Over the past several years staph infections have moved from the seemingly innocuous to some of the most serious threats to public health—mainly due to the rapid rise in drug resistance. Attempts to develop a vaccine against methicillin-resistant Staphylococcus aureus (MRSA) have failed to outsmart the superbug’s ubiquity and adaptability to antibiotics. However now, a new study from investigators at Washington University School of Medicine (WUSM) in St. Louis may help explain why previous attempts to develop a staph vaccine have failed, while also suggesting a new approach to vaccine design. Findings from the new study—published recently in the Journal of Clinical Investigation through an article titled “Staphylococcus aureus a-toxin suppresses antigen-specific T cell responses”— focuses on activating an untapped set of immune cells, as well as immunizing against staph in utero or within the first few days after birth.
“Across the globe, staph infections have become a pervasive health threat because of increasing antibiotic resistance,” explained senior study investigator Juliane Bubeck Wardenburg, MD, PhD, director of the university’s division of pediatric critical care. “Despite the medical community’s best efforts, the superbug has shown a consistent ability to elude treatment. Our findings indicate that a robust T-cell response is absolutely essential for protection against staph infections.”
The current study, in mice, found that T cells play a critical role in protecting against staph bacteria. Most vaccines rely solely on stimulating the other arm of the immune system—B cells, which produce antibodies to attack disease-causing microorganisms such as bacteria.
Remarkably, highly contagious, staph survives and thrives on human skin and can be spread through skin-to-skin contact or exposure via contaminated surfaces. Generally, the bacteria live harmlessly and invisibly in about one-third of the population. From their residence on the skin, the bacteria can cause red, pus-filled sores. Ever persistent, the superbug will deliver recurrent infections in about half of its victims.
Staph strains can enter the bloodstream, bones, or organs and lead to pneumonia, severe organ damage, and other serious complications in hundreds of thousands of people each year. More than 10,000 people die in the United States from drug-resistant staph infections annually.
“The focus in the vaccine field for Staphylococcus aureus during the past 20 years has been on generating antibody responses, not on specific T-cell responses,” Bubeck Wardenburg noted. “This new approach shows promise.”
“An important thing about the alpha-toxin is that it is found in all staph strains, meaning those that are and are not antibiotic-resistant,” she said. “Understanding this allowed us to devise studies in mice that examined the effect of alpha-toxin on the immune response in minor skin infections as well as in more serious infections that spread in the bloodstream.”
For almost 15 years, Bubeck Wardenburg has studied a single toxin—called alpha-toxin—made by staph. This toxin plays a role in tissue damage in multiple forms of infection. “An important thing about the alpha-toxin is that it is found in all staph strains, meaning those that are and are not antibiotic-resistant,” she remarked. “Understanding this allowed us to devise studies in mice that examined the effect of alpha-toxin on the immune response in minor skin infections as well as in more serious infections that spread in the bloodstream.”
For this study, the WUSM team found that the immune cells did not protect mice that had minor staph infections on their skin. However, mice that were exposed to life-threatening staph infections in the bloodstream did develop protection. “We discovered a robust T-cell response targeting staph in the bloodstream,” Bubeck Wardenburg said. “By contrast, T cells were diminished in skin infections as a result of the toxin. Because skin infection is very common, we think that staph uses alpha-toxin to prevent the body from activating a T-cell response that affords protection against the bacteria.”
“Utilizing a chicken egg ovalbumin (OVA)-expressing S. aureus strain to analyze OVA-specific T cell responses, we demonstrated that primary skin infection is associated with impaired development of T-cell memory,” the authors wrote. “Conversely, invasive infection-induced antigen-specific memory and protected against reinfection. This defect in adaptive immunity following skin infection was associated with a loss of dendritic cells, attributable to S. aureus a-toxin (Hla) expression. Genetic and immunization-based approaches to protect against Hla during skin infection restored the T-cell response. Within the human population, exposure to a-toxin through skin infection may modulate the establishment of T cell-mediated immunity, adversely impacting long-term protection.”
Further, protecting the T-cell response from the time of birth may reprogram the bacteria’s overall effect on the immune system. “This bug is deliberate and acts in a sinister way early on,” she said. “The bug appears to be using the toxin to shape the T-cell response in a way that’s favorable for the bug but not for humans.”
Previous vaccine development efforts have focused on adults. However, Bubeck Wardenburg said, a vaccine may be more likely to succeed if administered before infants first encounter staph. Therefore, immunization should happen before initial exposure to staph, to block the toxin and generate a vigorous T-cell response.
“We envision two strategies. One is immunizing pregnant women so they can transfer antibodies that protect infants against the toxin at birth. The second involves immunizing infants within a day or two after birth,” Bubeck Wardenburg concluded. “Neither of these strategies has been considered for staph vaccines to date.”