Structure-based changes of HA specificity can help the design of preemptive vaccines and mAbs.

Preparing vaccines and therapeutics that target a future mutant strain of H5N1 influenza virus may be possible, according to an NIAID team and a collaborator at Emory University School of Medicine.

They developed a strategy to generate vaccines and therapeutic antibodies that could target predicted H5N1 mutants before these viruses evolve naturally. This advance was made possible by creating mutations in the region of the H5N1 hemagglutinin (HA) protein that directs the virus to bird or human cells and elicites antibodies toward it.

“Structure-based modification of HA specificity can guide the development of preemptive vaccines and therapeutic monoclonal antibodies that can be evaluated before the emergence of human-adapted H5N1 strains,” the authors write in their study, published in the August 10 issue of Science.

Success hinges on anticipating and predicting the crucial mutations that would help the virus spread easily from person to person, the scientists explain. They focused narrowly on mutations that render H5N1 viruses better able to recognize and enter human cells.

The research group compared the structural proteins on the surface of bird-adapted H5N1 influenza virus with those on the surface of the human-adapted strain that caused the 1918 pandemic. They specifically looked at genetic changes to one portion of the H5 protein, the receptor binding domain. The investigators showed that as few as two mutations to this receptor binding domain could enhance the ability of H5N1 to recognize human cells.

Additional mutations would likely need to accumulate for H5N1 to spread more easily from person to person, says Gary Nabel, M.D., Ph.D., director of the NIAID’s Dale and Betty Bumpers Vaccine Research Center (VRC), who led the study. The few mutations he and his colleagues identified are likely just a subset, he emphasizes.

The team also found that these mutations change how the immune system recognizes the virus. Mouse antibodies that target H5N1 were up to 10-fold less potent against the mutants. Dr. Nabel and his colleagues then created vaccines and isolated new antibodies that might be used therapeutically against human-adapted mutants.

They vaccinated mice with the material from viruses they altered to contain the mutant receptors. The group discovered one broadly reactive antibody that could neutralize both the bird- and human-adapted forms of an H5N1 virus.

“Our findings build on elegant studies of the influenza HA protein by structural biologists,” notes Dr. Nabel. “Insight into the structure of the avian flu virus has enabled us to target a critical region of HA that directs its specificity.”

The research is published in the August 10 issue of Science.

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