One of the biggest mysteries of the current pandemic is why outcomes from SARS-CoV-2 infection vary so widely between different people. Researchers are searching for clues in the host immune response to the virus.
Most people who are infected with SARS-CoV-2 will clear the virus with few or no symptoms, whereas others will develop a severe illness that can lead to hospitalization and death.
“As with any virus, it’s your immune system that protects you against the deleterious consequences of an infection,” says Arne Akbar, professor of immunology at University College London. “But there’s something about the immune system that isn’t quite right in combating SARS-CoV-2 that gives these very bad outcomes in some individuals.”
But exactly what this immune dysfunction looks like is poorly understood – and is likely to differ between patients with severe disease.
“It appears that if the infection isn’t cleared straight away, some of the disease pathologies might be caused by the immune system rushing to try and fight it,” describes Deborah Dunn-Walters, professor of immunology at the University of Surrey and chair of the British Society of Immunology COVID-19 taskforce. “So it’s important to try and understand the balance of the immune response – what’s good and what’s not.”
Unraveling the complex interactions between SARS-CoV-2 and the immune system is challenging, but hugely important in shaping our response to the virus. Our knowledge of the host immune response is already helping to identify existing drugs for treating critically ill patients. It is also underpinning work to develop novel vaccines that offer our best hope of escaping the devastating impact of the current pandemic.
The call to arms
SARS-CoV-2 gains entry to cells through a receptor known as angiotensin-converting enzyme 2 (ACE2), which is found on the surface of cells lining the lungs and other places in the body. Our first lines of defense are non-specific “innate” responses that are rapidly mobilized following an infection – such as the virucidal proteins released by infected cells. But like many viruses, SARS-CoV-2 has evolved strategies to evade these initial immune responses, such as masking its genetic material and generating viral proteins that can block anti-viral responses.
“If the virus is cleared at that early stage, then nothing happens – which can help to explain why some people are asymptomatic,” says Akbar. “But if the virus breaches those initial defenses, then it starts causing problems.”
The next stage is the “adaptive” immune response, which takes longer to get up and running but generates a highly specific response against the virus. “The immune system has B cells that can produce neutralizing antibodies against the virus – and T cells that can recognize and kill virus-infected cells,” continues Akbar. “During the lag phase, as B and T cells become activated, innate immune cells can offer some protection, but they’re not as specialized in what they do.”
During the early stages of the pandemic, some people expressed concern that the host immune response to SARS-CoV-2 might deviate from the normal pattern.
“It’s been really positive to see the data accumulate,” says Lucy Walker, professor of immune regulation at University College London. “It’s panned out pretty much as we would expect, with most people generating antibodies and nice T-cell responses.”
Deciphering the Immune Response to Viral Infection
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Tipping the balance
The immune system is a powerful entity that can provide us with protection against everything we are likely to encounter in our lifetime.
“But like any army, it needs to be tightly controlled,” says Akbar. “If it’s not, this can lead to autoimmune conditions, like rheumatoid arthritis or type 1 diabetes, where the immune system starts to attack a person’s body tissues.”
Researchers are exploring what happens when the balance starts to shift the wrong way in COVID-19, leading to the immune system turning on the host.
“It’s rather like autoimmunity,” says Walker. “Most people clear the virus with few problems and switch off the immune response – but some end up with a prolonged response and immune-mediated damage.”
Researchers have uncovered a variety of factors that are known to increase the risk of severe COVID-19, including age and certain pre-existing health conditions – which could provide clues as to what might be going wrong.
“There’s a phenomenon called “inflamm-aging” where people have more background inflammation as they get older,” says Akbar. “Interestingly, some of the pre-existing health conditions that predispose to severe COVID-19 are associated with higher levels of these inflammatory mediators.”
Researchers are exploring the hypothesis that background inflammation could interfere with the body’s ability to get rid of the virus quickly without inducing tissue damage.
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The ability of the body to generate long-lived “memory” T and B cells holds the key to SARS-CoV-2 immunity.
“This immune memory should trigger a faster and bigger response if you encounter the virus again,” explains Walker. “That means you should clear the infection with far fewer symptoms compared to the first time – and hopefully none at all.”
A recent study showed that healthcare workers who have previously had COVID-19 are provided with 83% protection for at least 5 months. Another study showed that immunity may last up to eight months, indicated by the presence of neutralizing antibodies, memory B cells and T cells in the bloodstream.
“For the vast majority of people, once you’ve had it you don’t tend to get it again,” says Akbar. “A few anecdotal cases have generated a lot of attention, but it’s actually only a small number of people who get reinfected.”
Understanding how long protection lasts will be important for informing future vaccination strategies. Some researchers predict that immunization against SARS-CoV-2 may even generate a better immune memory compared to a natural infection.
“Viruses often have ways to evade the immune response,” explains Walker. “That’s one of the things that SARS-CoV-2 is quite good at – delaying or suppressing the initial immune response very early on in an infection, whereas vaccines don’t have those characteristics.”
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The road to treatments and vaccines
Drugs that can manipulate the immune response are already helping to prevent deaths from COVID-19. Dexamethasone, an immunosuppressant drug, was the first treatment proven to be effective for some patients with severe disease. More recently, preliminary results from a clinical trial suggest that two immunotherapies used to treat rheumatoid arthritis can help improve survival in critically ill patients.
There has been even faster progress in developing vaccines to protect against COVID-19 – and many are keen to emphasize the huge bedrock of fundamental science that has enabled this to happen.
“We’ve needed to draw on pre-existing knowledge about the normal immune response and the types of immune response you want to elicit with vaccines,” says Walker. “And we’ve also relied on the availability of immunological assays to measure these effects.”
Every vaccine candidate must first undergo extensive pre-clinical testing to find out whether they offer protection against the infection and the disease.
“You need the immunology to assess the safety and efficacy of a candidate vaccine before taking it into clinical trials,” explains Dunn-Walters. “You need to monitor for the presence of neutralizing antibodies and T-cell responses that are specific to the virus.”
Defining what’s known as the “correlates of protection” is key, providing scientists with the ability to assess a vaccine’s efficacy by measuring the immune response rather than through clinical outcomes.
“It gives you the tools to then look at different populations without having to challenge thousands of people with the virus,” says Dunn-Walters. “Once a vaccine is proven to work, it may even become unethical for people to take part in randomized placebo-controlled trials.”
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A legacy for science
Scientific investigation – and particularly the field of immunology – has been abruptly thrust into the spotlight due to the current pandemic. With the hope of an end now in sight, many are now starting to look at the longer-term opportunities from its aftermath.
“Every pandemic is going to be different so you can’t necessarily write a complete rule book,” reflects Dunn-Walters. “But we can learn lessons that will help us to be better prepared to deal with future threats.”
Others emphasize the importance of investing in a breadth of basic science, which has underpinned so much of what has been achieved.
“We don’t know where the next problem for humanity is going to come from and what we’re going to need to tackle it,” says Walker. “But having up-to-date textbooks about the basic principles will certainly put us in the best position to succeed.”