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Cutting off sugars may enable broad-spectrum flu vaccine

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By Anette Breindl
Science Editor

Scientists from the Taiwanese Academia Sinica reported that they have developed an influenza vaccine that was broadly protective in mice and ferrets by focusing not on the amino acid sequence of the vaccine antigen, but on how many sugars were attached to those amino acids.

The addition of sugars, also called glycosylation, is one form of post-translational modification, and serves a variety of functions, from stabilizing proteins to helping them fold correctly.

And by luck or design, one function of glycosylation of flu virus proteins is to hide conserved sequences from the immune system.

“When we compare the amino acid sequence of hemagglutinins among different strains, the sequences near glycosylation sites are more conserved,” Che Alex Ma told BioWorld Today. Ma is at the Academia Sinica and a corresponding author of the paper detailing the vaccination strategy, which appeared in the Jan. 27, 2014, advance online issue of the Proceedings of the National Academy of Sciences.

Hemagglutinin is one of the two major viral proteins used to classify influenza viruses, and one of the antigen components of flu vaccines.

Such vaccines currently need to be developed annually, because many parts of the flu virus change very rapidly. But the need for a broad-spectrum flu vaccine is clear and only becoming more urgent. Even for seasonal flu strains, annual vaccination presents a range of problems.

Predicting which flu strains will actually cause the biggest clinical issues in a given season – as much art as science – is followed by possible challenges in making a vaccine to those strains, and then the scramble to get that vaccine distributed and convince people to get their shots. If the distribution part worked out and their doctor has vaccine, that is.

Even when the system works as it is supposed to, it may not lead to particularly effective vaccine. Effectiveness is dependent on how well researchers have been able to predict the most dangerous flu strains at the beginning of the annual process. And some scientists now suggest that for large countries like China, circulating strains are so geographically diverse the optimal strategy would be to develop different vaccines for different latitudes.

The biggest public health threat, though, is the specter of a highly pathogenic flu strain causing a pandemic. Which strain has been most worrisome to public health officials over the years has varied. Recently, top honors have gone to avian influenza strain H7N9, which, according to World Health Organization updates, is now causing new infections in China on a daily basis.

H7N9’s fatality rate is about 25 percent. Like the even more lethal H5N1 strain that is also a pandemic candidate, it does not spread easily from human to human, or even particularly easily from birds to humans. But while H5N1 is as deadly to chickens as it is to humans, H7N9 is mostly harmless to birds – and that means this particular strain can spread undetected in poultry markets whose offerings are a staple of dietary protein for many Chinese individuals.

Earlier in January, the United Nations’ Food and Agriculture Organization (FAO) warned of the need to be vigilant with respect to possible cases of H7N9 infection during the upcoming Chinese New Year celebrations, as “millions of people and poultry are expected to be on the move and many households will slaughter poultry at home to celebrate the New Year.”

The realization that manipulating the glycosylation patterns may enable the development of a broad-spectrum vaccine, Ma said, was “an accidental discovery when we studied the roles of glycans in influenza virus infection.”

He added, “We did not anticipate reduction of glycans would lead to better protection.” But when the team removed sugar groups that did not affect protein folding from recombinant hemagglutinins, the proteins induced better cross-protection to different strains of the flu in both mice and ferrets.

The Academia Sinica is in a licensing deal with Opko Health Inc., which hopes to develop a broad-spectrum flu vaccine based on the approach.

And the relevance of the findings may not be limited to the flu. Ma pointed out that “viruses such as HIV and HCV are highly glycosylated and currently without good vaccines.”