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12 June 2019 by Christine Stevenson

Influenza, the difficulty of producing effective vaccines, and recent innovation in flu vaccines

There are several metrics by which the severity of a flu season is officially measured: the number visits to the doctor for flu-like symptoms, the number of flu-related hospitalizations, and, of course, the number of flu-related deaths.

By every one of these metrics, the current flu season is turning out to be a pretty bad one both in Europe and, even more so, in the U.S.

Some of this season’s severity has to do with the low effectiveness of the vaccine, which early data shows has offered a relatively low rate of protection compared to other years.

Why is this season’s vaccine particularly ineffective? The answer to that question is not a simple one, and has to do with both the routine challenges of developing seasonal flu vaccines along with other factors that are unique to this season.

First there’s the inherent difficulty of predicting which strains and clades of the flu ought to be included in the next season’s vaccine. Work on designing the vaccine for the coming flu season begins more than six months in advance of it, even as the previous season is still underway.

While this approach is necessary to leave enough time to manufacture sufficient vaccines by our current methods, it also leaves a lot of time for things to change—that is, for the virus to evolve and for researchers’ early predictions to not bear out.

This season, those predictions were a poor match for reality. In Europe, where the flu is now classified as medium to severe in nearly every reporting country, the most common flu species and strain is type B, B/Yamagata.

While this strain was included in the quadrivalent vaccine, it was left out of the trivalent vaccine. Although the quadrivalent vaccine has been moving to become standard since the 2014-2015 season, continued use of the trivalent vaccine may account for some of this season’s nastiness.

The picture is different in the in the U.S., where the dominant species and strain of flu is type A, H3N2. This strain is routinely included in the seasonal flu vaccine, but this time the clade was guessed wrong. Last season, 80% of H3N2 flu came from the 3c.2a1 subclade and therefore this type was built into this season’s vaccine.

Surveillance in the U.S. and Canada, however, now indicates that over 90% of circulating flu virus belongs to the 3c.2a clade—closely related to the one found in the vaccine, but not close enough for it to be a good match.

In fact, the H3N2 strain of flu has consistently proven more difficult than other strains to protect against. Thus, when H3N2 ends up being the dominant strain for a season, that season usually ends up being particularly severe.

H3N2 more often mutates in ways that make it a bad match for the vaccine that was prepared based upon earlier prediction. In addition, H3N2 seems to be more vulnerable to “egg-adapted changes,” the inevitable mutations that occur when viruses are grown inside chicken eggs.

But this season, egg-adapted changes can’t entirely explain the mismatch between vaccine and virus. That’s because for the first time ever the makers of Flublok® vaccines grew their H3N2 virus in animal cells (specifically Mandin-Darby Canine Kidney, or MDCK cells) as opposed to the traditional approach of using chicken eggs.

In addition to its benefits with respect to mutations, the cell-based method has the potential to shorten the long process of vaccine development because it relies upon a large supply of already-banked cells.

However, given that this technique has only just been rolled out, there’s not enough data to say whether this method is truly superior to the egg-based methods that represent the status quo of vaccine production.

But in the face of predictions that a devastating flu pandemic may be close on the horizon, the cell-based route is just one of the ways that flu vaccines are currently being innovated and improved.

In January, researchers from UCLA published on their development of a novel vaccine consisting of a type A influenza virus that had been genetically redesigned for increased sensitivity to interferons, the signaling proteins involved in mounting an immune response.

They found that this approach not only attenuated the virus, but also elicited a strong vaccine-like immune response in mice and ferrets. With further study, this technique could hold promise as completely novel approach to rapid vaccine development.

And of course, there’s the ongoing pursuit of a universal flu vaccine: one that offers broad protection against all strains of a particular flu species. To create such a vaccine, researchers have set their sights on using conserved viral proteins to induce an immune response rather than targeting the virus’ evolving surface antigens.

The very first trial of such a vaccine, developed by Oxford University and Vaccitech for protection against influenza A, began just months ago in the fall of 2017. Thus, even in the thick of this wicked flu season, there is reason to hope that a day will soon come when we finally have the upper hand in the ongoing battle against influenza virus.