored by Huazhong Agricultural University. The journal promotes the One Health initiative and is committed to publishing high-quality innovated and prospective works in animal disease research/application that are closely related to human health. The founding chief editors are Drs. Huanchun Chen (Huazhong Agricultural University, China) and Zhen F. Fu (University of Georgia, USA). It has been indexed by ESCI in 2024.
A new study demonstrates an advance in treating antibiotic-resistant infections in animals through personalized phage therapy. The treatment combined a specific anti-P. aeruginosa phage applied topically with ceftazidime administered intramuscularly, resulting in the complete healing of a persistent surgical wound after fourteenweeks. This highlights the potential of phage therapy as a practical and effective solution for antibiotic-resistant infections in veterinary practice, with implications for human medicine as well.
A new study led by Prof. Ronen Hazan and his team, from the Faculty of Dental Medicine at the Hebrew University of Jerusalem, in collaboration with the team of Vet Holim, JVMV -Veterinary medical center in Kiryat -Anavim, Israel, has shown an advance in the treatment of antibiotic-resistant infections in animals. This research, focusing on a five-year-old Siamese cat Squeaks with a multidrug-resistant Pseudomonas aeruginosa infection post-arthrodesis surgery, marks the first published documented application of personalized phage therapy in veterinary medicine.
Squeaks, initially treated at the JVMV for injuries sustained from a high-rise fall, developed a severe infection in the right hind leg following multiple surgeries. This infection persisted despite various antibiotic treatments over four months. Facing a potential implant-replacement surgery, the team turned to the new treatment which involved a meticulously designed combination of a specific anti-P. aeruginosa phage, a virus that kills bacteria, applied topically to the surgical wound and ceftazidime administered intramuscularly. Moreover, the owners of the cat, after short demonstration, provides most of the treatment doses of phages and antibiotics at their home.
The integration of phage therapy with antibiotics was aimed at targeting the pathogen effectively and directly at the site of infection, leveraging the phage’s ability to be applied topically, which simplifies administration and maximizes its concentration at the infection site. This approach allowed the surgical wound, which had remained open for five months, to fully heal after to fourteen weeks of treatment.
The successful outcome of this case underscores the critical need for novel therapeutics like phage therapy to address the growing concern of antibiotic-resistant infections, which affect up to 8.5% of surgical sites following orthopedic surgeries in companion animals. These infections not only pose significant health risks to the animals but also increase the morbidity, mortality, and costs associated with these procedures.
Recent studies suggest that phage therapy, already showing high success rates in human medicine for treating orthopedic infections and chronically infected wounds, can offer a promising solution for similar issues in veterinary practice. Moreover, the successful treatment of this cat by its owners at home highlights the practicality and efficacy of personalized phage therapy, which could be extended to treat other pets facing similar antimicrobial resistance challenges.
Interestingly, opposite to common situations, this case was performed on an animal based on the team's insights from treating humans first.
The positive reception from veterinarians and pet owners regarding phage therapy points to a growing awareness and acceptance of this treatment option. As the new treatment continues to be explored in veterinary settings, it not only improves the health and well-being of pets but also offers valuable data that contribute to the broader application of phage therapy in both animals and humans. This bridging of data can enhance treatment protocols and outcomes across a variety of bacterial infections, potentially changing the landscape of infection treatment in both veterinary and human medicine.
Successful phage-antibiotic therapy of P. aeruginosa implant-associated infection in a Siamese cat
Phage therapy: In-depth discussion on ethical considerations and regulatory landscape at upcoming European conference “Targeting Phage Therapy 2024”
MITOCHONDRIA-MICROBIOTA TASK FORCE
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BARBARA BRENNER, A LEGAL EXPERT IN MEDICAL LAW AND HUMAN RIGHTS, WILL DELIVER A TALK TITLED "REGULATORY RESTRICTIONS VS. HUMAN RIGHTS, THE HIPPOCRATIC OATH, AND THE FREEDOM OF THERAPY – THE LEGAL ASPECT OF PHAGE THERAPY" AT TARGETING PHAGE THERAPY ON JUNE 20-21, 2024
The 7th World Conference on Targeting Phage Therapy 2024 is set to take place on June 20-21 at the Corinthia Palace in Malta, welcoming over 150 attendees from 30 countries and featuring more than 32 communications. This annual event showcases the latest advancements in phage research and therapy, emphasizing how these developments could revolutionize healthcare practices globally.
The Ethical Considerations and Regulatory Landscape of Phage Therapy will be highlighted
Targeting Phage Therapy 2024 will include a dedicated session on the ethical and regulatory aspects of phage therapy, particularly in Europe. Barbara Brenner, a legal expert in medical law and human rights, will deliver a talk titled "Regulatory Restrictions vs. Human Rights, the Hippocratic Oath, and the Freedom of Therapy – The Legal Aspect of Phage Therapy". Her presentation will focus on balancing regulatory frameworks with the urgent need for accessible, life-saving treatments.
Phage therapy faces significant regulatory and ethical challenges, and Brenner will address several critical points:
- Regulatory Frameworks and Human Rights: Brenner will provide an overview of EU and German legal and regulatory frameworks, highlighting the tension between the right to safe drugs and the right to life-saving treatment in emergencies, especially concerning antimicrobial-resistant (AMR) infections and non-GMP phages.
- Ethical and Legal Questions: The session will explore whether it is ethical to deny life-saving treatments for safety reasons and whether regulatory bodies like the FDA and EMA can be held liable for prohibiting non-GMP phages if GMP phages are unavailable or unaffordable. Additionally, Brenner will discuss the validity of scientific evidence derived from anecdotal sources versus the necessity of randomized controlled trials (RCTs) and whether these trials need to be redesigned. The legal status of phage therapy as "experimental" and the potential liability of clinicians who refuse phage therapy when it could save a patient will also be examined.
- Combatting Antimicrobial Resistance (AMR): The presentation will include the One Health approach, integrating human, animal, and environmental health practices. Brenner will highlight Georgia's successful model, advocating for the promotion of phages as primary interventions, reserving chemical antibiotics for situations where phages are ineffective.
Speakers Lineup
Robert T. Schooley, University of California, San Diego, USA
Clinical Trials in Phage Therapeutics: Looking Under the Hood
Ekaterina Chernevskaya, Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Russia
Adaptive Phage Therapy in the Intensive Care Unit: From Science to Patients
Jean-Paul Pirnay, Queen Astrid Military Hospital, Belgium
Magistral Phage Preparations: Is This the Model for Everyone?
Barbara Brenner, Kanzlei BRENNER, Germany
Regulatory restrictions vs. Human Rights, the Hippocratic oath and the Freedom of therapy– The legal aspect ofphage therapy
Nannan Wu, Shanghai Public Health Clinical Center, Fudan University, China
Phage Therapy: A Glimpse into Clinical Studies Involving Over 150 Cases
Graham F. Hatfull, University of Pittsburgh, USA
Mycobacteriophages and Their Therapeutic Potential
Antonia P. Sagona, University of Warwick, United Kingdom
Genetic Engineering of Phages to Target Intracellular Bloodstream E.coli Infections
Paul Turner, Yale University, USA
Leveraging Evolutionary Trade-Offs in Development of Phage Therapy
Pieter-Jan Ceyssens, Sciensano, Belgium
Quality control of phage Active Pharmaceutical Ingredients (APIs) in Belgium
Wolfgang Weninger, Medical University of Vienna, Austria
The Phageome in Normal and Inflamed Human Skin
Sabrina Green, KU Leuven, Belgium
Making Antibiotics Great Again: Phage resistance in vivo correlates to resensitivity to antibiotics in pan-resistant Pseudomonas aeruginosa
Rodrigo Ibarra Chávez, University of Copenhagen, Denmark
Phage Satellites, a Diversity of Extradimensional Symbionts and Pathways to Phage Therapy
Domenico Frezza, University of Roma Tor Vergata, Italy
Towards efficient phage therapies: investigation of phage / bacteria equilibrium with metagenome of dark matter in natural samples
Besarion Lasareishvili, Eliava Institute of Bacteriophage, Microbiology and Virology, Georgia
Modern Concepts of Phage Therapy: An Immunologist’s Vision
Kilian Vogele, Invitris, Germany
Cell-Free Production of Personalized Therapeutic Phages Targeting Multidrug-Resistant Bacteria
Frederic Bertels, Max Planck Institute for Evolutionary Biology, Germany
Improving Phages through Experimental Evolution
Eugene V Koonin, National Institutes of Health, USA
Evolution and megataxonomy of viruses: the place of phages in the virosphere
Federica Briani, University of Milan, Italy
Addressing Phage Resistance to Enhance the Robustness of Phage Therapy for Pseudomonas aeruginosa Infections in People with Cystic Fibrosis
Jumpei Fujiki, University of California San Diego, USA
Phage therapy: Targeting intestinal bacterial microbiota for the treatment of liver disease
Zombie cells in the sea: Viruses keep the most common marine bacteria in check
MAX PLANCK INSTITUTE FOR MARINE MICROBIOLOGY
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SUNSET OVER THE ISLAND OF HELGOLAND IN THE GERMAN BIGHT, WHERE THE RESEARCHERS FROM THE MAX PLANCK INSTITUTE FOR MARINE MICROBIOLOGY OBTAINED THEIR SAMPLES.
CREDIT: JAN BRÃœWER/MAX PLANCK INSTITUTE FOR MARINE MICROBIOLOGY
The ocean waters surrounding the German island of Helgoland provide an ideal setting to study spring algae blooms, a focus of research at the Max Planck Institute for Marine Microbiology since 2009. In a previous study, the Max Planck scientists observed a group of bacteria called SAR11 to grow particularly fast during these blooms. However, despite their high growth rates, the abundance of SAR11 decreased by roughly 90% over five days. This suggested that the cells were quickly decimated by predators and/or viral infections. Now, the Max Planck researchers investigated what exactly lies behind this phenomenon.
Finding the phages infecting SAR11
“We wanted to find out if the low numbers of SAR11 were caused by phages, that is viruses that specifically infect bacteria”, explains Jan Brüwer, who conducted the study as part of his doctoral thesis. “Answering this seemingly simple question was methodologically very challenging”.
How does phage infection work? Phages infect bacteria by introducing their genetic material into them. Once there, it replicates, and utilizes the bacterial ribosomes to produce the proteins it needs. Researchers from Bremen used a technology that enabled them to “follow” the phage’s genetic material inside the cell. “We can stain the specific phage genes and then see them under the microscope. Since we can also stain the genetic material of SAR11, we can simultaneously detect phage-infected SAR11 cells”, explains Jan Brüwer.
While this might seem straightforward, the low brightness and small size of the phage genes made it challenging for researches to detect them. Nonetheless, thousands of microscope images were successfully analyzed, bringing some exciting news.
“We saw that SAR11 bacteria are under massive attack by phages”, says Jan Brüwer. “During periods of rapid growth, such as those associated with spring algae blooms, nearly 20% of the cells were infected, which explains the low cell numbers. So, phages are the missing link explaining this mystery.”
Zombie cells: A global phenomenon
To the surprise of the scientists, the images revealed even more. "We discovered that some of the phage-infected SAR11 cells no longer contained ribosomes. These cells are probably in a transitional state between life and death, thus we called them 'zombie' cells”, Brüwer explains.
Zombie cells represent a novel phenomenon observed not only in pure SAR11 cultures but also in samples collected off Helgoland. Furthermore, analysis of samples from the Atlantic, Southern Ocean, and Pacific Ocean revealed the presence of zombie cells, indicating this phenomenon occurs worldwide.
“In our study, zombie cells make up to 10% of all cells in the sea. The global occurrence of zombie cells broadens our understanding of the viral infection cycle”, Brüwer emphasizes. “We suspect that in zombie cells, the nucleic acids contained in the ribosomes are being broken down and recycled to make new phage DNA.”
Brüwer and his colleagues hypothesize that not only SAR11 bacteria, but also other bacteria, can be turned into zombies. Thus, they want to further investigate the distribution of zombie cells and their role in the viral infection cycle.
“This new finding proves that the SAR11 population, despite dividing so fast, is massively controlled and regulated by phages”, stresses Brüwer. “SAR11 is very important for global biogeochemical cycles, including the carbon cycle, therefore their role in the ocean must be redefined. Our work highlights the role of phages in the marine ecosystem and the importance of microbial interactions in the ocean”.
Infected cells and zombie cells
Under the microscope, scientists identified SAR11 zombie cells by their distinct lack of ribosomes. In an example comparing a live, infected SAR11 cell to an infected zombie cell: blue indicates bacterial DNA, yellow shows ribosomes, and purple highlights phage genes. The live cell (upper pictures) displays all three colors, while the zombie cell (lower pictures) lacks the yellow ribosome signal. The final column of images on the right merges these colors, clearly distinguishing the two cell types.
CREDIT
Jan Brüwer/Max Planck Institute for Marine Microbiology
Study suggests host response needs to be studied along with other bacteriophage research
Bacteriophage (magenta) attack Pseudomonas aeruginosa (teal) biofilms grown in association with respiratory epithelial cells (nuclei, yellow). Credit: Paula Zamora,
A team of micro- and immunobiologists from the Dartmouth Geisel School of Medicine, Yale University, and the University of Pittsburgh has found evidence suggesting that future research teams planning to use bacteriophages to treat patients with multidrug-resistant bacterial infections need to also consider how cells in the host's body respond to such treatment.
In their paper published in the open-access journal PLOS Biology, the group describes experiments they conducted that involved studying the way epithelial cells in the lungs respond to bacteriophages.
Over the past decade, medical scientists have found that many of the antibiotics used to treat bacterial infections are becoming resistant, making them increasingly useless. Because of this, other scientists have been looking for new ways to treat such infections. One possible approach has involved the use of bacteriophages, which are viruses that parasitize bacteria by infecting and reproducing inside of them, leaving them unable to reproduce.
To date, most of the research involving use of bacteriophages to treat infections has taken place in Eastern Europe, where some are currently undergoing clinical trials. But such trials, the researchers involved in this new study note, do not take into consideration how cells in the body respond to such treatment. Instead, they are focused on determining which phages can be used to fight which types of bacteria, and how well they perform once employed.
The reason so little attention is paid to host cell interaction, they note, is that prior research has shown that phages can only replicate inside of the bacterial cells they invade; thus, there is little opportunity for them to elicit a response in human cells.
In this new study, the research team suggests such thinking is misguided because it fails to take into consideration the immune response in the host. To demonstrate their point, the team conducted a series of experiments involving exposing human epithelial cells from the lungs (which are the ones that become infected as part of lung diseases) to bacteriophages meant to eradicate the bacteria causing an infection.
They found that in many cases, the immune system responded by producing proinflammatory cytokines in the epithelial cells. They noted further that different phages elicited different responses, and there exists the possibility that the unique properties of some phages could be used to improve the results obtained from such therapies. They conclude by suggesting that future bacteriophage research involve inclusion of host cell response.
More information: Paula F. Zamora et al, Lytic bacteriophages induce the secretion of antiviral and proinflammatory cytokines from human respiratory epithelial cells, PLOS Biology (2024). DOI: 10.1371/journal.pbio.3002566
COLUMBUS, Ohio – One of the many secrets to bacteria’s success is their ability to defend themselves from viruses, called phages, that infect bacteria and use their cellular machinery to make copies of themselves.
Technological advances have enabled recent identification of the proteins involved in these systems, but scientists are still digging deeper into what those proteins do.
In a new study, a team from The Ohio State University has reported on the molecular assembly of one of the most common anti-phage systems – from the family of proteins called Gabija – that is estimated to be used by at least 8.5%, and up to 18%, of all bacteria species on Earth.
Researchers found that one protein appears to have the power to fend off a phage, but when it binds to a partner protein, the resulting complex is highly adept at snipping the genome of an invading phage to render it unable to replicate.
“We think the two proteins need to form the complex to play a role in phage prevention, but we also believe one protein alone does have some anti-phage function,” said Zhangfei Shen, co-lead author of the study and a postdoctoral scholar in biological chemistry and pharmacology at Ohio State’s College of Medicine. “The full role of the second protein needs to be further studied.”
The findings add to scientific understanding of microorganisms’ evolutionary strategies and could one day be translated into biomedical applications, researchers say.
Shen and co-lead author Xiaoyuan Yang, a PhD student, work in the lab of senior author Tianmin Fu, assistant professor of biological chemistry and pharmacology at Ohio State.
The two proteins that make up this defense system are called Gabija A and Gabija B, or GajA and GajB for short.
Researchers used cryo-electron microscopy to determine the biochemical structures of GajA and GajB individually and of what is called a supramolecular complex, GajAB, created when the two bind to form a cluster consisting of four molecules from each protein.
In experiments using Bacillus cereus bacteria as a model, researchers observed the activity of the complex in the presence of phages to gain insight into how the defense system works.
Though GajA alone showed signs of activity that could disable a phage’s DNA, the complex it formed with GajB was much more effective at ensuring phages would not be able take over the bacterial cell.
“That’s the mysterious part,” Yang said. “GajA alone is sufficient to cleave the phage nucleus, but it also does form the complex with GajB when we incubate them together. Our hypothesis is that GajA recognizes the phage’s genomic sequence, but GajB enhances that recognition and helps to cut the phage DNA.”
The large size and elongated configuration of the complex made it difficult to get the full picture of GajB’s functional contributions when bound to GajA, Shen said, leaving the team to make some assumptions about protein roles that have yet to be confirmed.
“We only know GajB helps enhance GajA activity, but we don’t yet know how it works because we only see about 50% of it on the complex,” Shen said.
One of their hypotheses is that GajB may influence the concentration level of an energy source, the nucleotide ATP (adenosine triphosphate), in the cellular environment – specifically, by driving ATP down upon detection of the phage’s presence. That would have the dual effect of expanding GajA’s phage DNA-disabling activity and stealing energy that a phage would need to start replicating, Yang said.
There is more to learn about bacterial anti-phage defense systems, but this team has already shown that blocking virus replication isn’t the only weapon in the bacterial arsenal. In a previous study, Fu, Shen, Yang and colleagues described a different defense strategy: bacteria programming their own death rather than letting phages take over a community.
This work was supported by the National Institute of General Medical Sciences.
Additional co-authors are Jiale Xie, Jacelyn Greenwald, Ila Marathe, Qingpeng Lin and Vicki Wysocki of Ohio State, and Wenjun Xie of the University of Florida.
Molecular basis of Gabija anti-phage supramolecular assemblies
ARTICLE PUBLICATION DATE
16-Apr-2024
Thursday, April 25, 2024
A vaccine to fight antibiotic resistance
MSU, Harvard Medical School team up to expand vaccine science’s role in the fight against MRSA and other infections
MICHIGAN STATE UNIVERSITY
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AN ARTISTIC RECREATION OF MRSA. MICHIGAN STATE UNIVERSITY RESEARCHER XUEFEI HUANG IS DEVELOPING NEW VACCINE SCIENCE IN THE FIGHT AGAINST ANTIBIOTIC RESISTANCE.
CREDIT: JENNIFER OOSTHUIZEN, MEDICAL ILLUSTRATOR. CENTERS FOR DISEASE CONTROL AND PREVENTION PUBLIC HEALTH IMAGE LIBRARY.
Driven by the overuse of antimicrobials, pathogens are quickly building up resistances to once-successful treatments. It’s estimated that antimicrobial-resistant infections killed more than 1 million people worldwide in 2019, according to the World Health Organization.
“There are worries that at the rate things are going, in perhaps 20 or 30 years, few of our drugs will be effective at all,” said Xuefei Huang, a Michigan State University Research Foundation Professor in the departments of Chemistry and Biomedical Engineering.
“This would bring us back to the pre-antibiotic age.”
Now, in a new Nature Communications study, Huang and his collaborators have reported a breakthrough that will help tackle this global threat head-on. Specifically, the team has created a promising vaccine candidate for antibiotic-resistant bacteria.
Bacterial vaccines, along with antibiotics, are a crucial tool in the fight against deadly microbes.
In the latest paper, Huang announced several discoveries that will help the development of a carbohydrate-based vaccine for infections caused by Staphylococcus aureus and its “superbug” relative methicillin-resistant Staphylococcus aureus, or MRSA.
Staph aureus, or staph, and MRSA are among the most prevalent causes of bacterial infections.
Using an innovative delivery platform created by the Huang group at MSU, the team’s preclinical vaccine formulation offered high levels of immunity from lethal levels of staph and MRSA in animal trials.
With this work, Huang and his team have expanded the frontiers of vaccine science, equipping fellow researchers with new knowledge to improve and refine future bacterial vaccines.
Carbohydrate hurdles
To develop a vaccine, researchers must identify an effective antigen. This is a substance or molecule that the body flags as foreign, helping to trigger an immune response and the creation of antibodies that will fight future infection.
While most vaccines rely on protein antigens, Huang is an expert in the chemistry and biology of carbohydrates. These are chemical compounds comprised of saccharides, or sugars.
Developing carbohydrates to use as antigens in vaccines comes with its own unique challenges and advantages.
“Sugar structures are very specific to certain bacteria,” Huang explained. “A vaccine that works against one bacterium might not work at all against another, even if they’re very similar.”
This is why a single dose of a bacterial vaccine can contain many different antigens. For instance, the “20” in Pfizer’s PREVNAR 20 pediatric pneumonia vaccine refers to the 20 unique strains of bacteria it protects against.
If researchers can develop an antigen that’s shared among many — if not all — bacteria, vaccination coverage would be greatly improved.
Gerald Pier, professor of medicine at Harvard Medical School and Brigham and Women’s Hospital and a collaborator on the latest MSU-led paper, has studied one such antigen candidate for years.
Polysaccharide poly-β-(1−6)-N-acetylglucosamine, or PNAG, is a carbohydrate found on the cell wall of staph, many other bacteria and even fungi. This prevalence makes it extremely useful, offering potential protection against numerous pathogens at once.
By examining PNAG as an antigen candidate for staph, Pier, Huang and their colleagues are unlocking the secrets needed to make a more effective vaccine.
A molecular mosaic
Imagine creating a mosaic made from multicolored tiles.
Arrange these tiles in a precise pattern and you’ll end up with a striking work of art. Move just a few tiles around, however, and you’ll find yourself looking at a very different image.
PNAG — and carbohydrates in general — are kind of like mosaics. There are myriad ways to arrange their individual pieces, but only a select few have the effects that researchers desire.
Just as changing a few tiles in a mosaic can give you a completely different image, swapping out these pieces or even changing their location within a PNAG molecule changes its performance as a potential antigen.
“We were very interested in this molecule and these different patterns,” Huang said.
“We wanted to know: Was there a best combination to improve Staph aureus vaccine efficiency, and does the arrangement matter?”
The pieces that Huang and his colleagues were most interested in were biologically active molecular components known as amines and acetyl groups that adorn PNAG’s sugary backbone.
PNAG molecules can contain many amines. These amines can be acetylated, meaning they’re modified with an acetyl group, or they can be free and not bound to anything else.
Currently, most researchers investigating PNAG as an antigen focus on forms of the sugar that are either fully free or fully acetylated.
Huang and his colleagues believed there were promising opportunities in the understudied in-between space where there’s a mixture of free and acetylated amines.
For its research, the team created a library of 32 different PNAG structures. The structures were all pentasaccharides — made from five saccharides — but they differed in how they were decorated with amines and acetyl groups.
By screening these 32 structures with antibody studies, they made their discovery.
“The fine pattern matters quite a bit,” Huang said. “And the impact is drastic.”
An MSU mutant
The team identified two PNAG combinations that were especially promising. Going a step further, the researchers attached them to a groundbreaking vaccine delivery platform.
The platform is based on a bacteriophage, which is a virus that infects bacteria, called Qbeta, also written as Qβ (pronounced “cue beta”). Huang’s team modified the bacteriophage, giving it the power to deliver antigens for carbohydrate-based pathogens.
PNAG and other carbohydrates typically don’t provoke strong immune responses in our bodies, but the mutant Qbeta, or mQβ, helps create an enhanced reaction.
When coupled with mQβ, Huang and his collaborators found that the two most promising PNAG pentasaccharides offered high levels of protection in mice against staph and MRSA.
In animal studies, the team’s new vaccine construct outperformed another PNAG-vaccine delivery system that is currently in human trials.
The team also found their formulation had minimal impact on the biochemistry of the gut microbiome in tests.
As the team prepares for future tests of their new vaccine candidate, Huang is looking forward to the role bacterial vaccines will play in the larger fight against antibiotic resistance.
“Vaccines reduce the overall infection rate, which means there’s less of a need for antibiotics,” Huang said. “This reduces the chance for bacteria to develop resistance, breaking the cycle.
