“There’s a growing concern that within the next two to three decades, the efficacy of many of our medications could significantly decline,” warned Xuefei Huang, a Professor at Michigan State University’s Chemistry and Biomedical Engineering departments. “Such a scenario could regress us back to the era before antibiotics.” However, in a recent study published in Nature Communications, Huang and his team have unveiled a breakthrough to confront this looming global crisis. Their focus? Creating a promising vaccine candidate for antibiotic-resistant bacteria.
Bacterial vaccines, alongside antibiotics, serve as critical weapons in combating deadly microbes. In their latest research, Huang outlined several findings pivotal to the development of a carbohydrate-based vaccine targeting infections caused by Staphylococcus aureus and its resistant variant, methicillin-resistant Staphylococcus aureus (MRSA). These pathogens are among the leading causes of bacterial infections. Utilizing an innovative delivery platform pioneered by Huang’s group at MSU, their preclinical vaccine formulation exhibited significant immunity against lethal levels of both staph and MRSA in animal trials. This advancement not only pushes the boundaries of vaccine science but also furnishes fellow researchers with valuable insights to enhance future bacterial vaccines.
To create a vaccine, researchers must first identify an effective antigen—a substance that triggers an immune response in the body, leading to the production of antibodies to combat future infections.
While conventional vaccines primarily rely on protein antigens, Huang specializes in the chemistry and biology of carbohydrates. Carbohydrates, composed of sugars or saccharides, offer both unique challenges and advantages in vaccine development. “Sugar structures are highly specific to particular bacteria,” explained Huang. “A vaccine effective against one bacterium might be ineffective against another, even if they share similarities.” This variability necessitates that a single dose of a bacterial vaccine may contain numerous antigens, such as the pediatric pneumonia vaccine PREVNAR 20, which protects against 20 distinct bacterial strains.
The quest for a broadly effective antigen led researchers like Gerald Pier, a collaborator on Huang’s study and a professor at Harvard Medical School, to investigate polysaccharide poly-β-(1−6)-N-acetylglucosamine (PNAG). PNAG, found on the cell walls of staph and various other bacteria, presents a promising candidate due to its widespread presence across pathogens. By studying PNAG as a potential antigen for staph, Pier, Huang, and their team aim to unlock the secrets necessary for a more potent vaccine.
Carbohydrates like PNAG are akin to mosaics, offering numerous ways to arrange their individual components. However, only select arrangements yield the desired effects. Just as altering a few tiles in a mosaic can create an entirely different image, modifying the components or their positions within a PNAG molecule affects its performance as an antigen. Huang’s team focused on biologically active molecular components called amines and acetyl groups, which adorn PNAG’s sugar backbone. While previous research predominantly explored fully free or fully acetylated forms of PNAG, Huang’s team investigated the potential of a mixed state with both free and acetylated amines.
Through their research, the team created a library of 32 distinct PNAG structures, all pentasaccharides composed of five saccharides, each varying in amine and acetyl group decoration. By screening these structures using antibody studies, they made a significant discovery: “The fine pattern matters significantly,” affirmed Huang. The team identified two PNAG combinations with particularly promising outcomes. Furthermore, by coupling these combinations with a pioneering vaccine delivery platform based on a bacteriophage called Qbeta, or mQβ, they observed enhanced immune responses. This innovative delivery platform, recognized with MSU’s 2024 Technology Transfer Achievement Award, not only holds promise for bacterial vaccines but also for cancer and opioid addiction treatments.
In animal studies, the combination of the two most promising PNAG pentasaccharides with mQβ provided substantial protection against staph and MRSA, outperforming existing PNAG vaccine delivery systems currently in human trials. Additionally, their formulation showed minimal impact on the gut microbiome’s biochemistry in tests. As they prepare for further tests of their vaccine candidate, Huang anticipates the pivotal role bacterial vaccines will play in combating antibiotic resistance. “Vaccines reduce overall infection rates, reducing the reliance on antibiotics,” Huang emphasized. “This diminishes the likelihood of bacteria developing resistance, thus breaking the cycle. The two strategies are interlinked.”
- : public
