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Severity of H3N2 flu strain raises concerns about viral mutations

Scientists say a manufacturing process that uses hens’ eggs may allow the virus to change in ways that make the vaccine less effective.

Pharmacist Gregory Lachhman administers a flu shot during

Pharmacist Gregory Lachhman administers a flu shot during a free flu-shot drive by Rite Aid at Molloy College in Rockville Centre on Feb. 15, 2018. Photo Credit: Johnny Milano

Doctors, New York’s governor and just about every official in public health at the national, state and local levels are advising anyone who hasn’t gotten a flu vaccination to roll up their sleeves for a shot.

The advice comes at the height of the worst season for influenza since the 2009 pandemic and amid emerging research that suggests one of the key strains in the flu vaccine may be subject to mutations in hens’ eggs.

Millions of eggs are used in flu vaccine production, a process that hails from the early years of World War II.

This year, the key flu virus causing the most severe illnesses is an A strain known as H3N2 and the vaccine has not kept pace in boosting human immunity against it.

An interim federal report on the effectiveness of the 2017-18 flu vaccine indicates it has shown only about 25 percent adequacy against H3N2, a strain that has caused the deaths and hospitalizations of thousands of people across the nation.

Now, some experts are expressing concerns about flu viruses, eggs and potential mutations.

“The issue of low effectiveness for H3N2 has raised a lot of questions,” Dr. Anne Schuchat, acting director of the Centers for Disease Control and Prevention, said during a recent news briefing. “Scientists have been talking about egg-adapted changes.”

Emerging research from the New York Influenza Center of Excellence at the University of Rochester suggests that virtually any flu virus can mutate after being introduced into an egg — and the H3N2 strain is very unstable and more likely to change.

“The egg doesn’t cause it,” said Dr. Andrea Sant, a professor of immunology at the University of Rochester and a researcher at the influenza center. She said viral changes — mutations — that take place in the egg are driven by the virus itself.

Sant and her colleagues authored a scientific paper about H3N2’s affinity for mutations in a November issue of the Proceedings of the National Academy of Sciences. They showed how complex sugar molecules help alter certain proteins that stipple H3N2’s surface while it is in an egg. Those sugars essentially allow H3N2 to change its identity.

Yet more concern than usual has been focused on H3N2 this year because of the excessive amount of illness the virus has spawned, said Dr. Gary Leonardi, a virologist at Nassau University Medical Center in East Meadow.

“All influenza A viruses are highly variable. They all get point mutations, as well as getting complete changes in their genome,” Leonardi said. “This year’s vaccine doesn’t work well against H3N2. Maybe next year there will be a better match. Who knows?”

In the CDC’s interim report on the vaccine’s seasonal adequacy so far, the agency found it to be 36 percent effective for strains other than H3N2. Effectiveness in other flu seasons for all strains has ranged from a high of 60 percent in 2010-2011 to a low of 19 percent in 2014-2015.

Low vaccine effectiveness has revived interest in developing a universal flu vaccine, one that can be administered once or twice during a person’s lifetime to provide long-lasting protection. A bill introduced Thursday in the Senate, the Flu Vaccine Act, seeks a $1 billion federal commitment to develop a flu shot based on 21st-century science.

The idea of a onetime shot has been percolating for years. It could likely lead to widespread manufacturing that doesn’t use eggs, a step some manufacturers already have taken. For example, the vaccine maker Seqirus — a global company — manufactures flu vaccines in cell cultures at its North Carolina production facility, avoiding eggs.

Some scientists vigorously defend the current vaccine effort, much of which relies on a production method inspired nearly 80 years ago. Egg-based technology is used to manufacture the majority of the 140 million flu vaccine doses in the United States annually on a tight deadline.

“Old doesn’t mean bad,” said Dr. Doris Bucher, an influenza vaccine expert and professor at New York Medical College in Westchester County. Her laboratory has cultivated “seed” viral strains that then are sent to vaccine manufacturers for use in the production of flu vaccines. Her lab grew the seed strain for the influenza vaccine given during the 2009 pandemic.

“Eggs are used because influenza [virus] grows well in eggs,” Bucher said.

Every year, the primary strains causing influenza are identified by the World Health Organization, which works with a global cadre of virus hunters.

Modern vaccines include protection against as many as four key circulating strains. The pinpointed strains are recommended to the U.S. Food and Drug Administration, which announces in February its choices for the next flu season in this country.

From there, robust “seed” viruses are grown in select labs, such as Bucher’s. Vaccine-makers further propagate the viruses in eggs before subjecting them to further processing.

“The vaccine manufacturers carefully check their seed lots to ensure that the virus doesn’t undergo significant antigenic change in eggs during virus production for the vaccine,” Bucher said, referring to the molecules — the antigens — on the viral surface, which the human immune system recognizes in mounting a response.

The annual production of flu vaccine has been called one of the biggest annual public health efforts, involving global scientists, the U.S. government, academia and private industry. Despite that, scores of doses are trashed annually because only 40 percent of people in this country get vaccinated, flu scientists said.

Statistics from the interim federal report on this season’s vaccine effectiveness show 75 percent of people who have died of flu complications were not vaccinated.

“If a patient has influenza and has received the vaccine, there is evidence the disease they get is less severe,” said Dr. Leonard Friedland, vice president and director of scientific affairs and public health at GlaxoSmithKline Vaccines.

The pharmaceutical giant produces 39 million doses of flu vaccine annually for the U.S. market. GSK relies on egg-based manufacturing. He calls “egg-adapted mutations” a hypothesis.

“This is technology that has been used over many decades in the United States safely and effectively,” Friedland said. “This is a tried-and-true way to make the [flu] vaccine.”

Egg-based flu vaccine production is derived from a World War II-era concept. Top scientists were brought together by the federal government in 1941 to do something that had never been done before: develop a vaccine that could be mass-produced to prevent the flu. The undertaking was historic.

At the time, many people knew of someone who had died in the 1918 flu pandemic, the worst influenza outbreak in history. More than 600,000 people succumbed in the United States alone. The belief was that influenza accompanied global conflict as the 1918 pandemic did, emerging as it did at the end of World War I. In the 1940s, the U.S. military wanted to be prepared.

Today, egg-based vaccine manufacturing is used for the production of both the “flu shot” and the live attenuated, or weakened, vaccine, which is administered as a nasal spray. For the flu shot, the virus is killed after it is grown in eggs.

Dr. Aaron Glatt, chairman of medicine at South Nassau Communities Hospital in Oceanside and a specialist in infectious diseases, noted that flu immunization helps to reduce mortality during the winter months.

Studies suggest that not only is mortality from pneumonia reduced, but so are deaths from heart and pulmonary diseases, and even cancer.

Mismatches between vaccines and circulating viruses or lower vaccination effectiveness against a particular strain should never stop people from getting the flu shot, he said.

“We are still in the midst of it and have not yet hit the apex,” Glatt said of the epidemic.

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