Over the past few weeks, cases of flu have begun to creep up across the U.S., with spikes in the southeast and south central part of the country. Flu hospitalizations are also on the rise. According to the Centers for Disease Control and Prevention’s influenza tracking team, all signs point to an earlier than usual flu season.
At the same time, hospitals across the country are filling up with children who’ve contracted RSV — a virus that causes common cold-like symptoms that can sometimes lead to serious illness, particularly in infants and older adults.
With the third Covid winter approaching, and public health precautions like masking and social distancing all but abandoned, the next few months could see the American health care system pushed to capacity by multiple surges in respiratory disease.
That’s why experts are advising that the best thing people can do to protect themselves and prevent their local hospitals from overflowing is to get immunized against the circulating viruses. Pfizer’s experimental RSV vaccine is still in testing, but Covid-19 and flu shots are now available to almost everyone.
Experts agree that the best time to get vaccinated is now, before these viral ripples build into waves. But there are other, more subtle questions of timing that scientists are still investigating, including whether time of day or combining vaccines matters. Here’s what we know and don’t know:
Does getting the flu and Covid shots together make either less effective?
Probably not. The science is clear that the human immune system is sophisticated enough to handle seeing more than one antigen at a time and responding in a robust way. And there’s a lot of data to support this, including from trials of combination vaccines like the MMR (measles-mumps-rubella) and DTap (diphtheria, tetanus, pertussis) shots, which have been in use in the U.S. for decades.
“The immune system is extraordinary at recognizing many things at the same time,” said Shane Crotty, an immunologist at the La Jolla Institute for Immunology. “Right now in your intestine alone, your immune system is dealing with 500,000 potential targets. Adding one more thing to that is usually just like a rain drop falling into the ocean.”
Vaccines work primarily by activating two types of adaptive immune cells. The first are B cells, which churn out antibodies that recognize bits of a bacteria or virus — in the case of SARS-CoV-2, its spike protein. The second are T cells, which roam the body and kill any infected cells as well as coordinate the activity of other immune system players.
If a person’s body has seen a particular virus before, either in the form of a vaccine or a prior infection, then a booster shot or an annual flu jab serves to activate the pre-existing populations of B cells that already carry the instruction manuals for making antibodies specific to those pathogens. In other words, the vaccines usually aren’t competing for immune resources. The human body also keeps a reserve of B cells capable of creating novel antibodies against any new threats.
“Most of the time you can give two vaccines together and it all works fine,” said Crotty. However, some vaccine components meant to boost the immune response, called adjuvants, can interact or interfere with other shots when given in combination. The mRNA Covid vaccines contain an adjuvant in the form of lipid nanoparticles, the flu vaccine doesn’t. Definitive evidence on how co-administering the two shots impacts either’s efficacy is not yet available.
That’s why Crotty advises people to get the flu and Covid shots in different appendages — arms for adults and older children, legs for young children. “The immune system certainly has no problem recognizing vaccines if given that way because it’s two different processes happening simultaneously in localized ways,” he said.
While there’s not much data from human studies yet, lab experiments suggest even combined shots don’t decrease efficacy. One study published last year showed that mice and ferrets simultaneously vaccinated against SARS-CoV-2 and H1N1 influenza produced the same levels of antibodies as animals that received the shots in sequence. When they were later infected with those viruses, both vaccination strategies protected the animals from severe disease.
In fact, some researchers are already investigating whether the two vaccines might be combined into a single shot. This summer, scientists in China reported that their combination SARS-CoV-2/influenza mRNA vaccine protected mice from co-infection with H1N1 and the Alpha and Delta SARS-CoV-2 variants.
The only reason to space them out, say experts, is if you’re someone who tends to experience more intense reactions to immunizations, things like muscle or joint pain, chills, and headache. It’s possible that those reactions can be exacerbated by getting both jabs at once. A CDC study published in JAMA in July found that among 981,000 individuals, getting a simultaneous flu shot and Covid-19 booster was associated with an 8% to 11% increase in such systemic side effects, compared with a Covid-19 booster alone.
“It’s important to get both, and to get them now if you haven’t already,” said Kawsar Talaat, a Johns Hopkins infectious disease physician and vaccine researcher. “Whether it’s separate or together, the important thing is just to get them.”
Does the time of day I get my shots matter?
That the immune system follows a roughly 24-hour rhythm has been known since the early 1960s. But only in the last decade or two have the circadian clocks that control the activity of immune cells become a field of intense study, including by vaccine researchers.
Studies in mice have shown that in the morning, T cells turn on genes that make molecules involved in recognizing antigens and cranking out clone armies of T cells that can go patrol the body for more of the foreign invaders. At night, they produce molecules that silence that response.
“It seems there’s a whole program in the T cells that makes them very efficient at responding in the day and being less efficient at night,” said Nicolas Cermakian, a chronobiologist at McGill University and the Douglas Research Centre in Montreal. In a 2019 PNAS study, his team showed that vaccines delivered during the day produced more T cell activation than those delivered at night.
Data from human studies, at least from the 10 or so that have been conducted so far, painted a more complicated picture. In a Cell Research paper published last year, researchers in China found that among 63 health care workers, those that received a shot of the Sinovac vaccine in the morning produced twice as many antibodies against SARS-CoV-2 as workers who got the jab in the afternoon.
But another study from the U.K. of 2,784 health care workers inoculated with either Pfizer’s or AstraZeneca’s Covid vaccine found that higher antibody levels were observed in people who’d received the shots in the afternoon.
Perhaps the strongest evidence for an AM jab comes from a 2016 study of influenza conducted in the U.K. — the first large-scale randomized trial of vaccine timing. It found that among 276 older adults, those who received their annual influenza vaccination in the morning had a more than three-fold higher antibody response to one of the influenza strains than those who got the shot in the afternoon.
However, it’s still too early and the data too sparse to extract any sort of rules or recommendations. While it’s clear that the immune system responds to vaccines differently at different times of day, whether or not those enhancements translate to better protection against a viral threat remains unknown. And different types of vaccines may have their own biologically optimized timing. Still, said Cermakian, it’s worth studying. Because adjusting the timing of vaccination may be a simple and inexpensive way to get the most out of currently available vaccines, particularly in older adults who tend to have dampened immune responses.
“Even a two-fold improvement for older populations could be very beneficial,” he said. “Imagine only needing to get a Covid-19 booster once a year instead of every five or six months. It would make a big difference in terms of cost and in terms of making it easier for people to stay protected for longer.”
With SARS-CoV-2 continuing to evolve, and the vaccines most commonly used in the U.S. only offering short-term protection against Covid-19, it’s a strategy vaccine makers and regulators contemplating the future of boosters may need to consider. But for now, said Cermakian, you should worry less about what time of day to make a vaccine appointment, and more about getting a good night’s sleep in the run-up to it.
“Sleeping well in the days before a vaccine is one thing people should do to get a better response,” he said. “We know that being well-rested is a big plus.”
Will we have to keep getting Covid boosters every six months and flu shots every year forever?
No one can predict the future, but public health officials are starting to look ahead to what a long-term vaccination strategy for our multi-respiratory-virus reality might look like. If researchers can pull off the long-elusive universal flu vaccine approach, that would certainly be a game-changer. But Crotty’s latest work suggests that there might be technologically simpler ways to push people’s immune systems to evolve all the antibodies they might ever need.
In a paper published last month in Nature, Crotty and his colleagues discovered that if they inoculated rhesus monkeys with a modest amount of HIV protein slowly, over 12 days, that six months later, some of the animals’ B cells were still actively working on building immunity to HIV. In particular, they saw sustained activity of B cells called germinal centers, which are kind of like the body’s antibody evolution engine. These cells were keeping those bits of protein and passing them around, learning from them, and evolving a diverse menagerie of antibody-producing memory B cells in the background.
“Mimicking a viral infection by dosing over a longer time frame helps the vaccine engage more of the immune system — it does a much better job at recruiting rare B cells with rare antigen-recognizing properties,” said Crotty.
This approach might be overkill for a lot of pathogens that the immune system has a pretty easy time recognizing. But for bugs that cloak their key regions, or mutate very quickly, like HIV, influenza, and to some extent, SARS-CoV-2, then a longer vaccine dose could help overcome that, by giving the body’s immune system more time to come up with more potential ways of seeing the virus.
“We wanted to test whether time of exposure mattered or not, and it turns out it can matter a lot,” said Crotty. “For me the take-home message was that we helped reveal a process that we think happens fairly regularly and just hadn’t been realized or observed.”
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