Long-term immunity..

This is what long-term immunity to Covid-19 might look like

Antibodies aren’t the whole story.

By Umair Irfan 

Over the past two years, the United States has seen more than 63 million Covid-19 cases, with some people infected more than once. More than 240 million people in the US have received at least one dose of a Covid-19 vaccine. More than 60 million have received three.

While Covid-19 infections are never a good thing, these numbers still add up to a glimmer of good news: A large majority of Americans now have some immunity against SARS-CoV-2, the virus that causes Covid-19. That’s a big step toward defanging the disease.

When the human body is infected by the virus or encounters a fragment of the pathogen in a vaccine, our immune systems change in subtle but important ways. Across a huge swath of the population, these changes could eventually help transform Covid-19 from a world-stopping catastrophe into a mild annoyance.

Antibodies, proteins that attach to the virus, are a critical part of the immune response and are often the center of discussions about protection from Covid-19. But they rise during infection and decline naturally over time. Fortunately, antibodies are not the whole story when it comes to the immune system.

Other, longer-lasting tools against infection are hiding inside our bones. The immune system draws on stem cells living in bone marrow to produce an array of components that we don’t hear as much about. They form many kinds of white blood cells that jump into action right away when they encounter a virus for the first time, and that essentially take notes to start planning for the next infection.

It’s this immune system memory that’s key to long-term protection against Covid-19. What’s reassuring is that as white blood cells get more practice against SARS-CoV-2, they seem to get better at containing the virus — even when it evolves into new variants. That appears to be happening in the omicron wave of Covid-19.

What makes the omicron variant so strange and surprising

Omicron is the most transmissible variant of the coronavirus known to date. It also appears to be better at dodging immune protection from Covid-19 vaccines. Cases have reached record levels in many parts of the United States, and hospitals are once again straining under the burden.

But the fraction of cases leading to hospitalizations and deaths appears to be far smaller compared to other variants. While there are more reports of breakthrough infections and reinfections with omicron, many previously exposed people report mild, cold-like symptoms.

One reason is that the virus itself appears to have mutated in a way that leads to fewer dangerous complications. Yet it’s also clear that widespread immunity is absorbing some of the worst effects of the disease, a hopeful trend that is likely to continue in 2022 and beyond.

Meet your B cells and T cells, your enduring pandemic protectors

The world is full of so many things that can make us sick — viruses, bacteria, parasites, fungi, even mutated versions of our own cells. The threats are varied and unrelenting, but so too is our immune system. It’s an orchestra of cells, proteins, organs, and pathways that all harmonize to keep invaders at bay. In simplified form, here’s how.

When a pathogen like the coronavirus enters the body for the first time, it confronts the innate immune system, which provides generalized protection against all pathogens, but isn’t always enough to prevent illness on its own. After an infection takes root, the immune system launches a more targeted response with what’s known as the adaptive immune system.

Neutralizing antibodies form the pillar of the adaptive immune system. The virus is studded with spike proteins (giving it its namesake corona, meaning crown in Latin), which attach to human cells to begin the infection process. Y-shaped antibodies can attach to the spikes on the virus and prevent it from entering cells, thereby neutralizing the pathogen. The parts of a virus that can trigger an immune response are known as antigens.

“In general, neutralizing antibodies keep you from getting infected in the first place,” said Lewis Lanier, chair of the microbiology and immunology department at the University of California San Francisco.

Neutralizing antibodies are picky about the parts of the virus they recognize, known as epitopes. If those attachment points on the virus change, as they do in many coronavirus variants, antibodies can become less effective. In the months following an infection or immunization, the amount of these neutralizing antibodies declines as well. That’s expected. Making antibodies takes a lot of energy, so the body makes fewer of them after an infection is gone.

That decline may sound worrisome, but the immune system has other powerful tools in its shed. To start, there are non-neutralizing antibodies. These don’t directly interfere with how the virus functions, but they can help the immune system detect infected cells and mark them for destruction. This is a crucial task because viruses can’t make copies of themselves on their own: They need to commandeer a host cell to reproduce. Once a virus enters a cell, it’s not accessible to neutralizing antibodies, but non-neutralizing antibodies that learned to recognize infected cells can still raise the alarm.

The task of eliminating infected cells falls to a group of white blood cells known as cytotoxic T cells, sometimes called killer T cells. They arise from stem cells in bone marrow and cause infected cells to self-destruct, without messing with normal cells.

“T cells, they cannot prevent infection,” said Lanier. “The only way a T cell can recognize you have an infection is after a cell has been infected.”

Helper T cells are another important white blood cell variety. They spur the production of antibodies by a different group of white blood cells called B cells. B cells form in bone marrow and then migrate to lymph nodes or the spleen.

After an infection or a vaccination, some B cells and T cells stick around, becoming memory B cells and T cells. They sit idle, sometimes for decades, waiting to see if a pathogen returns. If it does, they can quickly reactivate.

This is why we a decline in neutralizing antibody counts isn’t always a disaster. Even if concentrations of neutralizing antibodies dip so low that they can no longer prevent an infection, other parts of the immune system can spool up to make sure the virus doesn’t do too much damage.

“There is a window of time after virus gets into the body before it really starts manifesting disease in the person,” said Deborah Fuller, a professor of microbiology at the University of Washington School of Medicine. “That window of time enables the immune system that has been vaccinated and has memory immune responses to recall very quickly and shut down the virus before it actually causes disease.”

Our immune systems are adapting — but so is the virus

Some health officials now say that Covid-19 is so rampant that most people are likely to become infected at some point. “It’s hard to process what’s actually happening right now, which is most people are going to get Covid,” Janet Woodcock, acting commissioner of the Food and Drug Administration told the Senate health committee on Tuesday. “What we need to do is make sure the hospitals can still function, transportation, other essential services are not disrupted while this happens.”

However, waves of infection can crest just as quickly as they form. Countries like the United Kingdom and South Africa experienced awful omicron spikes but subsequently saw precipitous drops in cases thereafter. Omicron cases also appear to be leveling off in some parts of the US, a sign that a decline may be ahead.

Whether these spikes in Covid-19 cases lead to severe health outcomes hinges on the teamwork of B cells, T cells, and antibodies, and how they hold up against any new mutations in the virus. It’s an area of active research for scientists.

“Vaccines and prior infection may not prevent you from being infected by the next waves of variants, but it may well keep you out of the hospital,” Lanier said.

For the past two years, with recurring spikes in Covid-19 cases, neutralizing antibodies have taken center stage. “We’re really more concerned right now in the middle of the pandemic about the durability of that antibody because what we’re trying to do is prevent transmission,” said Fuller. But that could change.

Neutralizing antibodies remain a key benchmark for vaccines: Scientists judge the success and timing of vaccines in part by measuring the number of antibodies they provoke in our blood, and how long the antibodies stick around. When the mRNA vaccines from Moderna and Pfizer/BioNTech were in development, they demonstrated that they could elicit a high level of neutralizing antibodies. Further clinical trials showed that this translated to more than 90 percent efficacy in preventing illness.

The next test is how well antibody production ramps back up if the same virus invades again. It can take up to two weeks to generate antibodies after being exposed to a virus for the first time, but production can ramp up much faster during a second infection.

At the same time, a virus is rarely the same when it comes back. Viruses mutate frequently as they reproduce, and RNA viruses like SARS-CoV-2 are especially prone to change. Versions of the virus with distinct groupings of mutations are categorized as variants, like omicron, delta, and alpha. Our immune systems are getting stronger and faster, but changes to the virus still have the potential to throw them for a loop.

Already, some companies are developing omicron-specific vaccines, but they may not hit the market for months. The reformulated shots may be too little, too late. In the meantime, we have to rely on the immunity we already have, including boosts to our antibody counts that come from booster doses of Covid-19 vaccines.

We will eventually reach a balance with Covid-19

There is still much to learn about how all the elements of the immune system work together over time to hold off Covid-19, and some of the answers will only become evident with time. And the odd behavior of omicron is forcing researchers to rethink what they’ve learned.

The good news is that many aspects of our immune system also appear to handle the latest variant well. “From what I’ve seen, the T cell responses are still working rather well against omicron,” said Brianne Barker, a vaccine researcher at Drew University. “I think that we’ve still got a bit of time” in which immune protections will remain intact.

Immunity will continue building across the population and will blunt the sharp edges of the pandemic, even as the virus changes. Covid-19 is unlikely to go away entirely. As it circulates, it will continue to mutate and may cause sporadic outbreaks. But our immune systems are making progress.

“As you expose the human body, even to the same antigen over and over again, our immune system evolves as well,” Fuller said. “What we’re starting to see in people with third immunizations is an antibody [response] that is broader.”

It’s a good sign that improvements in our immune system are likely to outpace changes in the virus. But the pandemic has also made it clear that there is nothing about its trajectory we can take for granted. While the cells within us may shield against infection, it’s still a good idea to limit transmission of the virus in any other way we can. The fewer people it infects, the fewer unpleasant surprises ahead.