Crucell, Scripps researchers find broadly acting flu antibody

LA JOLLA,Calif.—Annually changing flu vaccines with their hit-and-miss effectiveness maysoon give way to a single, near-universal flu vaccine, according to a newreport from scientists at the Scripps Research Institute and the Dutchbiopharmaceutical company Crucell. They describe an antibody that, in animaltests, can prevent or cure infections with a broad variety of influenzaviruses, including seasonal and potentially pandemic strains.

The finding,published in the journal Science Express on July 7, shows the influenza subtypesneutralized with the new antibody include H3N2, strains of which killed anestimated 1 million people in Asia in the late 1960s.

"Together, thisantibody and the one we reported in 2009 have the potential to protect peopleagainst most influenza viruses," says Ian Wilson, who is the Hansen Professorof Structural Biology and a member of the Skaggs Institute for Chemical Biologyat Scripps Research, as well as senior author of the new paper with Crucell'schief scientific officer Jaap Goudsmit.

Damian Ekiertand Crucell Vice President for Antibody Discovery Robert H. E. Friesen areco-first authors of the Science Express report.

Wilson'slaboratory has been working with Crucell scientists since 2008 to help themovercome the major shortcoming of current influenza vaccines: they work onlyagainst the narrow set of flu strains that the vaccine makers predict willdominate in a given year, so their effectiveness is temporary. In addition,current influenza vaccines provide little or no protection against unforeseenstrains.

Theseshortcomings reflect a basic flu-virus defense mechanism. The viruses comepackaged in spherical or filamentous envelopes that are studded withmushroom-shaped hemaglutinin (HA) proteins, whose more accessible outerstructures effectively serve as decoys for a normal antibody response.

"The outer loopson the HA head seem to draw most of the antibodies, but in a given strain,these loops can mutate to evade an antibody response within months," saysWilson.

Antiviral drugsaimed at these and other viral targets also lose effectiveness as flu viruspopulations evolve.

By siftingthrough the blood of people who had been immunized with flu vaccines, Goudsmitand his colleagues several years ago discovered an antibody that bound to onesuch vulnerable structure. In mice, an injection of the antibody, CR6261, couldprevent or cure an otherwise-lethal infection by about half of flu viruses,including H1 viruses such as H1N1, strains of which caused deadly globalpandemics in 1918 and 2009.

The Crucellresearchers approached Wilson, whose structural biology lab has world-classexpertise at characterizing antibodies and their viral targets. Ekiert, Wilsonand their colleagues soon determined the three-dimensional molecular structureof CR6261 and its binding site on HA, as they reported in Science in 2009. That binding site, or "epitope,"turned out to be on HA's lower, less-accessible stalk portion. The binding ofCR6261 to that region apparently interferes with flu viruses' ability todeliver their genetic material into host cells and start a new infection. Thatantibody is about to begin tests in human volunteers.

Crucellresearchers subsequently searched for an antibody that could neutralize some orall of the remaining flu viruses unaffected by CR6261, and recently found one,CR8020, that fits this description. As the team now reports in the ScienceExpress paper, CR8020powerfully neutralizes a range of human-affecting flu viruses in lab-dish testsand in mice. The affected viruses include H3 and H7, two subtypes of greatconcern for human health that have already caused a pandemic (H3) or sporadichuman infections (H7).

As with theCR6261 project, Ekiert and colleagues were able to grow crystals of the newantibody bound to an HA protein from a deadly strain of H3N2, and to use X-raycrystallography techniques to determine the antibody's structure and itsprecise epitope on the viral HA protein.

"It's even loweron the HA stalk than the CR6261 epitope; in fact, it's closer to the viralenvelope than any other influenza antibody epitope we've ever seen," saysEkiert.

Crucell is aboutto begin initial clinical trials of CR6261 in human volunteers, and the companyexpects eventually to begin similar trials of CR8020. If those trials succeed,aside from a vaccine, the two antibodies could be combined and used in a"passive immunotherapy" approach.

"This wouldmainly be useful as a fast-acting therapy against epidemic or pandemicinfluenza viruses," says Wilson. "The ultimate goal is an active vaccine thatelicits a robust, long-term antibody response against those vulnerableepitopes; but developing that is going to be a challenging task."

The study, "A Highly Conserved Neutralizing Epitope on Group 2 InfluenzaA Viruses," was supported by the U.S. National Institute of Allergy andInfectious Diseases, the National Institutes of Health, the U.S. Department ofEnergy and Crucell Holland BV.