No one knows if you need another Covid booster

Covid isn’t going anywhere. SARS-CoV-2 is still circulating at significant levels in the US and many European countries, with Covid becoming a major, persistent cause of illness. Boosters can protect against the worst effects, but these are shots in the dark: insurance against serious illness, but may not be necessary. This is because we do not know how long their protection against serious diseases actually lasts.

It’s about time we found out, but that means a different focus. At the level of basic biology, this means paying less attention to the antibodies that generate vaccines and more attention to another very important but overlooked component 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,” said Paul Offit, a professor of vaccinology at the University of Pennsylvania and a vaccine advisor to the FDA.

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

For germs that get through here, then, there’s short-term or humoral immunity: the rapid response tailored to a particular invading threat, such as a virus, that dominates early after it arrives to try to prevent infection. This defensive wave is led by neutralizing antibodies specially made to fight against whatever has entered the body.

But when this antibody response fails to prevent Covid from gaining a foothold and the virus enters cells so it can multiply, a third protective strand comes into play: long-lasting, cellular immunity. Memory T cells, which are also tailored to the specific threat, are an important part of this.

“Once a virus infects cells, T cells can limit the amount of viral replication,” says Céline Gounder, an infectious disease specialist and general editor at KFF Health News. When a virus like Covid reproduces, it parks parts of itself in the cell’s outer membrane, announcing to the host that the cell is infected. T cells – primed, by vaccination or previous infection, to notice these foreign parts – then kick into gear, killing infected cells and directing the production of more antibodies. “That prevents the disease from developing,” says Gounder.

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

And there is a third big advantage. In Covid, some of the viral bits that land on cell membranes and attract T cells are “highly conserved” internal 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 usually targeted by antibodies, are much more likely to mutate, making those antibodies less effective.

Cellular immunity is clearly important – it protects against the worst of Covid, doesn’t fade as quickly as humoral immunity and is harder for the virus to mutate away. But in testing and approving Covid vaccines, developers and regulators have not looked closely. They relied on studies of the humoral response. Think about all the times you’ve heard about a vaccine’s ability to elicit an antibody response or how long antibody levels last. Fortunately, studies on this showed a rapid strong increase in antibodies that could neutralize SARS-CoV-2 after vaccination.

Not looking at T-cells may feel like a mistake, but it made sense at the time. With the pandemic coming into full force, regulators were quick to know whether vaccines would be useful in fighting the virus and neutralizing antibodies to peak SARS-CoV-2 within a few weeks. In contrast, the response of the T cells can take months to mature. In addition, lab tests for T cells are more complicated than those for antibodies, and differ from lab to lab, making large-scale comparisons more difficult.

In addition, regulators are used to seeing antibody readings neutralize and call off accordingly. Even if neutralizing antibodies fail to stop an infection completely, they generally limit it while being present in good amounts – so if they spiked after vaccination suggested the Covid vaccines would help protect people. Trials then backed this up by showing much lower rates of hospitalization and serious illness among the vaccinees in the first few months after they received their shot, 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 the short-term antibody response really misses the boat,” said Dan Barouch, a professor at Harvard Medical School and chief of the vaccine research division at Beth Israel Deaconess Medical Center in Boston. Looking so closely at antibodies has left us none the wiser about the strength and durability of protection against serious disease that T cells provide.

So to try and understand this better, researchers have started comparing T cell responses between the major vaccines. Scientists at the La Jolla Institute for Immunology in California 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 following vaccination. Over the same period, the antibodies generated by the Pfizer and Moderna injections faded, providing a first rough draft of the picture of long-lasting immunity to Covid.

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: could even relatively low levels be enough? And are some T cells more effective than others? Part of the difficulty is choosing one voice from the chorus of the immune system. “It’s hard to prove that one part of the immune system is responsible for protection when all components work together,” says Barouch. There is also still no robust estimate of how long these T cells last, even though we know they last longer than antibodies.

Our understanding of cellular immunity is 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 company that develops a Covid vaccine. “Funding to support and accelerate this critical area of ​​vaccine development has been and remains weak and declining along with the general interest in Covid,” he says.

There are interest groups. Barouch and his colleagues are also trying to measure how well current vaccines build cellular immunity, while others are trying to create vaccines that specifically target generating a T-cell response. For example, researchers at the University of Tübingen in Germany have conducted a trial to test the safety of a vaccine made from SARS-CoV-2 proteins known to induce 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. “No one denies that cellular immunity is important,” said 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 minor role in protection compared to antibodies.

Moore points to something called “affinity maturation,” where the immune system learns to build more accurate antibodies against a pathogen over time the more it’s exposed to it. Researchers from New York and California have shown that this happens with SARS-CoV-2. So if you know that you already have vaccines that generate good amounts of antibodies, and that each time a vaccine is given, the antibodies produced will be stronger than before, that might be enough – you don’t have to worry about T- cells. In addition, says Moore, preliminary studies have shown that neutralizing antibodies protect well against severe covid. And if that’s the case, anyone would stay safe by regularly topping it up with occasional boosters.

However, Offit is confident enough in T cells that he thinks boosters may not be necessary in anyone but the most vulnerable (such as the elderly or the immunocompromised), at least until the T cell response can be seen to have subsided. “If it turns out that memory cells only last a year, for example, you might need an annual booster,” he says. “If they last two years, three years, four years, you may not need a booster.” Still, there are no signs that T cell numbers are decreasing over time: In addition to the La Jolla study, a report in Science Immunology has shown that T cell responses to various vaccines remain stable and are not enhanced by boosters.

Anyway, the FDA has proposed its annual booster schedule for Covid, with the idea that boosters could be updated each year to handle the latest variants of the virus, to make sure the antibodies created are well-matched to whatever form of the virus is circulating. This essentially mirrors how the world is dealing with changes in flu viruses.

For Bright, it’s the wrong way to do things: He’d like to see more focus instead of building vaccines that target those parts of the virus that don’t change. “We can track the limitations of flu vaccine development,” he says. “Or we can make vaccines that activate a full arsenal of both cellular and humoral immunity.” If we go down the flu vaccine route and continue to focus on antibodies, he argues, we will chase SARS-CoV-2 forever. Right now, it looks like we’re headed in this direction.