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Friday, June 21, 2024

No One Knows if You Need Another Covid Booster

The US Food and Drug Administration is pushing for you to get an annual Covid booster. The problem is, the data isn’t clear on whether you need one. 

Covid isn’t going anywhere. In the US and many European countries, SARS-CoV-2 is still circulating at significant levels, with Covid settling into being a major, ongoing cause of illness. Boosters may protect against its worst effects, but these are shots in the dark: insurance against severe disease, but possibly not necessary. This is because we don’t know how long their protection against severe illness actually lasts. 

It’s time we found out, but that means switching focus. At the level of basic biology, it means paying less attention to the antibodies vaccines generate and focusing more on another very important but overlooked part of the immune system: memory T cells. “The way you’re going to know who needs boosters is to know how long memory cells last,” says Paul Offit, a professor of vaccinology at the University of Pennsylvania and a vaccine advisor to the FDA.

The immune system is complex, but fundamentally it has three parts. There’s innate immunity, the physical or chemical barriers—such as your skin or the mucus in your nose—that are constantly working to keep disease-causing microbes at bay. 

For germs that get past this, there’s then short-term or humoral immunity: the rapid response tailored to a particular invading threat, such as a virus, that dominates early after it has arrived to try to keep an infection from taking hold. This defensive wave is led by neutralizing antibodies made specifically to fight whatever has invaded the body. 

But when this antibody response fails to stop Covid from gaining a foothold and the virus gets inside cells so it can reproduce, a third protective strand comes into play: long-term, cellular immunity. Memory T cells, which are also tailored to the specific threat, are a key part of this. 

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“Once a virus infects cells, T cells can then limit the amount of viral replication,” says Céline Gounder, an infectious disease specialist and editor at large at KFF Health News. When a virus like Covid reproduces, it parks parts of itself in the outer membrane of the cell, which announces to the host that the cell is infected. T cells—primed, through vaccination or prior infection, to notice these odd parts—then kick into gear, killing infected cells and directing the production of more antibodies. “That’s preventing the disease from progressing,” Gounder says. 

So while cellular immunity doesn’t stop an initial infection, it’s what keeps people out of the hospital, out of the intensive care unit, and out of the morgue, says Offit. “The second thing that’s good is that T cells often live for years, decades, or lifetimes,” he says—meaning the protection they offer against severe illness can be long-lasting. 

And there’s a third major benefit. In Covid, some of the viral bits that wind up on cell membranes and attract T cells are “highly conserved” interior parts of the coronavirus—bits that are much less likely to mutate and become invisible to the immune system. The proteins that coat the outside of the virus, which are what typically end up being targeted by antibodies, are much more likely to mutate, leaving those antibodies less effective.

Cellular immunity is clearly important—it protects against Covid’s worst, doesn’t fade as quickly as humoral immunity, and is harder for the virus to mutate away from. Yet when testing and approving Covid vaccines, developers and regulators didn’t look closely at it. They relied on studies of the humoral response. Think of all the times you’ve heard about a vaccine’s ability to create an antibody response or about how long antibody levels last. Thankfully, studies into this showed quick sharp increases in antibodies that could neutralize SARS-CoV-2 following vaccination. 

Not looking at T cells might feel like an oversight, but it made sense at the time. With the pandemic accelerating up to full force, regulators wanted to find out quickly if vaccines would be useful in fighting the virus and neutralizing antibodies to SARS-CoV-2 peak within a couple of weeks. The T-cell response, on the other hand, can take months to mature. Additionally, lab tests for T cells are more complicated than those for antibodies, and they differ from lab to lab, making large-scale comparisons harder. 

Plus, regulators are used to seeing neutralizing antibody measurements and making calls off of these. Even if neutralizing antibodies fail to halt an infection completely, they generally limit it while they are present in good quantities—so seeing them spike after vaccination suggested the Covid vaccines would help protect people. Trials then backed this up by showing far lower rates of hospitalization and severe disease in the vaccinated in the first few months after they had received their jabs, when the humoral response was strongest.

But we now know that these antibodies fade over time, and that the coronavirus can mutate to evade antibodies made against its earlier forms. “Focusing on short-term antibody response is really missing the boat,” says Dan Barouch, a professor at Harvard Medical School and head of the vaccine research division at Beth Israel Deaconess Medical Center in Boston. Looking so intently at antibodies has left us none the wiser about the strength and durability of protection against severe illness offered by T cells. 

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So to try to better understand this, researchers have started comparing T-cell responses among the major vaccines. Scientists from the La Jolla Institute for Immunology in California, for example, reported in the journal Cell last summer that the mRNA vaccines from Pfizer and Moderna (as well as two other vaccines that work by different mechanisms) produced relatively consistent levels of a key T cell in the six months after vaccination. Over the same period, antibodies generated by the Pfizer and Moderna shots faded—offering an initial rough sketch of the picture of long-term Covid immunity.   

But this is just the beginning. We still need to know how the strength of the T-cell response corresponds to protection against the disease: Can even relatively low levels be sufficient? And are some T cells more effective than others? Part of the difficulty is picking one voice out of the immune system’s chorus. “It’s hard to prove one component of the immune system is responsible for protection when all the components work together,” says Barouch. There’s also still no robust estimate of how long these T cells last, even if we do know they’re longer-lasting than antibodies. 

Our understanding of cellular immunity has been hampered by a lack of attention, says Rick Bright, an immunologist, former director of the US Biomedical Advanced Research and Development Authority, and former senior vice president of R&D at Novavax, a biotech firm that makes a Covid vaccine. “Funding to support and accelerate this critical area of vaccine development has been—and remains—weak and is waning along with the overall interest in Covid,” he says.

There are pockets of interest. Barouch and his colleagues are also trying to measure how well the current vaccines build cellular immunity, while others are trying to make vaccines that specifically focus on generating a T-cell response. Researchers at the University of Tübingen in Germany, for example, have a trial going to test the safety of a vaccine made of SARS-CoV-2 proteins that are known to spark T-cell immunity. And at the Massachusetts Institute of Technology, an mRNA vaccine that generates T cells by targeting highly conserved parts of the coronavirus has shown promise in mice.

But there are also doubters. “Nobody denies that cellular immunity is important,” says John Moore, a professor of microbiology and immunology at Weill Cornell Medicine. But in the eyes of many researchers, he says, T cells play a subsidiary role in protection compared to antibodies.

Moore points to something called “affinity maturation,” where the immune system learns to build more precise antibodies against a pathogen over time, the more it is exposed to it. Researchers from New York and California have shown that this happens with SARS-CoV-2. So if you know you already have vaccines that generate good levels of antibodies, and that every time a vaccine is given, the antibodies created will be stronger than before, then perhaps that’s enough—you don’t need to worry about T cells. Plus, Moore says, preliminary studies have shown that neutralizing antibodies do a good job of protecting against severe Covid. And if that’s the case, then keeping these regularly topped up with occasional boosters would keep everyone safe. 

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Offit, though, is confident enough in T cells that he thinks boosters might not be needed in anyone but the most vulnerable (such as the elderly or immunocompromised), at least until it can be seen that the T-cell response has disappeared. “If it turns out memory cells last only a year, for example, you may need a yearly booster,” he says. “If they last two years, three years, four years, then you might not need a booster.” Yet there aren’t yet any signs of T-cell levels declining over time: In addition to the La Jolla research, a report in Science Immunology has shown that T-cell responses to various vaccines remain stable and aren’t improved by boosters.

Regardless, the FDA has proposed its annual booster schedule for Covid, the idea being that boosters can be updated each year to handle the latest variants of the virus, to ensure that the antibodies created are well matched to whatever form of the virus is circulating. This essentially mirrors how the world handles changes to flu viruses.

For Bright, it’s the wrong way of doing things: He would like to see more of a focus instead on building vaccines that target those bits of the virus that don’t change. “We can follow the limitations of influenza vaccine development,” he says. “Or we can create vaccines that trigger a full arsenal of both cellular and humoral immunity.” If we go the way of the flu vaccine and keep focusing on antibodies, he argues, we’ll just be chasing SARS-CoV-2 forever. Right now, it’s looking like this is the way we’re headed.

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