Scientists Describe the Biochemistry of Vaccine Adjuvants
By Jason Socrates
A team of scientists at The Scripps Research Institute 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 effectivein
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 adjuvantslike double
stranded RNA, a common form of viral genome, or lipopolysaccharide
(LPS), a fatty component of certain bacteriathe 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 Scripps Research Professor
Bruce Beutler, who led the research with Kasper Hoebe, 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
cellslike killer T cells and antibody-producing B cellsthat
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 responderscells 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.
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, Scripps Research
Associate Professor Jiahuai Han. Scripps Research postdoctoral
fellow Sung Kim, 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 symptomsto 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 transduceran 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 responsewhich, 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 Scripps Research investigators to study a broad
range of problems in innate immunity.