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A study conducted by Childrens Hospital & Research Center Oakland and University of Massachusetts Medical Center scientists identifies a new mutant vaccine antigen for Neisseria meningitidis (also called meningococcus) that has the potential to improve vaccine development against dangerous bacterial infections including meningitis.
The study, authored by Childrens Hospital Oakland Research Institute (CHORI) scientists Dan Granoff, MD, and Peter Beernink, PhD, and colleagues at the University of Massachusetts Medical Center, Worcester MA, will be featured in the March 15, 2011 issue of the Journal of Immunology (published online Feb. 16, 2011).
"Its really quite gratifying to have a study like this that has direct translation into making better vaccines against infections, especially meningococcal disease," says Granoff, director of CHORIs Center for Immunobiology and Vaccine Development. "This deadly disease affects hundreds of thousands of children throughout the world. Almost no other infection can kill a previously healthy child as fast as the meningococcus."
Meningococci are bacteria responsible for causing meningitis and severe bloodstream infections. Young children and teenagers are particularly vulnerable. Even with the best treatment, 10 percent of those infected will not survive. About 20 percent of those who survive are left with long-term medical problems including loss of hearing, chronic seizures, and amputation of limbs.
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. Currently, there are two vaccines targeting group B strains in development. These vaccines utilize a novel antigen called factor H-binding protein (fHbp) to stimulate human immune responses against the bacteria. The fHbp antigen in the vaccines binds with human factor H (fH), a protein normally present in the bloodstream.
Granoffs research, however, demonstrates that a simple change in the protein can greatly improve the efficacy of the vaccines. Because fH in animals differs from that in humans, genetically engineered mice were created in order to investigate the effect of fH binding on the fHbp vaccines.
A traditional animal study would not be able to capture the effects of this because fH in animals is slightly different than it is in humans. Granoff and his team got some help from genetically engineered mice.
When the mice with human fH (created by Sanjay Ram, MD, and Peter Rice, MD, at the University of Massachusetts in Worcester) were immunized, the fHbp antigen vaccine worked well in normal mice whose fH didnt bind to the vaccine. But in the mice with human fH, the protective ability of the vaccine dropped four- to eight-fold. The more human fH a mouse had, the worse the level of protection the vaccine provided.
The same study, however, demonstrated a solution: Granoff and his colleagues showed that using an fHbp antigen with a slight mutation 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 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 bacteria that also utilize fH binding, like pneumococcus and Bordatella.
"Our study suggests that while a vaccine that actually targets fH binding proteins offers a unique opportunity to prevent disease, you probably need to develop forms of the vaccine that dont bind to the host protein, says Granoff. "What we need to be looking for are mutants that make the antigen look like the fH binding proteins, but that remove the binding function."
The study provides a solid foundation for the development of second-generation meningococcal vaccines while also providing an approach for creating highly effective vaccines against other infectious bacteria.