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Eradicating Disease
CHORI Scientists Discover New Vaccine Antigen
In the February issue of the Journal of Immunology, CHORI scientists, Dan Granoff, MD, and Peter Beernink, PhD, and their colleagues describe a newly identified mutant vaccine antigen for Neisseria meningitidis (also called meningococci) that has the potential to improve vaccine development not only for meningitis, but for other bacterial infections as well.

"It's really quite gratifying to have a study like this that has direct translation into making better vaccines against infections, especially the meningococcal disease," says Dr. Granoff, who is Director of CHORI's Center for Immunobiology and Vaccine Development. "Almost no other infection can kill a previously healthy child as fast as the meningococcus."

“It's really quite gratifying to have a study like this that has direct translation into making better vaccines against infections, especially the meningococcal disease.”

Meningococci are bacteria responsible for causing meningitis and severe blood stream infections. Young children and teenagers are particularly vulnerable. Even with the best of treatment, 10 percent of those infected will not survive. About 20 percent of those who survive are left with long-term medical problems including deafness, seizures or limb amputation.

While there are vaccines available for prevention of certain strains of the bacteria, there is no vaccine against "group B" strains, which account for approximately 40 percent of cases in the United States. Two drug companies have been developing new vaccines that target group B strains. These vaccines are expected to supplement coverage against other meningitis strains as well, and utilize a novel antigen, called factor H-binding protein (fHbp), to stimulate human immune responses against the bacteria.

"These vaccines are in advanced clinical development. One already has been submitted for regulatory approval in Europe," says Dr. Granoff.
“Both vaccines stimulate protective antibodies but our study shows how a relatively simple change in the proteins can greatly improve their efficacy.”
At issue is the fact that the fHbp antigen in the vaccines binds with human factor H (fH), which is a protein normally present in the bloodstream. Animal studies would not be able to capture the effects of this, because fH in animals is slightly different than it is in humans, and the fHbp vaccine only binds with human fH, not animal fH.

"In order to investigate the effect of fH binding on the fHbp vaccine, our colleagues, Sanjay Ram, MD, and Peter Rice, MD, at the University of Massachusetts in Worcester, developed a mouse that has human fH," explains Dr. Granoff.

When these mice were immunized, the results were striking. The fHbp antigen vaccines worked exceptionally well in normal mice whose human fH didn't bind to the vaccine. But in the mice with human fH, the protective ability of the vaccine dropped four- to eight-fold.
“The drop in protection was dose dependant, in that the more human fH a mouse had, the worse the level of protection the vaccine provided.”
"It's actually even a little worse than that," says. Dr. Granoff.

The good news, however, is that in the same study, Dr. Granoff and his colleagues also showed that using an fHbp antigen with a slight mutation in it resulted in significant increases in protection.

"This mutant antigen has just one amino acid difference between it and the fHbp in the current vaccines, but that difference means that it no longer binds to human fH, and that resulted in much higher protective responses," says Dr. Granoff.
In addition to significantly improving the current meningitis vaccines, the study also provides proof of principle that has the potential to be applied to vaccines against other bacterial infections that also utilize fH binding.

"We know that fH binding proteins are found in many other bacteria as well, such as the pneumococcus and Bordatella, and we know that fH binding is an important aspect of how the bacteria survive and evade the host immune system," says Dr. Granoff.

"What our study suggests is that while a vaccine that actually targets fH binding proteins offers the unique opportunity to prevent disease, you probably need to develop forms of the vaccine that don't bind to the host protein. What we need to be looking at are mutants that make the antigen look like the fH binding proteins, but that remove the function instead."

While the results of Granoff and his colleagues still need to be replicated by other labs, the study provides a solid foundation for the development of second generation meningococcal vaccines while also providing the methodology for creating highly effective vaccines against other infectious bacteria.


Revised: Monday, April 11, 2011 12:18 PM


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