Flu shot season is upon us.

Three years ago, STAT laid out some of the questions surrounding flu vaccination in an article you can find here. Lots of flu vaccine studies have been published in the interval — clearing up some of the questions we raised, adding to the confusion with others.

Given that a lot of you are either about to roll up a sleeve or are debating whether you should, we decided to revisit the issues we explored previously, based on new information. We’ll also raise a few more questions percolating in the world of influenza science.

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Is it too soon to get your flu shot? And is it possible to wait too long?

One of the questions about flu vaccine relates to how long its protection lasts. In particular, researchers have been exploring whether that protection erodes during the course of a single season — and if it does, how quickly.

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If you get vaccinated in August or September and flu season really only takes off in January, how much protection will you have left? On the other hand if you wait until December to get your shot, what if flu season starts early?

It’s now pretty clear that “intra-season waning” — the erosion of protection within a season — does occur. A study from the Centers for Disease Control and Prevention published in 2017 estimated the decline at about 7% a month from the time of vaccination. A study from the Kaiser Permanente Vaccine Study Center published this spring suggested the erosion was more rapid: roughly 16% for every block of 28 days after vaccination.

Marc Lipsitch, an infectious diseases epidemiologist at Harvard University’s T.H. Chan School of Public Health, had concerns that the methodology used in the latter study might have been flawed. He worked with the researchers to reanalyze the data using a different study design. They reached the same conclusion.

“I think the best estimate at the moment with the tools we have — which are pretty good but not perfect — is that there is substantial waning,” Lipsitch said.

This is a situation, though, where what’s best from a scientific point of view isn’t necessarily what’s doable from a real world point of view. The annual flu vaccination program is a massive endeavor.

About 45% of the U.S. population gets a flu shot, more than in any other country in the world. Given the demands that places on health care delivery — and the evidence that people who leave getting a flu shot too late often don’t get one in the end — the CDC recommends people try to get vaccinated before the end of October.

“It is a big logistic issue for the health care system in the U.S. every year,” said Dr. Dan Jernigan, director of the agency’s influenza division. “We think getting it around the October time frame is good, but any time from September to November is better than not getting it.”

Still, given the evidence of waning protection, Lipsitch argued it is “perfectly reasonable and probably best” for people to get a flu shot later, if they can, and for flu shot clinic organizers to keep waning in mind. “It’s no harder to hold three flu clinics in October and November than it is to hold them in September and August.”

Is FluMist effective? Can I get it?

FluMist, the only non-injected influenza vaccine, has been through a rough patch. This year could have been the vaccine’s comeback — but it won’t be.

Made by AstraZeneca, FluMist suffered a major setback when the expert committee that advises the CDC on vaccines recommended it not be used for the 2016-2017 flu season, and later the 2017-2018 flu season as well. Data collected over the previous three years suggested it hadn’t been effective. That virtually sealed off most of the U.S. market to FluMist for two years.

In 2018 the CDC committee concluded changes that AstraZeneca made to the vaccine appeared to have solved the effectiveness problem, and it again recommended FluMist could be used.

But by the time that recommendation was made, many of the companies that buy flu vaccine in bulk had already placed their orders for the 2018-2019 season. And the American Academy of Pediatrics wasn’t convinced the changes had resolved FluMist’s issues; it recommended that pediatricians urge families to give their children flu shots instead.

This year all of the constraints of the previous three seasons were lifted. But then new misfortunate befell FluMist. AstraZeneca had problems producing the viruses needed for two of the four components of the vaccine.

The U.S. market is getting a paltry amount — about 758,000 doses. Parents looking for FluMist will have a hard time finding it this year. It could be even harder in other countries. Pediatricians in Israel and Canada were informed there would be no FluMist available there for the coming flu season.

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AstraZeneca has declined to make anyone available to talk about the situation. But the company confirmed that it had yield problems for the parts of the vaccine that protect against influenza A viruses H1N1 and H3N2. (The vaccine also protects against two influenza B viruses.)

This occurs from time to time with vaccine production. It is unfortunate for AstraZeneca, though, that it happened in a year when FluMist might have been poised for a resurgence.

Do I have to be worried about the statin factor when getting a flu shot?

There have been concerns that commonly used cholesterol-lowering drugs, statins, might actually undermine the effectiveness of flu vaccine.

A couple of studies had raised questions about the possibility that the drugs might dampen the immune response triggered by vaccine. That was particularly worrying because the people who take statins — adults in late-middle age and older — are often the people who are at highest risk of becoming seriously ill or dying from influenza. (At least in H3N2 flu seasons; more on this later.)

The evidence amassed in recent years, however, suggests these fears were not founded. Researchers at the Marshfield Clinic Research Institute in Marshfield, Wis., looked at data over six flu seasons and saw no significant lowering of vaccine effectiveness among statin users.

And researchers from the Food and Drug Administration and the CDC analyzed the medical records of 2.8 million Medicare beneficiaries. They saw no sign that people who used statins and were vaccinated were more likely to have serious bouts of flu than people who were vaccinated but didn’t take statins.

For the CDC, this question is answered. “We’re not doing anything further with that now,” Jernigan said.

Can repeated vaccination actually backfire?

There’s been a growing belief that getting a flu shot year after year can impede the immune system’s ability to generate a strong response to the vaccine.

It’s not thought that this phenomenon happens every year. But in some years when the viruses in the vaccine haven’t been updated but the viruses that are circulating are different from the vaccine version, people who have been repeatedly vaccinated may end up being less well protected. Influenza researchers call this “negative interference.”

Dr. Danuta Skowronski of the British Columbia Center for Disease Control has published papers showing this effect. She said the research community’s consensus appears to be accepting that this is real.

“There really has been a shift, a palpable shift, from ‘Are these signals real?’ to almost a sense of ‘Of course they’re real. Now why?’” she said.

Dr. Mark Loeb, a flu research at McMaster University in Hamilton, Ontario, looks at the issue a different way. Loeb’s group conducted a massive meta-analysis, looking at all of the scientific literature on the question, screening thousands of papers. The conclusion: Repeat vaccination isn’t consistently undermining the protection the vaccine offers.

“To me the bottom line is the data to date don’t really support a reduction in vaccine efficacy with repeat flu vaccination,” Loeb said. “They don’t rule it out completely. So I think it’s still a bit of an open question.”

Loeb doesn’t rule it out; Skowronski definitely rules it in — sometimes. But neither thinks current recommendations to get annual flu shots should be changed.

A separate effect seen with influenza — known as original antigenic sin or imprinting — is based on the idea that the first flu viruses you encounter in your life leave an indelible mark on your immune system. If your first infection was caused by an H3N2 virus, you’ll always produce more antibodies to H3 viruses when you get vaccinated than you will to the other influenza A viruses, H1N1, and vice-versa.

This idea has really taken root in the flu research community. The data on who gets sickest each flu season are making the pattern “very clear,” Jernigan said, pointing to a recently published paper by Alicia Budd of the CDC.

It shows that since the 2009 flu pandemic, caused by a new H1N1 virus, different age groups are getting hospitalized with severe flu infections in H1N1 years.

The mantra that flu seasons are hardest on the elderly may shift to “some flu seasons.” The elderly fared pretty well in the H1N1 pandemic — their immune systems recognizing it as a distant relative of a flu virus they’d encountered earlier in life. But people who were born in the late 1950s and the 1960s had their first infections with other viruses, and H1N1 viruses are a bigger threat for them.

An earlier version of this story said people who have been repeatedly vaccinated might be more likely to contract influenza over time. In fact, repeated vaccination might diminish the protection the vaccine provides some people over time.