Outwitting influenza with designer vaccines

http://news.bmn.com/news/story?day=020118&story=1

Outwitting influenza with designer vaccines

17 January 2002 8:40 EST

by Rabiya S. Tuma, BioMedNet News

In anticipation of a major flu pandemic like that of 1918, some researchers suggest an overhaul of the methods used to make flu vaccines.

Speaking last night at the New York Academy of Sciences, Adolpho Garcia-Sastre, an associate professor of microbiology at Mount Sinai School of Medicine in New York, said that he hopes to begin clinical trials of genetically-engineered influenza A vaccines in the not too distant future.

In preclinical trials, Garcia-Sastre and his collaborators find they can reconstitute a virus simply by transfecting tissue culture cells with plasmid DNA encoding the eight major influenza proteins. And if they truncate the coding region of a single influenza A gene, NS1, they generate an attenuated virus that is unable to cause disease in a healthy host but can still replicate, which is necessary to induce a strong and durable host immune response.

But truncating the NS1 protein in a single viral strain isn't sufficient to engineer a new vaccine, because the viral strains circulating the globe are constantly changing. Each one expresses different variations of the major antigenic proteins, haemagluttinin (HA) and neuraminidase.

To get around this antigenic variation, Garcia-Sastre proposes to develop a master vaccine strain of the virus, with a truncated NS1 protein, with which the preclinical and clinical tests can be performed. Then, as new circulating strains appear each year or two, scientists can simply replace the master strain's HA gene with the gene from the circulating strain. And voila! A new vaccine against the now-common strain is ready without having to rely on chance or extensive clinical testing.

This calculated method of generating a vaccine strain contrasts strongly with the method in use today. Currently, influenza vaccines are produced by infecting an embryonated chicken egg with two virus strains - a master strain that is known to grow well in eggs and the newly circulating strain. At some random frequency, the genes of the two strains will be mixed and matched to generate a new viral strain that carries the growth-related genes from the master strain and the antigen-encoding genes of the circulating strain. This new strain, which becomes the vaccine strain, is grown in large quantities, killed, and used to inoculate people.

Identifying the recombined vaccine strain can be time-consuming, and not all vaccine strains grow efficiently in the eggs. When a vaccine strain fails to grow well, vaccine shortages occur - as has happened for the past two years. With Garcia-Sastre's reverse-genetics strategy, the growth characteristics of the viral strain would remain unchanged, because the only gene altered between the master strain and the new vaccine strain would be the HA gene.

Doris Bucher, a microbiologist at the New York Medical College in Valhalla, New York, has reservations about using a reverse-genetics approach in vaccine generation. She suggests that the microvariation available in the current egg-recombining system might be important, and it would be lost in an engineered vaccine.

"It is another level of complexity that has to be considered," said Bucher. After all, she concluded, "the egg is very intelligent in getting what it needs."

While Garcia-Sastre admits there might be something to this criticism, he still thinks the controlled approach is likely to be better. "We think using this method, the generation of the vaccine will be faster," he told BioMedNet News, and the genetic information of this vaccine will be more stable than the genetic information for the previously generated vaccines."

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