Yale Researchers Describe How Vaccine Adjuvant Jump-Starts Immune System

Yale University researchers have determined how a key component of many vaccines activates an immune system response, a finding that opens up promising new avenues of research on better ways to prevent infections. 

A team of scientists led by Stephanie C. Eisenbarth and Richard A. Flavell of the departments of immunobiology and laboratory medicine at the Yale School of Medicine describe one way aluminum hydroxide - a key adjuvant used in many of the world’s vaccines – helps fight off pathogens in a paper published Wednesday in the online edition of the journal Nature.

Yale University scientists helped spur a revolution in immunology a decade ago by describing the key role played by Toll-like receptors, or TLRs, in triggering inflammatory responses. TLRs are a key receptor in the evolutionarily older and more generalized innate immune system that senses the presence of foreign invaders. TLRs must be activated before the younger adaptive immune system, - which can respond to specific pathogens and has long-term memory - can begin to fight infections in people.

However, scientists have found that the aluminum hydroxide, or alum, used in vaccines does not require that TLRs be activated to trigger an immune response, and the molecular mechanisms that explain its efficacy remained a mystery.

Eisenbarth and Flavell found that a crucial player in the process is a part of another weapon in the immune system’s arsenal called Nod-like receptors, specifically a protein complex called the Nalp3 inflammasome that is located within cells. They found that alum adjuvant activated the Nalp3 inflammasome, which is also triggered when cells come under stress. They also showed that when Nalp3 inflammasome was removed from cells they failed to produce cytokines known as interleukins, part of the immune system response usually triggered by the adjuvant. Also, antibody and T Cell responses were reduced in mice lacking parts of the inflammasome.

For vaccinologists, the paper is important because it describes at least one molecular basis for how an adjuvant like alum activates the immune system. Researchers hope to harness that knowledge to find new ways to use adjuvants to bolster immune system responses,

“As a physician, that is the most important thing. We need to know how these adjuvants actually work.’’ Eisenbarth said.

But as a researcher, Eisenbarth said, she is also fascinated by the role Nod-like receptors like the Nalp3 inflammasome might play in the fundamental activation of the arm of the immune system that mediates long-term protection against pathogens.

“The paper also adds a new aspect to one of the most exciting fields in immunology – how the innate, or ancient immune system, needs to be activated before the more sophisticated adaptive immune system can do its work,’’ she said.

Other Yale researchers involved in the study are Oscar R. Colegio of the Departments of Dermatology and Immunobiology, William O’Connor Jr, of the Department of Immunology and Fayyaz S. Sutterwala, now of the University of Iowa.