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Omicron vs. T cells: Why scientists are banking on the immune system's 'memory'

Even as antibody levels against the variant wane, the immune system may still be primed by vaccines or previous infections to “remember” the virus.
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It's a worrisome convergence: falling antibody levels and a new variant.

Scientists have warned that a coronavirus variant like omicron, which appears able to dodge some protective antibodies generated by the vaccines, could be a major setback in the pandemic. But as the world waits for more data on the heavily mutated variant, experts say there are some early but encouraging signs that our immune systems have amassed a range of tools to fight Covid-19.

“It may be that our antibodies may not work as well, but the immune system has these backup plans that give us some resilience against omicron,” said E. John Wherry, director of the Institute for Immunology at the University of Pennsylvania.

There are some early indications that booster shots may be needed to counter the drop in antibodies with omicron. Pfizer-BioNTech announced Wednesday that a third dose offers comparably strong protection against omicron as the company's initial two-dose regimen did against the original strain of the virus.

Yet even as antibody levels wane against the variant, the immune system may still be primed by vaccines or from previous infections to "remember" the virus. The focus now is on whether the parts of the immune system that power this long-term protection — primarily T cells — will hold up against omicron.

If that's the case, immune responses could ramp up quickly after infection and protect people from the worst effects of the virus.

More research is needed, but the ability of the body's immune system to recall the virus will likely be key in how severely or not the current wave of infections plays out across the globe. It will also help scientists better characterize the omicron variant, including the risk of breakthrough infections in vaccinated individuals and the potential for reinfections in those who were sickened by a previous strain.

In South Africa, where the first major outbreak of the variant was reported, omicron is driving a sharp spike in cases. Though it’s still early, the increase in infections has not yet been associated with a surge in severe illness or hospitalizations.

South Africa has had limited access to vaccines, and thus its population has significantly lower vaccination rates than the United States and Europe but high levels of natural immunity from infections in previous waves of the pandemic.

Wherry said if hospitalization rates remain relatively low as omicron spreads, it may indicate that the immune system is still mounting a robust response against this latest variant. But he added it's too soon to know for sure, as hospitalizations and deaths can lag weeks behind infections, and researchers are still racing to understand the basics of omicron, such as how contagious it is compared to delta and other previously identified variants.

There is mounting evidence, however, that omicron's slate of mutations in the coronavirus' spike protein may enable it to evade neutralizing antibodies generated by vaccines. These antibodies normally bind to specific targets along the spike protein and prevent the virus from getting into cells, but sufficient enough mutations can hamper this biological mechanism.

Yet antibodies are just one part of how the immune system orchestrates protective immunity.

"Antibodies are your first line of defense," Wherry said. "But we have other cells that can recognize the virus in completely different ways."

In particular, there are two types of so-called T cells that are designed to lie in wait until they detect foreign invaders. One type, known as T helper cells, coordinate the body's various immune responses. The second, called cytotoxic T cells or killer T cells, are designed to recognize tiny snippets of the virus inside cells and eliminate them.

"T helper cells are like the generals of the immune system, and killer T cells are like the assassins," said Andrew Redd, a virologist at the National Institute of Allergy and Infectious Diseases.

Since T cells don't target specific areas on the surface of viruses the way antibodies do, they tend to be less affected when a pathogen undergoes mutations, Redd said.

In a pre-print study that has yet to be peer-reviewed, Redd and his colleagues examined whether omicron's mutations effectively changed the snippets of the virus that killer T cells can recognize. The researchers looked at 52 pieces of the virus that were identified from 30 patients who were infected with Covid early last year and had since recovered. They found only one mutation in a section that T cells recognize, and only in two of the 30 people studied.

The findings were similar to a separate NIAID study published by Redd and his colleagues in March that found that T cell responses were largely unaffected by mutations in three previous variants: alpha, which was first detected in late 2020 in the United Kingdom; beta, which was first reported in December 2020 in South Africa; and gamma, which was first detected in January in Brazil.

"It suggests that T cell responses remain largely intact and should remain largely intact against omicron," Redd said.

That means even if antibody levels wane, most people who are vaccinated — with two doses of the Pfizer-BioNTech or Moderna vaccines or one shot of the Johnson & Johnson vaccine — or have natural immunity may be protected from getting seriously ill if they test positive for omicron.

"It should, I hope, keep the majority of infected people from having to go to the hospital," said Rachel Graham, an assistant professor in the department of epidemiology at the University of North Carolina at Chapel Hill.

In addition to T cells, the body also produces what's known as memory cells, which can recall pathogens and rapidly activate immune responses. Certain memory cells can, for instance, ramp up production of antibodies, while others can jump-start killer T cells.

It’s this complex interplay of biological mechanisms and responses that fuels optimism among some experts that the immune system can bank on more than one weapon in its arsenal to fight omicron and other variants that may emerge.

Graham said the situation underscores the importance of being fully vaccinated because even lower antibody levels can confer some protection, especially in those who also received a booster shot.

"Even if the vaccine is not as effective against omicron, it’s still going to be more effective than not being vaccinated," she said.

Preliminary data showed that the Pfizer-BioNTech vaccine appears to be less effective against omicron, but the company announced Wednesday that a third dose appears to provide strong protection against the variant. More results on vaccine efficacy are expected in the coming weeks.

But beyond vaccines and antibodies, gathering data on T cell responses is significantly more difficult, Redd said.

Unlike testing for antibodies, a relatively straightforward procedure that can be done with a blood sample, studying T cells requires purifying white blood cells from a sample and testing all of the possible areas T cells could recognize to measure the responses. Wherry said it's not only expensive but very labor intensive, and the process, which includes sifting through reams of resulting data, can't be automated in any way.

"It's easily a week or more of work to analyze T cell responses in 10 or a dozen people, whereas in one day you can analyze the antibody response from thousands of people," Wherry said.

But with the coronavirus still circulating around the world, opening up the possibility for other new variants to emerge, it will remain essential for scientists to keep tabs on how the body's immune responses change as the virus evolves.

"If we can't get the world vaccinated, we're going to continue to see variants like omicron," Wherry said. "My big concern is the implications for whatever next variant comes in the future."