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Finding New Ways to Fight Meningitis
Factor H Binding Protein: A Novel Vaccine for N. meningiditis B

“The more we under-stand about what fHbp does, the better we’re able to think about it as a vaccine candidate.”

CHORI scientist Dan Granoff, MD, of the Center for Immunobiology & Vaccine Development, and his colleagues have been making waves recently with their studies of a special lipoprotein, called factor H binding protein (fHbp). This protein just may contain the solution to finding a vaccine for Neisseria meningitidis group B strains, which is a bacteria responsible for meningitis and severe blood stream infections. In a recent spate of nearly a half dozen publications on the subject, Dr. Granoff has proven the viability of fHbp as an exemplary vaccine candidate as well as elucidating critical characteristics of its role in allowing the bacteria to survive in the human blood stream and cause disease.

“The more we understand about what fHbp does, the better we’re able to think about it as a vaccine candidate,” says Dr. Granoff, who has with his colleagues, used the results of their numerous studies to develop a novel vaccine for N. meningitidis B that has demonstrated incredibly broad coverage.

The superiority of fHbp results, in part, from the fact that it targets complement factor H (fH), a molecule that participates in the body’s innate immune system – its natural ability to fight off previously unknown pathogens.

“Complement proteins are a critical component of our innate immune system. If you activate one, it then activates a second, which activates a third, and so on,” explains Dr. Granoff. “The complement system serves a variety of functions, including recognizing foreign substances such as bacteria and allowing them to be killed before the bacteria can cause serious disease.”

To prevent the inflammatory responses caused by complement activation from becoming harmful to the host, however, the body also uses “down regulatory” complement molecules to maintain tight regulation over the activation of the complement system. Factor H is one of the most important down-regulatory molecules in the system .
“It turns out that N. meningitidis has sort of hijacked this mechanism that the body normally uses to protect itself from damage from complement activation, by using fHbp to capture the complement fH down-regulator."
"It basically shuts down the body’s innate defenses against the bacteria.”

In Dr. Granoff’s most recent series of articles, he and his colleagues have shown that N. meningitidis only binds with human fH even though all mammals have the down-regulatory complement fH as well."

“There are just a few amino acid differences between the human and non-human animal forms of fH, but these differences are enough for the bacteria to only recognize the human form of the molecule,” says Dr. Granoff. “If fH is not on the bacterial surface, the complement system of the animals can kill the bacteria.”

While researchers have known for a long time that N. meningitidis causes disease only in humans, the fact that N. meningitidis only binds with human fH adds to a list of specific mechanisms that explain why the innate immunity of all other mammals except humans is able to handle the bacteria.
In other recent studies, Dr. Granoff and his colleagues have shown that fHbp vaccines stimulate antibodies that block complement fH from binding to the bacteria, which increases susceptibility of the bacteria to killing by complement.

“If you have a vaccine that targets an antigen the bacteria really needs to cause a disease, that means it’s a very good target – the bacteria can’t do with out it,” says Dr. Granoff.

The latest version of Dr. Granoff’s vaccine is made using the outer membrane of mutant bacteria that he and his colleagues engineered to make much higher amounts of fHbp than in the normal bacteria. This vaccine in mice protects against all N. meningitidis B strains. The commercial rights to develop this novel vaccine have been acquired by a pharmaceutical company, with another series of studies planned to confirm its safety and efficacy before clinical trials begin.


Tuesday, May 17, 2011 8:49 AM

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