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Scientists at The Scripps Research Institute Describe the Biochemistry of Vaccine Adjuvants

November 21, 2003, La Jolla, CA - A team of scientists at The Scripps Research Institute (TSRI) has published a paper that explains how adjuvants work in greater biochemical detail than has been known previously.

Adjuvants are preparations like killed bacteria mixed with mineral oil that are usually administered with a vaccine. Vaccines themselves are also composed of specific proteins or other bacterial or viral markers that prime the immune system to recognize the strain of virus or bacteria from which they are derived. Immunization works by priming the immune system to recognize this material so it can respond quickly and clear the infection from the system.

For reasons that were not entirely understood, adjuvants help this process by co-stimulating the immune system when the vaccine is given. Adjuvants make vaccines more effective - in fact, immune responses to vaccines are usually meager in the absence of co-administered adjuvant.

But while scientists have known for eighty years that certain components of microbes make good adjuvants - like double stranded RNA, a common form of viral genome, or lipopolysaccharide (LPS), a fatty component of certain bacteria - the biochemical basis for their action has not been understood at all.

The new research, which appears in an upcoming issue of the journal Nature Immunology, has changed this.

"We have now found a highly specific biochemical pathway required for adjuvanticity," says TSRI Professor Bruce Beutler, M.D., who led the research with Kasper Hoebe, Ph.D., a postdoctoral fellow in the Beutler laboratory.

In their paper, Beutler, Hoebe, and their colleagues show that LPS and dsRNA create an adjuvant effect by inducing the synthesis of molecules known as type I interferons.

These appear to be the primary molecular "bridge" between innate immunity and adaptive immunity. This discovery raises the possibility that responses against many different viral or bacterial antigens could be augmented by administration of type I interferons instead of existing adjuvants.

The paper has important implications for the design of vaccines in the future because active immunity against practically any pathogens or toxins might be encouraged in this manner.

Immune Recognition and Immunization

Immunization is based on the body's "adaptive" immune system that can make a strong response to an invading microbe after it has been primed to do so. Once it has been primed, the adaptive immune system expands a number of immune effector cells - like killer T cells and antibody-producing B cells - that track down and eliminate the foreign bacteria or virus particles.

However, this process also involves the other, "innate" arm of the immune system. The innate immune system is composed of first responders - cells like macrophages which engulf and destroy pathogens upon recognition and induce inflammation at the site of an infection. Macrophages also present antigen (pieces of viruses or bacteria) to cells of the adaptive immune system. For T and B cells to be stimulated, they need to be primed by innate immune cells.

Adjuvants are important for vaccine preparations because they activate macrophages and other cells of the innate immune system, and this activation induces them to prime the T and B cells of the adaptive immune system.

But how?

Now, thanks to the efforts of Beutler, Hoebe, and their collaborators Edith Janssen, a research scientist at the La Jolla Institute for Allergy and Immunology, TSRI Associate Professor Jiahuai Han, Ph.D. TSRI postdoctoral fellow Sung Kim, Ph.D., and two scientists from the Yale University School of Medicine, the answer is becoming clearer.

The team of scientists showed that when an adjuvant is introduced into the bloodstream, it encounters innate immune cells like macrophages, which recognize the bacterial or viral components of the adjuvant through the help of receptor proteins on their surface. Bacteria and viruses are completely different classes of pathogens, and, not surprisingly, the body uses different molecular receptors to detect them.

Paradoxically, while the detection systems are different, the actual immune defenses the body employs to clear the system of viral or bacterial infection are much the same. As are the symptoms - to you or me, fighting off bacteria or viruses can produce the same fatigue, inflammation, or hacking cough.

Earlier this year, Beutler and Hoebe showed that the proximal reason for these similar symptoms is a single protein called Trif, which associates with the different receptors that detect a virus or a bacterium on the surfaces of human cells.

Trif is a signal transducer - an adaptor molecule that helps turn these positive detections into immune reactions. Significantly, Trif is the topmost protein shared by the pathway that detects gram-negative bacteria and the pathway that detects most viruses. It is like a waiter who brings orders from two different customers into the same kitchen.

Now, in their latest paper, Beutler and Hoebe demonstrate the pathway whereby recognition of adjuvant by a macrophage receptor leads to the activation of trif and ultimately leads to the adaptive immune response - which, in the restaurant analogy, is like describing each person involved in the preparation of a meal (cooks, waiters, bus boys, etc.) and the steps that go into its preparation.

In brief, adjuvants bind to receptors on the macrophages, and this binding kicks Trif into action. Trif stimulates the maturation of the macrophages by inducing these macrophages to make and release stimulatory molecules known as type-1 interferons. These type-1 interferons interact with receptors on the surface of other macrophages, activating them (called paracrine activation), or the type-1 interferons interact with the same macrophage that produced them, activate it (known as autocrine activation). In either case, the activated macrophages then begin to express essential "costimulatory" molecules like CD80, CD86, and CD40 that finally activate T-cells of the adaptive immune system, and the active T cells produce a highly specific immune response against the invader.

The article, "Upregulation of costimulatory molecules induced by lipopolysaccharide and double-stranded RNA occurs by Trif-dependent and Trif-independent pathways" was authored by Kasper Hoebe, Edith M Janssen, Sung O Kim, L Alexopoulou, Richard A. Flavell, Jiahuai Han, and Bruce Beutler and appears in the Advance Online Publication edition of the journal Nature Immunology on November 16, 2003. See: http://dx.doi.org/10.1038/Ni1010. The article will appear in print later this year.

The work was funded by grants from the National Institutes of Health, including a multi-center grant from the National Institute of Allergy and Infectious Diseases (NIAID) that has permitted TSRI investigators to study a broad range of problems in innate immunity.


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