August 05, 2002
Immune System Abnormality Foils Lyme Disease Vaccine
A subtle abnormality in the immune system may prevent certain people
from responding favorably to a vaccine for Lyme disease, report
researchers from the Howard Hughes Medical Institute at Yale University
School of Medicine.
The discovery of the immune system abnormality, which otherwise
exerts no ill effect on people who have it, underscores the importance
of the multiple protective pathways that the immune system uses in
fending off microorganisms. The studies also suggest several routes for
improving the Lyme disease vaccine.
“The research tells us that in the human population there is a low frequency of a variant gene that prevented response to this vaccine protein, and therefore presumably to some infectious agents.”
Richard A. Flavell
The researchers, led by Erol Fikrig and Howard Hughes Medical
Institute investigators Richard
A. Flavell and Ruslan
Medzhitov, all of whom are at the Yale University School of
Medicine, published their findings in the August 2002, issue of
Nature Medicine. Other co-authors are from SmithKline Beecham
Biologicals in Belgium and the University of North Carolina at
Charlotte.
The Lyme disease vaccine, which was approved by the Food and Drug
Administration in 1998, generated a protective immune response in 95
percent of people who used the vaccine. However, the vaccine’s
manufacturer GlaxoSmithKline, PLC, withdrew the vaccine LYMErix from
the market in February 2002, citing poor sales.
During phase III clinical trials of LYMErix at Yale University
School of Medicine, researchers noted that seven of 492 people
generated no immune response to the vaccine. Flavell and his colleagues
found it intriguing that such a small group would show no response, so
they set about the task of trying to find out why.
“While numerically there were very few of these people, they
were significant because it tells us that in the human population there
is a low frequency of a variant gene that prevented their response to
this vaccine protein, and therefore presumably to some infectious
agents,” said Flavell.
The Lyme disease vaccine relies on a cell surface protein from the
causative bacterium, Borrelia burgdorferi, to generate an immune
response in humans. That protein, called outer-surface protein A
(OspA), is among the most abundant immune-reactive antigens found on
the surface of the Lyme bacteria.
According to Medzhitov, the scientists suspected that low immune
response to the vaccine might be due to a defect in one of a family of
receptors on the surface of immune cells called macrophages. When these
receptors, called Toll-like receptors (TLRs), detect distinctive
molecules on the surface of bacteria, they help activate the immune
system to fend off the bacteria.
“Because the immune systems of non-responders (to the vaccine)
behaved as if they couldn’t recognize OspA, our hypothesis was
that they had a defect in the innate immune system, and therefore, most
likely in Toll-like receptors,” said Medzhitov. The receptor TLR2
was known to be instrumental in recognizing microbial lipoproteins (a
class of bacterial products which includes OspA), and TLR2 was known to
functionally cooperate and to form heterodimers with TLR1, although the
ligand for the TLR2/TLR1 pair was unknown, he said. Based on this
information, the scientists decided to search for defects in TLR
receptors in the seven people who did not respond to the vaccine.
In studying macrophages isolated from this group of people,
Medzhitov and his colleagues observed that the macrophages generated a
low immune response to OspA. “So, that suggested immediately that
something was wrong with the recognition system in these people, which
most likely involved these Toll-like receptors,” said
Medzhitov.
Additional studies of the macrophages revealed that the components
of their immune-system machinery that depended on TLR2 were normal. And
in analyzing the TLR genes in the macrophages, the researchers found no
abnormalities in the TLR2 gene or its protein. However, while
they found no defects in the TLR1 gene itself, they did find
lower-than-normal expression of the TLR1 protein on the surface of the
macrophages.
In a parallel set of experiments, Flavell and his colleagues
developed mutant mice that lacked the TLR1 gene. Mice lacking the
TLR2 gene were obtained from another group of researchers. In
studying both types of mutant mice, the scientists found that, like the
humans in the Yale clinical trial, the animals also lacked
responsiveness to the OspA protein, although their other immune
responses appeared normal.
In additional tests, the researchers found that
TLR2-deficient mice generated lower antibody levels against OspA
alone when compared to wild-type mice. However, when the scientists
added an adjuvant that boosted immune response, the TLR2-deficient mice
responded similarly to wild-type mice.
According to Flavell, finding that faulty TLR1 expression is
involved in generating a poor response to the Lyme vaccine suggests
that altering components of the vaccine might enhance its efficacy. For
example, he said, a different adjuvant might improve the immune
response by involving an alternate immune system pathway that
circumvents the TLR1-dependent pathway.
“This problem is broader, however, in that there are other
vaccines in which we have non-responders and in which the mechanisms
are not well understood,” said Flavell. “And there may be
equivalent situations with these vaccines, in which different
formulations are necessary to overcome low response.”
Medzhitov emphasized the significance of the single defect in the
immune systems of low-responding people. “It’s very
important to note that non-responders exhibited a very specific defect
in TLR1,” he said. “If the defect had been more general,
these people would not have survived to adulthood. However, they were
only unresponsive to a narrow set of pathogens, and to this particular
type of vaccination.”
According to Medzhitov, pinpointing the specific defect in
low-responders to the vaccine could greatly improve understanding of
how TLR genes are expressed and how their receptors travel to the
surface of macrophages.
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