My past couple COVID-19 booster shots have coincided with the start of flu season, and I’ve faced a deliberation in the line at my local pharmacy that seems to have become commonplace: Do I want both shots at once? I wound up agreeing to a shot in each arm, and was good to go after a couple days of trying not to sleep on either side.
Admittedly, this is the pinnacle of champagne problems, especially compared to what life was like during the pandemic when vaccines were not readily available. But it’s one that many people have faced, enough to prompt specific guidance from the U.S. Centers for Disease Control and Prevention (they say it’s safe to get both shots at once, and individuals can decide to receive one in each arm or both into one arm. The CDC did note, however, that people who received both a COVID booster and flu shot concurrently were slightly more likely to experience side effects like headache, fatigue, and muscle ache than those who got COVID boosters on their own.)
These statistics were enough to make Northeastern University pharmaceutical sciences researcher Mansoor Amiji hesitate when asked if he wanted to add a flu shot onto his scheduled COVID booster last year, he told The Daily Beast.
He started weighing concerns: Would the second shot prolong his recovery? And did he really want to disrupt his day-to-day activities by having two sore arms? “It’s human nature that we don’t like to get needle sticks in our arms multiple times,” Amiji said.
For both scientific and economic reasons, the time for COVID vaccine innovation is now. With the understanding that preventing COVID reinfections means engineering boosters that keep abreast of emerging immune-evading variants, researchers like Amiji have set their sights on products like intranasal vaccines. In the same vein, protecting the most vulnerable groups of people from severe disease requires everyone to do their part, and creating the most palatable vaccines possible could help increase uptake. Last of all, waning sales of COVID vaccines incentivize large pharmaceutical companies to create products that they believe individuals and governments will want to pay for.
The result of these conditions is a behind-the-scenes vaccine race taking place three years after the first one. Instead of standalone mRNA and subunit vaccines, the goal is a shot that combines COVID with flu and potentially another virus, like respiratory syncytial virus (RSV). And according to the Food and Drug Administration’s top vaccine official, the winners of this race will start crossing the finish line as soon as next year.
“It’s human nature that we don’t like to get needle sticks in our arms multiple times.”
— Mansoor Amiji, Northeastern University
A More Effective Tool
Combining a COVID vaccine with one for flu or another seasonal virus would be a straightforward process, partly because of the use of an mRNA platform, Amiji said. As a refresher, mRNA vaccines like those made by Pfizer-BioNTech or Moderna work by giving human cells the instructions for the SARS-CoV-2 spike protein, so that the immune system can recognize and destroy the virus upon exposure to it. The mRNA instructions are housed inside tiny protective bubbles of fat called nanoparticles since they’d be too fragile on their own.
There shouldn’t be restrictions on what kinds of instructions the mRNA provides—whether it’s the SARS-CoV-2 spike protein, an influenza virus protein, or both, Amiji said.
“The recipe for creating nanoparticles that combine multiple copies of mRNA is the same recipe that you would have for a single copy of mRNA,” he said. “You’re not changing the recipe in any way if you’re combining protection against two infections in one vaccine.”
Pfizer and Moderna are both taking advantage of this fact with ongoing combination vaccine programs. Pfizer and BioNTech are part-way through clinical trials to test a COVID-19 and influenza combination vaccine; while Moderna’s combination vaccine program is trialing both a triple combination vaccine for COVID-19, influenza, and RSV as well as a combination flu and RSV shot.
“We really do think that the triple combo—the flu, plus COVID, plus RSV—is really going to be the ideal shot for us to get every year,” Moderna president Stephen Hoge told CBC News in November 2022.
CureVac and GSK may also be hopping on the mRNA bandwagon—though CureVac’s CEO told analysts in early January that it was “a bit too early to say” whether a combination shot would be commercially viable, GSK’s chief commercial officer told Fierce Pharma later in the month that the company sees “real interest” in a flu-COVID-19 combination vaccine. Novavax, meanwhile, is trialing a protein and nanoparticle vaccine in early-stage clinical trials.
Based on the progress of these trials, Peter Marks, the director for the FDA’s Center for Biologics Evaluation and Research, said in March that the goal is to have a combined option approved by 2024.
Amiji stressed that combination vaccines are not new and are, in fact, widely used in childhood immunizations—for example, the measles, mumps, and rubella (MMR) combination vaccine. The key difference with any of the COVID combinations is the use of an mRNA platform. In the same way that the standalone shot can be easily updated with instructions to fight off the newest COVID variant, so can an mRNA combination shot provide more responsiveness to a flu variant than existing flu vaccines can. The public health justification for an improved flu shot is huge, Amiji added, since today’s shots are only up to 60 percent effective at preventing flu illness.
“The expectation with mRNA is that even with flu, you could bring the level of protection higher than 60 percent. That in and of itself will be a huge game changer,” he said.
But some researchers have reservations about an impending combination craze, particularly when it means treating several different viruses as a monolith. In fact, each of these viruses could have distinct seasons when they are prevalent, and hit slightly different populations the hardest.
“In the same way that the standalone shot can be easily updated with instructions to fight off the newest COVID variant, so can an mRNA combination shot provide more responsiveness to a flu variant than existing flu vaccines can.”
Isaac Bogoch, a University of Toronto infectious disease researcher, told CBC News in November that a COVID-flu-RSV combination shot might not be fully necessary based on how long a single shot protects individuals for each of the three viruses.
“I would be very careful now to assume that making a three-in-one vaccine that’s administered annually is needed,” he said. “Clearly, we need vaccines for all three, but we don’t know what the frequency of vaccination is going to be.”
RSV, for instance, can be deadly for children under 5 and adults older than 65—but for most people, infection resembles a common cold. Even as the FDA has approved two RSV vaccines for use in older adults, it’s not known whether such a shot would provide enough of a benefit in younger people to be recommended.
Combination shots for COVID and other viruses could affect vaccine uptake, but there are economic considerations for the pharmaceutical companies producing the shots, too, Amiji said. “The companies making these vaccines think about the business aspect of it, like will this sell? Is it something that will actually have a market?” he said. Three- or four-in-one vaccines may prove more expensive to develop than they’re worth, due to a shrinking target patient population.
Finally, lumping viruses like COVID and flu together could have unintended consequences on future waves of each, as well as public perception about the two diseases. Researchers have been split over the FDA’s plan for annual COVID boosters given around the same time as flu shots in the fall. Those opposed to the plan have argued that COVID variants emerge at a different rate than flu, and that it’s too soon to predict that the virus will share the same infection season as flu has: The Delta wave that hit the U.S. in the summer and fall of 2021 is an example of the two diseases behaving differently.
A COVID and flu combination shot could also lead the public to believe both viruses are similarly dangerous. While categorically untrue in 2020, such a shift in perception may not be so misplaced today, Amiji said.
“COVID is a different disease today in 2023 than it was in 2020,” he said. “A discussion that’s happening right now, that many are still not ready to accept, is whether COVID is still a pandemic, or whether it’s moving to an endemic state—like it is for flu.”