Early experiments in mice have shown how a vaccine that targets the toxic leukocidin molecules released by Staphylococcal bacteria can protect animals against infection with potentially deadly methicillin-resistant Staphylococcal aureus, or MRSA.
Rather than targeting the bacteria themselves, the NYU Grossman School of Medicine team’s toxin-targeting vaccine effectively blocks leukocidin-mediated immune evasion, allowing the mouse immune system to generate antibodies against the MRSA pathogen, and also stopping the bacteria from killing other key immune system cells.
“By targeting the toxins released by the bacteria, our experimental vaccine not only stops the bacteria from killing neutrophils, a key type of leukocyte the immune system uses to destroy the invading pathogen, but also defends other leukocytes, such as T cells and B cells, needed to provide long-term protection from future infection,” said study senior investigator Victor J. Torres, PhD, the C.V. Starr professor of microbiology at NYU Langone. “This strategy is based on maximum disarmament of the bacterium’s ability to kill all types of immune system cells … Our study provides a roadmap for developing an effective vaccine against all Staphylococcal infections, especially MRSA.”
Torres and colleagues reported on the development of the vaccine in the Journal of Experimental Medicine. Their paper is titled, “Targeting leukocidin-mediated immune evasion protects mice from Staphylococcus aureus bacteremia.”
Staphylococcus aureus is a gram-positive bacterium that can cause a range of diseases, from mild skin and soft-tissue infections to life-threatening conditions such as bacteremia. Estimates suggest that more than 119,000 people in the United States suffered from Staphylococcal bloodstream infections (BSIs) in 2017, leading to nearly 20,000 deaths.
Antibiotics are a standard treatment approach to S. aureus infection, but use of such drugs has contributed to the rise of multidrug-resistant strains. While an anti-S. aureus vaccine would offer a potential solution to what the team calls “this epidemic of antimicrobial resistance,” attempts to develop such vaccines have so far failed, researchers say, in part because the toxic bacterial leukocidins kill the host immune system cells needed to fight the pathogen, production of which the vaccine would trigger.
In fact, Staphylococcal bacteria release leukocidins to evade not only an immediate immune cell attack, but also to prevent the infected host—whether human or mouse—from developing any long-term immunity through antibodies. Pathogenic strains of S. aureus that infect humans can produce and secrete up to five different leukocidins. “S. aureus leukocidins are widely recognized as professional leukocyte killers and are important virulence factors during S. aureus pathogenesis,” the team explained. “Together, the leukocidins can target and kill a wide array of primary human leukocytes critical for innate immune defenses and adaptive immunity, including neutrophils, monocytes, macrophages, dendritic cells, and effector memory T cells.”
Torres and colleagues reasoned that developing a vaccine to inhibit or destroying these leukocidins would allow the immune system to mount a response against an infection by S. aureus. “We hypothesize that the leukocidins act as immune subversion molecules that interfere with the development of adaptive immunity during S. aureus infection. Therefore, neutralizing the activity of these immune evasion molecules through vaccination can protect the host from S. aureus infection.”
Through their reported study the researchers showed that mice repeatedly infected with toxin-releasing Staphylococcal bacteria did demonstrate an immune response to the infection, and produced antibodies to both the bacteria and its leukocidins. However, mice infected with bacteria that had been engineered not to produce the toxins had twice as many antibodies targeting the bacteria, showing a much stronger immune response when the toxins were absent. This heightened immune response is what researchers say led them to target leukocidins as the best possible means of giving the body the upper hand in fighting the bacterium.
Previous work by the researchers had found that mice could survive infection with Staphylococcal bacteria whose leukocidins had been genetically modified to lose their toxic effects. These nontoxic leukocidins formed the basis of the experimental vaccine. Initial tests in a mouse model of recurrent bacteremia showed that infection with a leukocidin mutant resulted in increased levels of anti-S.aureus antibodies when compared with mice infected with a wild-type strain of the virus, “… indicating that leukocidins negatively impact the generation of anti-S. aureus antibodies in vivo,” they wrote.
Their experiments found that 70% of mice given the experimental leukocidin-targeting vaccine survived infections with the bacterium, whereas none of the non-vaccinated mice survived. “In our model, leukocidin-based immunization results in the production of toxin-neutralizing antibodies and the generation of Th1/Th17 responses … Leukocidin-based immunization prevents the cytotoxic and immune suppressive effects of the toxins in vivo and provides the host with protection during BSI.”
Torres cautioned that a commercially available anti-leukocidin vaccine is years away. The next step for his team will be clinical trials to investigate whether humans vaccinated against the toxins show a similar toxin-specific immune response as seen in the mice. “We posit that a successful anti–S. aureus vaccine should include antigens that elicit antibody and T cell responses that will restrain the bacterium’s ability to evade host immune defenses while promoting clearance of the bacterium,” the team concluded. “This study identifies the leukocidins as potential vaccine antigens that lead to the disarmament of the bacteria and activation of antibody and T cell responses, ultimately resulting in enhanced host protection.”
Torres said investigators also want to find out if the same antitoxin effects occur for any of the hundreds of other molecules released during Staphylococcal infections. He suggested that a “foolproof” vaccine against the bacteria, including MRSA, will likely involve targeting more than just its leukocidin toxins. “… the protective effect of a leukocidin-based vaccine is limited to S. aureus strains that can produce leukocidins; therefore, additional antigens must be explored to extend protective efficacy to strains that produce little to no toxins,” the investigators noted.