In the late 1980s, 15 healthy people moved to new apartments in Salisbury, UK. On their third day, everyone was asked to sniff a nostril of solution containing a coronavirus – one of several viruses that cause the common cold. Then, for three weeks, volunteers quarantined at the Common Cold Unit, part of the Medical Research Council, where researchers monitored a range of symptoms. Some student participants likened staying at the Common Cold Unit to a vacation – if that was the case, it was a vacation complete with blood draws and nasal washes.
About a year later, 14 of the volunteers returned to do it again. This time, researchers were anxious to know if the participants’ exposure to the virus had made them immune. The answer: sort of. Although they showed no symptoms, analyzes revealed that almost all were infected before their immune system could launch an effective defense.1.
It was an early hint at the answer to a question that researchers, doctors and politicians are keeping awake at night: can the human immune system build a lasting defense against the pandemic virus SARS-CoV-2? The answer is vital to understanding whether a vaccine will provide adequate protection, if those who have recovered from COVID-19 can return to pre-pandemic behavior, and how easily the world can reduce the threat posed by the disease.
Researchers have rummaged through results of the Common Cold Study and others like it, while scrambling to understand the human immune response to SARS-CoV-2 using animals and cell cultures, along with the latest molecular techniques. They have catalyzed antibodies and immune cell responses at unusual speeds, determining which are likely to be most effective, and designed vaccines and therapies that, in animal studies and small human studies, provoke at least short-term immune responses. But there is no rapid and simple experiment that can firmly determine whether immunity will be effective or lasting. It’s just too soon to know.
“Only the future can tell us,” says Reinhold Förster, an immunologist at Hannover Medical School in Germany.
Sporadic accounts of reinfection – people recovering from COVID-19, only to fall ill and retest positive for the disease – have raised fears that immunity may be short-lived. Media outlets have confirmed such reports, and have provided gloomy predictions about the chances of a fax. But scientists are paying more attention.
“We all hear anecdotes, but I do not know if any of us know what to think about it,” said John Wherry, an immunologist at the University of Pennsylvania in Philadelphia. So far, reports of reinfection have not provided enough information about the person’s immune responses to rule out other possibilities, he says.
For those scientists who dig deep into the details of the immune response to SARS-CoV-2, the data so far have not been surprising – and that proves good. “We see great immune responses and fantastic-looking antibodies. We just do not know the longing for that answer, “said Mehul Suthar, a viral immunologist at Emory University in Atlanta, Georgia.” Unfortunately, that will take time. “
Antibodies are processes for immunity
The immune system has numerous ways to protect and restrain viral invaders. It selects for the B cells that produce antibodies that can bind to the virus. It also creeps away a store with long-lived memory B cells that produce those antibodies and that jump into action when the virus returns. Another defense illustrates T cells, which patrol the body searching for and destroying infected cells, in order to reproduce the ability of the virus. These immune cells can also last for years.
Long-term immunity can vary by type as well as by degree of response. Vaccine developers often hope to evoke what is known as sterilization of immunity, a reaction, typically mediated by antibodies, that can quickly prevent a recurring virus from entering the body. But not all vaccines or infections attract the neutralizing antibodies needed to sterilize immunity. For example, HIV rarely induces neutralizing antibodies2, a fact that has complicated attempts to counter faxes.
The signs so far for SARS-CoV2 are encouraging. Several teams of researchers were quick to isolate neutralizing antibodies from people infected with the virus3; most were able to mount such an anti-antibody response within days after positive testing. And several vaccine candidates against SARS-CoV-2 provoke a strong anti-inflammatory response, a positive sign that the vaccines can generate immunity.
But some scientists have advice on the preliminary data. Anti-anti responses were most high in people with the most severe infection. Those with mild infections – that is to say most people who have COVID-19 – sometimes produced small amounts of neutralizing antibody. This pattern is often seen with viruses: the longer, more severe infections more often produce strong, lasting responses. This is one reason why common cold coronaviruses sometimes do not produce long-lasting immunity, says Shane Crotty, a virologist at the La Jolla Institute for Immunology in California.
Antibody levels go down shortly after a coronavirus infection, but then disappear. That’s probably not a bad thing.Credit: Alessandro Grassani / NYT / Redux / eyevine
Then there is the question of how long antibodies last. When researchers followed COVID-19 patients over time, they found that the amount of antibody peaked in the days after the onset of symptoms, and then began to decrease. In some study participants, the antibodies were virtually undetectable for about three months4,5. Several major media outlets reported this as a loss of immunity, saying it would complicate fax efforts.
However, many immunologists found that statement a little too early. The data showed a perfectly normal response to a viral infection, says Luis Barreiro at the University of Chicago in Illinois, who is studying the evolution of immune responses to pathogens. When a virus attacks, it stimulates the proliferation of B cells that produce antibodies that can recognize pieces of the virus. But once the infection is gone, anti-antibody levels typically win. “There’s a lot of fear,” says Miles Carroll, an infectious disease specialist at Public Health England in Porton Down, UK. “But I think, on the whole, that it’s a pretty robust immune response.”
To determine how important that decay may be, researchers still need to know how much antibody it takes to successfully protect SARS-CoV-2. “Even small amounts of antibodies can potentially be protective,” says Mala Maini, a viral immunologist at University College London.
They also need to monitor longer antibody levels, to find out if they end up keeping a low concentration – as is usual with viral infections – or continue to decrease rapidly. In view of these unknowns, virologist Katie Doores of King’s College London, lead author on one of the antibody studies, says she escaped the negative press coverage of her work. “Everyone likes ‘Argh!’ To be, ”she says. “But we do not know what level of antibodies are needed for protection.”
Plans B and T
Even as antibody levels deepen to low levels, the immune system often has a back-up plan. Memory B cells hang in the bone marrow until a virus returns, when they assume a new identity as antibody-producing plasma cells. Data on the role of memory B cells in protecting COVID-19 are incomplete – they are more difficult to find and count than antibodies – but so far the evidence suggests that they are proliferating, says Marcus Buggert, an immunologist. at the Karolinska Institute in Stockholm. One recent study, which has not yet been peer reviewed, found memory B cells capable of producing neutralizing antibodies that recognize SARS-CoV-2 in people who have their mild COVID-19 levels.9.
Furthermore, immunity is not entirely dependent on antibodies. T cells may be able to recognize and destroy virally infected cells, which limits the spread of the virus throughout the body. Like memory B cells, T cells are more complex to examine than antibodies, but studies have so far suggested that they are called in action in SARS-CoV-2 infection. One recent study examined immune responses in 36 people recovering from COVID-19, and found T cells that recognize the coronavirus in all of them6. “It looks like a virus that is very stimulating to T cells,” says immunologist Danny Altmann at Imperial College London. “Most people have very good T cell responses to it.”
Fax promises
T-cell studies also convert to the possibility of cross-reactivity, in which T-cells that recognize other coronaviruses also recognize SARS-CoV-2. Various studies7 have found T cells that respond to SARS-CoV-2 in blood samples from people who were not exposed to the virus. And one team recently reported that some of these T cells not only respond to SARS-CoV-2, but also to some common cold coronaviruses.8. The results suggest that there may be some persistent cross-immunity between these cold coronaviruses and SARS-CoV-2, leading to speculation that this may be partly responsible for the wild differences in the severity of COVID-19 symptoms between individuals.
Lessons learned from other viruses also give reasons to be optimistic that immunity to SARS-CoV-2 will last. T cells against the virus responsible for severe acute respiratory syndrome (SARS) were found 17 years after infection6. Also, SARS-CoV-2 does not seem to mutate as fast as the flu viruses, notes Barreiro, who change so often that fresh vaccination is needed every year.
The Common Cold Unit study found not much sign of hope for sterilizing immunity to its common-cold coronavirus, but the results also suggested that immunity might be strong enough to reduce or even eliminate symptoms. Sterilizing immunity to COVID-19 would be ideal as it would reduce the risk of people with minimal symptoms spreading the infection widely. But at this point, a vaccine that could reduce mortality would probably still be useful, says Alessandro Sette, an immunologist also at the La Jolla Institute of Immunology.
In general, the diverse and sometimes devastating effects of SARS-CoV-2 on the body and the ease of spread have made it an unusual enemy. But the immune system’s response to the virus has not come as much of a surprise so far, Barreiro said. In this case, he adds, ‘boring’ bodes well for long-lasting immunity. “There are still many things we do not know, but so far nothing is really unique.”
