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Flu Vaccine Adjuvant Stretches Supplies, Hastens Immunity

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By Anette Breindl
Science Editor

From a public health perspective, the response to an influenza pandemic is a race against an emerging virus. And in that race, the virus has several advantages.

For one thing, the reason a flu virus has pandemic potential in the first place is that it is unrelated enough to seasonal strains so that it does not come under crossfire – which, in the immune system, goes by the name cross-reactivity – from immune memory to previous seasonal strains. That means while a single shot will do for seasonal flu vaccines, a pandemic vaccine usually needs to be given twice, in a so-called prime-boost regimen.

Researchers have described an adjuvant that might allow pandemic vaccine immunization with just one shot. For now, the work is preclinical, but "we were surprised by how potent the adjuvant was," Christopher Clegg told BioWorld Today. In ferrets, which are the classical animal model to study flu infections, "we could get protection with a single immunization using very little antigen, and that was pretty novel."

Clegg is at TRIA Bioscience Corp. and the corresponding author of a paper in the Oct. 8, 2012, advance online edition of the Proceedings of the National Academy of Sciences.

In their paper, Clegg and his colleagues used their adjuvant, which is called GLA-SE and consists of a TLR4 receptor activator combined with the current standard oil-in-water emulsion, to boost the response to a recombinantly manufactured hemagglutinin protein. When the immune system responds to a flu virus, it produces antibodies directed against the viral HA protein, which prevents infection.

The prime-boost regimen, in addition to taking more time to stimulate effective protection, also takes more vaccine than a single shot. And that need for extra vaccine collides with a rather outdated vaccine production system, which still relies mainly on eggs.

Eggs may be, at least according to the American Egg Board, nature's perfect food. But they are clearly not nature's perfect vaccine production system.

The main issue, Clegg said, is that "one must replicate the whole virus," which takes longer than manufacturing just an antigen in cell culture. But "recombinant proteins are inherently less immunogenic than whole virus," meaning that any increases in manufacturing speed can rather easily be gobbled up by the need for more vaccine.

Clegg and his team looked at whether the recombinant protein's immunogenicity could be boosted by combining it with GLA-SE, and found that it did. When animals were vaccinated with either antigen alone, antigen with standard adjuvant or antigen with GLA-SE, only animals that received vaccine with adjuvant survived a subsequent flu infection. GLA-SE induced a greater antibody response than standard adjuvant, and mice vaccinated with GLA-SE had a milder course of disease than those receiving standard adjuvant.

"Without an adjuvant, typical avian flu vaccines require about 90 micrograms of hemagglutinin for each prime and boost injection, but with current adjuvants one can get an effective response with as little as 3 micrograms of hemagglutinin per injection," Clegg said. In other words, adjuvants are "dose sparing" and between the smaller amounts of hemagglutinin and the need for only one dose, "you can vaccinate 30 times more people with the adjuvant on board."

In addition, GLA-SE adjuvant broadened the immune response to the recombinant protein. Such broadening is significant because it makes it less likely that the virus will easily escape from the immune response that the vaccine induces. Ideally, Clegg said, it would be possible to develop and stockpile "a pre-pandemic vaccine" to a flu strain that is related, but not identical, to an emerging pandemic virus.

Adjuvants are not used in seasonal flu vaccines in the U.S., although they are used in Europe, specifically in the elderly. They are used in some but not all childhood vaccinations. In the U.S., the overall attitude toward adjuvants is one of caution. But Clegg said the governmental response to pandemic preparedness since the 2009 H1N1 "swine flu" pandemic suggests that regulatory agencies are more aware of and open to the need for new vaccine technologies.

The 2009 pandemic, he said, was "the perfect test case for mobilization," or how rapidly a pandemic vaccine can be ready for the general population. "And there were a lot of hiccups." Among those hiccups was the fact that the H1N1 vaccine strain grew poorly in eggs, leading to a yield that was at best half of that seen with seasonal flu strains. (See BioWorld Today, July 14, 2009.)

Such hiccups were ultimately not catastrophic because the H1N1 pandemic strain caused comparatively mild illness. But with a strain such as H5N1, whose lethality is estimated to be up to 60 percent, they might have far more dire consequences.