What an under-appreciated cell can tell us about a future Covid-19 vaccine

Antibodies – Y-shaped proteins that can declaw pathogens – weren't part of the public vernacular a year ago, but now they're the talk of the socially-distanced town.

The stark truth is that antibodies can't free you from social distancing. But when it comes to developing a vaccine, they've become the focal point on which we pin our dreams of Covid-19 immunity.

That attention isn't unwarranted, but experts tell Inverse that to truly create the best Covid-19 vaccine possible we need to be thinking about another type of immune response too.

Neutralizing antibodies, which stop the virus from entering cells, are typically the gold standard by which immunologists measure how the immune system reacts to a virus. But, as scientists are continually pointing out, immunity has never been just about antibodies.

Antibodies are one part of a multi-layered immune response. If you're looking to get a more complete picture of how immunity to coronavirus might work, you also need to consider another type of immunity — the type induced by T-cells. Some T-cells help the body produce antibodies; others kill virus-infected cells.

There are many open questions about how T-cells may mediate Covid-19's severity, and how exactly they fight off SARS-CoV-2 isn't clear.

Scientists do know that T-cells will be an important measure of how well a vaccine can truly fight off Covid-19, says Raj Thaker, a lecturer at the University of Essex who studies T-cell responses.

"We know a lot about antibody responses but we don’t know much about the T-cells and how they are responding in an [Covid-19] infection," he tells Inverse. "That’s something we can actually use to measure the efficacy of the vaccine and how they are priming immune systems in terms of the T-cells."

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What you need to know about T-cells – The immune system can be broken down into a few layers. There is:

• The innate immune system: a generalized tool that keeps pathogens out (like the skin).
• The adaptive immune system: systems in the body that learn go after pathogens. That's the system a vaccine looks to train against SARS-CoV-2.

Zoom in on the adaptive immune system and you've got two more layers: the humoral immune system and the cell-mediated immune system.

The humoral immune system is comprised of free-floating molecules or proteins – like antibodies – that can recognize a pathogen. The cell-mediated immune system is where you'll find T-cell responses. Zoom in one more layer, and you'll find two types of T-cells: helper T-cells (or CD4⁺) and killer T-cells (or CD8⁺).

All of these layers are interconnected, Thaker says. If you're seeing antibodies, you're probably also those helper T-cells, because they help make antibodies. It's also likely that those killer T-cells are around, but that's not for certain. Antibodies "don't necessarily go with the killer T-cell response," Rama Rao Amara, a professor at the Emory Vaccine Center, explains.

"It is very important that vaccines induce a strong T-cell response, in particular, the killer T-cell response," Amara tells Inverse.

What T-cells can do — When it comes to inducing immunity to Covid-19 (as a vaccine should), you want to be sure that full arsenal will be deployed.

In the case that the virus "mutates" to avoid our existing antibody responses — it hasn't so far — T-cells might help immunity stay somewhat intact, even in the long-term, says Amara.

He adds that studies have found that there may be some people who already have helper T-cell's that recognize aspects of the SARS-CoV-2 (like the spike protein), even if they've never had coronavirus. Those cells represent a well that we may be able to draw from to increase immune responses, though this work is early-stage.

"People think this is because of the exposure to other coronaviruses," Amara says. "Because of that, there is some pre-existing T-cell immunity that could protect."

Amara couches that with the assertion that T-cell immunity, on its own, likely isn't enough. More broadly, the T-cells responses just tell us that the immune system is really firing on all cylinders.

T-cells and coronavirus vaccines – Crucially, the type of vaccine we use may define the roles of T-cell immunity and antibody immunity.

The best method to get both at once, are viral vector vaccines, Amara explains. Those vaccines deliver Covid-19's genetic material into the body through another non-infectious virus, like chimpanzee adenovirus.

Those types of vaccines are especially good at invoking T-cell responses and antibodies, Amara says. This is also the delivery method he favors — he is also working on a vaccine candidate.

"In general, the viral vector-based vaccines provide both strong antibody response as well as the strong T-cell response," Amara says.

Meanwhile, vaccines like DNA or RNA based vaccines, deliver a bit of Covid-19's genetic material to the body directly. Those, he says, are more "intermediate."

"The general feeling is that the RNA and DNA based vaccines induce lower [levels] of killer cells than the viral vector-based vaccines," Amara explains.

It could turn out that all these vaccines help fill different niches depending on individual immune responses. That's the opinion of Francis Collins, the direction of the National Institutes of Health, and Anthony Fauci, director of the Institute of Allergy and Infectious Diseases. They argued that stance in a perspective published in May in Science.

The history of vaccination supports that idea, Amara says. For example, when it came to yellow fever, a vaccine induced a very strong antibody response in some, and a very strong killer T-cell response in others.

How future vaccines and our immune systems will intertwine remains to be seen. What we know right now is that Covid-19 vaccines can take more than one route on their way to destroy the virus – and hopefully, the vaccines we receive will use them all.