December 6, 2017 Kim Krisberg 0Comment

Scott Hensley wants to make one thing clear: You should still get a flu shot after reading this article.

“Even in times of vaccine mismatches, it can still help reduce the severity of infection,” said Hensley, an associate professor in the Department of Microbiology at the University of Pennsylvania. “We’re talking about one (flu) strain here, but other strains seem to be very well matched.”

That one strain Hensley’s referring to is H3N2, which seemed somewhat impervious to the 2016-2017 flu vaccine. In particular, last year’s flu shot was only about 30 percent effective against the virus, which dominated during the last flu season. Hensley and his colleagues wanted to find out why the vaccine’s effectiveness against H3N2 was so low — data that’s key to making sure the 2018-2019 flu vaccine is manufactured to be a better match. They found the problem. But fixing it will take a lot more than tweaking a vaccine formula.

In a study published last month in the Proceedings of the National Academy of Sciences (PNAS), the researchers reported that the vaccine’s ineffectiveness against H3N2 was due to a mutation that stems directly from the manufacturing process — i.e., the traditional process of growing flu vaccine viruses in chicken eggs. Hensley noted that his study isn’t the first to highlight the need to rethink how the flu shot is manufactured, but he knows it’s a heavy lift considering how invested manufacturers already are in egg-based vaccine production.

“The problem is inherent to growing in eggs,” Hensley told me, adding that “in this case, there’s no workaround with an egg-based system.”

Flu shots work like other vaccines — they create immunity by tricking your body into generating antibodies capable of fighting off certain diseases. A new flu vaccine is produced each year to do just that based on the particular flu strains that scientists predict are mostly likely to circulate and cause illness. During the 2014-2015 flu season, Hensley said, H3N2 dominated in the Northern Hemisphere and the vaccine’s effectiveness against it was particularly low — “close to zero,” he said. To avoid another such mismatch, the 2016-2017 flu vaccine was updated using an H3N2 strain isolated in 2014. Overall, Hensley said, last season’s flu shot seemed to be pretty well matched to the flu strains in circulation, but it provided only a mediocre defense against H3N2, with an effectiveness rate between 20 and 30 percent.

The primary reason, Hensley and colleagues reported in PNAS, is because the H3N2 virus used to create last year’s vaccine doesn’t bind well to chicken cells, resulting in such a disruptive mutation that the eventual vaccine given to people isn’t well matched to the H3N2 virus in circulation. The study notes that vaccine strains grown in eggs often develop adaptive mutations that allow them to attach to chicken cells. But in the case of egg-adapted H3N2, the mutation meant that the final vaccine generated antibodies in people that couldn’t effectively bind to — and thus, neutralize — H3N2. The final vaccine only offered good protection against egg-adapted H3N2; its antibodies could no longer recognize and attach to the strain that was infecting people out in the real world.

And Hensley said there’s no real solution to the problem using an egg-based production process.

“This particular strain simply doesn’t replicate well in chicken cells — that’s why it didn’t work,” he told me. “It’s one of the first times this has been such a big problem. …(The viruses) all undergo some adaptive process in chicken eggs, but we think this past season, there was such an important change that occurred as the virus was adapting that it made a much larger impact than in previous years.”

But there is an effective alternative. While the study found that the egg-produced 2016-2017 strain did a bad job generating effective antibodies in humans and ferrets, they also found that an H3N2 vaccine produced using recombinant DNA technology — a process that doesn’t use eggs — was effective in neutralizing the virus in humans and ferrets. Hensley and study co-authors Seth Zost, Kaela Parkhouse, Megan Gumina, Kangchon Kim, Sebastian Diaz Perez, Patrick Wilson, John Treanor, Andrea Sant and Sarah Cobey write: “A major effort should be made to develop and utilize new systems that produce influenza antigens that are not dependent on egg or cell culture-adaptive mutations. Antigens that do not possess adaptive mutations will likely offer better protection against influenza virus strains that circulate in the human population.“

Hensley said that even though flu vaccine manufacturers are already heavily invested in egg-based production, continued research into alternative vaccine production methods could help drive change in the industry. He added that if we weren’t already making flu vaccine, there’s “no way” we’d choose eggs as the platform for starting production.

“We, as a community, should probably invest more in alternative (vaccine) technologies,” he said, noting that his lab isn’t affiliated with any vaccine manufacturers. (In fact, Hensley said the study, conducted with support from the National Institutes of Health, is a “good example of why we should fund basic scientific research.”)

And he still urges people to go out and get their flu shots: “These vaccines, although they’re not always as ideal as we’d like them to be, are still better than nothing — they still save lives even when they’re not a complete match.”

According to the latest data from the Centers for Disease Control and Prevention, H3N2 has been the most predominant virus so far this flu season. As of late November, four states reported widespread flu activity, 10 states reported regional flu activity and 24 states had reported local flu activity.

For a full copy of the H3N2 vaccine study, visit PNAS.

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