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Friday, April 19, 2013

What do adjuvants do anyway?

It’s been known for nearly a century that vaccines are more effective when they include adjuvants. In fact, vaccines that don’t contain entire live pathogens (which is most of them these days) work rather poorly without adjuvants. Luckily, alum is a very good and safe adjuvant that can be added to just about any vaccine. Unluckily, we didn’t used to have any idea of how adjuvants work. That has now changed, thanks to work by researchers from the University of Colorado and from the Howard Hughes Medical Institute.

To understand adjuvants, you have to understand vaccines at the molecular level. What exactly is going on after the needle punctures your arm? The immune system is immensely complex with myriad cellular and protein actors that I can't possibly untangle here. Suffice it to say that one of the first events is the arrival at the scene of a type of white blood cell called the neutrophil. These first responders release various chemical cues to encourage other cells to enter the fray. Among them are the dendritic cells that engulf the antigens within the vaccine and display them on their surfaces to T-cells. These T-cells in turn initiate antibody production. 

Where does the adjuvant come into the picture? Neutrophils happen to be extremely short-lived cells. Very soon after encountering the intruding antigens, the neutrophils die, releasing streams of DNA. If a vaccine includes the adjuvant alum, that DNA will coat the alum. Then other dendritic cells end up engulfing the entire complex of host DNA-alum-antigen. It turns out that the T-cells are much more interested in the DNA-associated antigens; they form longer and stronger interactions with dendritic cells that have ingested the DNA-alum morass along with the target antigens. The scientists confirmed this by adding DNase (an enzyme that digests DNA) along with their vaccines.

Amy McKee of the University of Colorado, and lead author of the paper, explains:
The DNA makes the antigen-presenting cell stickier. We believe that extended engagement provides a stronger signal to the T-cell, which makes the immune response more robust.  
Why should this be so? We can't really answer that question yet. However, I find it intriguing that the adjuvant places host DNA in such close contact with the foreign antigen. Remember, it's the immune system's job to distinguish host from non-host. Perhaps this juxtaposition makes that contrast more stark.

McKee, A., Burchill, M., Munks, M., Jin, L., Kappler, J., Friedman, R., Jacobelli, J., & Marrack, P. (2013). Host DNA released in response to aluminum adjuvant enhances MHC class II-mediated antigen presentation and prolongs CD4 T-cell interactions with dendritic cells. Proceedings of the National Academy of Sciences, 110 (12) DOI: 10.1073/pnas.1300392110.