Staphylococcus aureus vaccine failure is associated with interleukin production and antibody inactivation

Staphylococcus aureus (Staphylococcus aureus. in/in) is a leading cause of skin and soft tissue infections that can lead to sepsis and toxic shock syndrome. and many Staphylococcus aureus Although the vaccine candidate has been effective in mice, about 30 human clinical trials have failed so far. “This is a pathogen that urgently needs to be controlled because it causes significant morbidity and mortality in the United States and around the world,” said George Liu, professor and chief of pediatric infectious diseases at the University of California (UC). said the M.D. Ph.D. ), San Diego School of Medicine and Rady Children's Hospital of San Diego.

Liu is leading a team of researchers at the University of California, San Diego, who have identified the main potential cause of the trial's failure and could modify the vaccine to be effective in humans. It suggests that. In their research, Journal of Clinical Investigation (JCI), The title is “”IL-10-mediated pathogen-induced antibody sialylation inhibits vaccination'', Liu reported along with lead author Chih-Ming Tsai and others. Staphylococcus aureus It induces excess interleukin-10 (IL-10) in B cells, causing antibody inactivation and making them unable to kill. Staphylococcus aureus. “Overall, we demonstrate a pathogen-centric mechanism that modulates antibody glycosylation through IL-10 and leads to loss of staphylococcal vaccine efficacy,” they concluded in their paper. .

In a related study published on the same day, nature communications (“Pathogen-induced suppressive immune imprint blocks T cell vaccine responses”), Liu, along with lead author Dr. Irshad Ahmed Hajam, Tsai, and a team of scientists from the University of California, San Diego School of Medicine, reported that excess IL-10 occurs in response to infection. Staphylococcus aureus It blocks the ability of helper T cells to fight pathogens. In their paper, the research team said, “…imprinting of IL-10-secreting and SA-experienced CD4+ T cells represents a staphylococcal immune evasion mechanism and should be considered in future vaccine development.” he suggested.

the majority of us are colonized Staphylococcus aureus (SA) At an early age, the authors say in their book: nature communications paper. “SA is a pathogen that colonizes and infects humans from early infancy, with up to 50% of infants exposed to SA by the age of 6 months.” Reporting Team JCI Furthermore, “Sa, as a brilliantly adapted 'pathoorganism,' has evolved complex mechanisms that facilitate coexistence with the host.''

Staphylococcus aureus Liu pointed out that they share a long history with humans. “For bacteria to colonize our noses and guts, they must develop strategies to effectively dampen the immune response in order to survive.” Saureus It is the leading cause of bacterial skin, soft tissue, and invasive infections in humans and poses a significant threat to public health, which is further exacerbated by the prevalence of methicillin-resistant bacteria. Staphylococcus Staphylococcus aureus (MRSA). The main opportunistic pathogens are Staphylococcus aureus The research team noted that it has been the subject of vaccine research since 1903. However, despite the demonstrated efficacy of numerous anti-Sa vaccine candidates in naïve mice, approximately 30 human clinical trials have failed to yield a functional vaccine for unclear reasons. do not have.” JCI The author pointed out. “Laboratory animals are largely naive to human Sa, which is in stark contrast to humans, who encounter Sa from infancy.”

In most cases this bacteria is harmless, but previously study A research team led by Tsai, a project scientific assistant in Liu's lab, showed that this early exposure tricks immune cells into producing modified antibodies that cannot mount an effective defense. Staphylococcus aureus. Additionally, bacteria retain a “memory” of these non-protective antibodies and can bring them back during subsequent infections.

Tsai said this is why a vaccine candidate that worked well in mice that had never been exposed to the pathogen failed to protect humans from new infections. Staphylococcus aureus. When researchers exposed mice to humans Staphylococcus aureus Vaccines no longer worked because they created antibodies before vaccination, recreating early human experience with bacteria. Their findings showed that Sa infection produces these non-protective “antibody imprints.”Staphylococcus aureus Vaccination may cause a suboptimal vaccine response. “Imprinting therefore emerges as a plausible explanation for the widespread failure of Sa vaccines,” the authors said. JCI research states.

What caused Tsai, Liu, and colleagues to Staphylococcus aureus Antibodies after vaccination are useless in fighting pathogens. “Although humoral imprinting has been shown to impede effective vaccination, the mechanism by which the pathogen Sa disables anti-Sa antibodies in various vaccines remained unclear,” the researchers wrote. I mentioned it in my paper. JCI.

For the newly described study, researchers Staphylococcus aureusThey were then vaccinated with iron surface determinant B (IsdB) vaccine. This vaccine has previously been shown to confer immunity. Staphylococcus aureus in mice that had never been infected with bacteria.

The research team discovered that B cells (white blood cells that make antibodies) secrete abundant amounts of IL-10 when they receive immune stimulation. Staphylococcus aureus Second time. Inside B cells, IL-10 instructs enzymes to add sugars called sialic acids to the Fc region of antibodies. This is involved in generating an appropriate immune response. The abundance of sugar neutralizes the anti-staphylococcal activity of antibodies produced by B cells, rendering them unable to kill the pathogen. “…we report a mechanism by which the pathogen Sa induces the anti-inflammatory cytokine IL-10 to modify the sialylation of anti-Sa antibodies, thereby neutralizing its host protective activity,” researchers wrote in their paper It is stated in JCI. “This non-protective humoral response is recalled during vaccination, thus rendering the vaccine response ineffective.”

“IL-10 helps produce large amounts of this type of sugar, and in doing so turns off our immune system,” Tsai explained. However, researchers also found that blocking IL-10 at the time of vaccination restored vaccine effectiveness. “The same vaccines that were previously ineffective are now fully effective in mice,” Tsai added.

on the other hand, JCI This study focused on the role of IL-10 in B cells. nature communicationsHajam, an assistant project scientist in Liu's lab, and colleagues investigated how. Staphylococcus aureus It interacts with CD4+ helper T lymphocytes, white blood cells that detect infections and activate other immune cells to attack and kill pathogens.

Researchers found that, like B cells, helper T cells also secrete excess IL-10 in response to conditions such as: Staphylococcus aureus Mice previously exposed and later vaccinated Staphylococcus aureus.

IL-10 blocks the ability of helper T cells to produce a cytokine that is particularly effective in combating interleukin 17 (IL-17A). Staphylococcus aureus infection. “In this study, we showed that the alum/IsdB vaccine recalled CD4+ T cells that secreted abundant IL-10,” the researchers wrote. nature communications Report. “IL-10, in turn, suppresses the host protective IL-17 response. This is consistent with our previous finding that SA evades the IL-17 response via IL-10. 'But by adding a substance called CAF01, which is known to increase vaccine efficacy by blocking IL-10 or increasing T cell responses to microbial infections, the researchers found that IL-10 I was able to recover my 17A level. “Staphylococcal vaccine interference can be overcome by applying a potent IL-17-inducing adjuvant containing vaccine antigen to hosts experiencing SA,” the research team commented. “By adding CAF01 during vaccination, we were able to turn an ineffective IsdB vaccine into an effective one. Staphylococcus aureus“I was exposed to rats,” Hajam said. “Surprisingly, it was also effective against several other failed vaccines. Staphylococcus aureus”

Both findings could be good news for humanity Staphylococcus aureus Vaccine development. Liu said it may be possible to create something that has already been developed but failed. Staphylococcus aureus Vaccines work by blocking IL-10 or boosting IL-17A during vaccination. he,(clostridioides difficile) This may be the reason why promising vaccines for these conditions have failed in human trials, suggesting that blocking cytokines could also restore vaccine efficacy. “Some vaccines that are difficult to produce are C. difficile and pathogens such as Mycobacterium tuberculosis“Herpes simplex virus, human immunodeficiency virus, and Plasmodium species are also reportedly associated with abundant IL-10,” the authors write. nature communications.

“The role of IL-10 in evading vaccine protection against these pathogens would be worth investigating.” among them JCI In this paper, the scientists further found that antibodies in cystic fibrosis patients are also nonfunctional, and that peripheral blood mononuclear cells from cystic fibrosis patients have higher IL-10 levels compared to cells from normal people. It was pointed out that it shows a level of induction. “These observations strengthen the association between sialylation and IL-10 in pathogens other than Sa,” the researchers wrote. “These findings should facilitate a more comprehensive evaluation of human anti-Sa antibodies and expand the investigation to include antibodies against other pathogens and from unsuccessful human vaccine trials.”