Recent mutations in circulating influenza viruses could make flu shots less effective this year, leading to an especially brutal flu season.
It’s not a new problem.
Flu viruses are infamous for their ability to evolve quickly and without warning, creating a mismatch between the shots already on the market and the viral strains spreading from person to person.
Over the past 15 years, the effectiveness of seasonal flu vaccines has ranged from 19% to 60%, according to the Centers for Disease Control and Prevention.
A big part of the problem is that most flu vaccines today use a slow process in which influenza viruses are grown in fertilized eggs, a technique first used in the 1940s. Making flu vaccines this way requires huge numbers of eggs and takes about six months. In order for flu vaccines to be ready by fall, researchers have to choose which viral strains to include by February, according to Bill Hanage, PhD, a professor of epidemiology at the Harvard T.H. Chan School of Public Health.
“An issue with eggs in vaccine production is that the virus can adapt to the eggs, and the mutations involved in that reduce the match to the target strain and reduce the efficacy,” Hanage told CIDRAP News. “If you are growing things in eggs, it takes more time and a lot of eggs, which may be in short supply” due to bird flu outbreaks that have killed or led to the culling of millions of chickens.
Scientists have looked for solutions for years.
The search for more effective flu vaccines
The Holy Grail of flu vaccines would be a “universal flu shot,” which would protect against many strains of influenza and protect people for multiple years, for more than a decade. Progress has been slow going.
The Food and Drug Administration (FDA) approved two newer types of flu vaccines that are more effective than egg-based vaccines and which can be made more quickly, said Amesh Adalja, MD, an infectious disease physician and senior scholar at the Johns Hopkins Center for Health Security. The FDA approved the first flu shots made in cell cultures in 2012, as well as flu vaccines made with recombinant technology that are created synthetically in labs in 2013.
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But given how much flu vaccine manufacturers have invested in egg-based production, most have been slow to transition to new technology, Adalja said.
“More manufacturers should move away from egg-based vaccines,” he said.
“With non-egg based vaccines, decisions about strain selection could be delayed until closer to the season’s start, lessening the chance of a vaccine strain mismatch,” Adalja explained. “Also, during a pandemic a vaccine could be made more quickly. During the last influenza pandemic, in 2009, the bulk of the egg-based pandemic vaccine was being administered after the peak of viral activity.”
More manufacturers should move away from egg-based vaccines.
One of the most promising vaccine technologies uses modified mRNA, a platform that allowed manufacturers to rapidly produce hundreds of millions of COVID-19 shots during the pandemic.
Hanage said a safe and effective flu shot made with mRNA could be a game changer, allowing manufacturers to quickly respond to genetic mutations in circulating viruses.
“It would obviously be really helpful to rapidly produce a matched vaccine offering better protection,” he said.
Trial finds higher efficacy with mRNA flu shot
The results of a large clinical trial, published today in the New England Journal of Medicine, show that researchers are making progress on experimental mRNA flu shots, even if they aren’t yet ready to be rolled out to consumers.
In the study, people randomly assigned to receive a flu shot made with modified mRNA were 29% less likely to be diagnosed with a lab-confirmed case of influenza by the end of winter than people given a conventional flu shot.
The experimental mRNA vaccine prevented 60% to 67% of flu infections, while the conventional vaccine prevented 44% to 54% of infections, said Kelly Lindert, MD, vice president of clinical research and development at Pfizer and senior author of the new study.
Authors of the study, which was funded by Pfizer, tested the experimental mRNA vaccine in more than 18,000 adults age 18 to 64 during the 2022-2023 flu season.
“This really is exciting and promising,” said Hanage, who was not involved in the new study. The modified mRNA vaccine “is plainly capable of protecting for at least a season and doing so better than the one with which it was being compared.”
By showing that mRNA vaccines can help prevent seasonal influenza, the study “sets the stage for its use against pandemic influenza, when the rapid vaccine development process specific to mRNA vaccine technologies is critical,” said Adalja, who also was not involved in the new study.
Adalja noted that the study compared mRNA vaccines to Sanofi’s Fluzone, which is manufactured in eggs.
So researchers don’t know how mRNA vaccines would measure up to flu shots that use newer technologies, Adalja added. Flucelvax, made by Seqirus, Inc. and first approved in 2012, is grown in mammalian cells, rather than eggs. Flublok, a recombinant vaccine approved in 2013 and sold by Sanofi Pasteur, is created synthetically in a lab. Both of these vaccines have moderately higher efficacy rates than flu shots grown in eggs.
Higher risk of side effects
Mild to moderate side effects were much more common in those who received the mRNA shot, however.
About 70% of adults given the mRNA vaccine developed redness, swelling, or pain in the part of their arm where they received the injection, compared with43% of those who received the traditional vaccine, according to the study, which included participants in the United States, South Africa, and the Philippines.
About two-thirds of those vaccinated with an mRNA flu shot developed a fever, headache, fatigue, chills, vomiting, diarrhea, and muscle pain or joint pain, compared with about half of those given the traditional vaccine. Although participants in the study were healthy or medically stable, one-quarter had at least one risk factor for severe influenza.
The number of serious side effects was low and about the same among people who received the mRNA or the traditional vaccine. For example, none of the study participants developed myocarditis, an inflammation of the heart muscle that can lead to chest pain, fatigue, shortness of breath, and even heart failure.
Researchers will need to reduce the number of side effects to make mRNA shots palatable, Hanage said.
“While there’s no evidence of an excess of really serious adverse events, there are clearly more of the moderate and not-pleasant adverse events,” Hanage said. “For many folks, this has been their dominant memory of COVID shots, and people will be reluctant to get vaccines on an annual basis which make them feel rotten.”
Side effects are an especially important consideration for the healthy, younger adults included in the trial, most of whom aren’t at high risk of being hospitalized by the flu, Adalja said.
People will be reluctant to get vaccines on an annual basis which make them feel rotten.
In an accompanying editorial, infectious disease specialists Hana M. El Sahly, MD, and Robert L. Atmar, MD, pointed out that the published study didn’t provide any information about the mRNA vaccine’s use in adults over 65 or people with chronic illness, who have the highest risk of hospitalization or death, or include children, who have the highest incidence of flu.. They note that the mRNA vaccine and conventional vaccine had similar efficacy in older adults, although this data wasn’t included in the New England Journal of Medicine article.
Pfizer is developing a newer version of the mRNA flu shot that will be tested in adults age 65 and up, Lindert said.
Loss of federal funding could stymie future vaccine development
In one of the few success stories of the pandemic, the federal government worked with private companies on Operation Warp Speed, which brought COVID-19 vaccines to the public in less than a year. But in August, the Trump administration reversed course, announcing the cancellation of nearly $500 million in mRNA vaccine research.
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In spite of the promising research published today, the Department of Health and Human Services (HHS) said it has no plans to restore mRNA vaccine funding.
A spokesperson said the agency decided to “wind down federal mRNA vaccine development” after finding that “several emergency-funded projects no longer meet HHS’s current standards for transparency, reproducibility and long-term safety.”
The federal health agency “is prioritizing vaccine platforms with stronger safety records and open clinical and manufacturing data, including whole-virus, protein-based, and next-generation adjuvanted technologies,” she added.
[This study] certainly shows that cutting the funding for research was a short sighted decision which sets us back significantly.
That decision has been sharply criticized by many scientists and public health advocates.
The new mRNA study published today “certainly shows that cutting the funding for research was a short-sighted decision which sets us back significantly,” Hanage said.
“These results should excite anyone interested in preventing sickness and suffering due to influenza," he said. "The way to address these concerns is with more research, and that research will be slower and more difficult, or may not be possible at all, in the absence of funding.”
