UK-CIC supporter, the British Society for Immunology (BSI) worked with the Academy of Medical Sciences back in May to produce a report to summarise what we do not know about the new coronavirus and the immune system, and what the immunology research priorities should be for scientists tackling this global, deadly pandemic. The information in this review was put together by their joint expert group, led by UK-CIC Science Advisory Board chair, Professor Arne Akbar. Many of the research priorities identified in this report formed the basis of the research themes for UK-CIC.
Since the new coronavirus first appeared in China in December 2019, scientists from around the world have been working together like never before to study the disease and develop new vaccines and drugs. The UK is at the heart of this work. This report from the British Society for Immunology and the Academy of Medical Sciences is a summary of what we know, what we do not know, and what the immunology research priorities should be for scientists tackling this global, deadly pandemic.
If I am exposed to the new coronavirus, what are my chances of becoming infected?
The virus is highly infectious. A typical infected person is likely to spread the disease to between 2.5 and 3.5 people on average – a far higher number than related viruses such as SARS1, which infected 8,000 people worldwide between 2002 and 2004, killing 770.
One likely reason it spreads so easily is that it tends to infect the upper respiratory tract – the nose, sinuses, pharynx and larynx - while SARS1 tended to infect the lower respiratory tract – the bronchial tubes and the lungs. That means the new coronavirus doesn’t have so far to travel down a person’s airways before it reaches a body cell it can attack and use to make copies of itself, and so is able to infect the body relatively easily.
Why is the early immune response important?
The first line of defence against the new coronavirus is the ‘innate immune response’, the body’s general reaction to any virus or attacking organism it does not recognise. The innate immune response prevents infections or reduces the severity of a disease and its strength is influenced by many factors including health and age.
It is likely that someone’s immune response to the new coronavirus, along with the severity of the disease, will influence how long they remain infectious. Some studies suggest people with mild or moderate symptoms may remain infectious eight days after their first symptoms. But severe cases could be infectious for weeks. This suggests people with persistent symptoms should self-isolate for longer than seven days.
Can people without symptoms of COVID-19 be infectious?
People can be infected with the new coronavirus without showing any symptoms. Some develop symptoms such as fever and cough, on average five days after infection, but others may never develop noticeable symptoms. There is good evidence that people without symptoms can still spread the disease. Research from China estimates that 44 per cent to 60 per cent of infections come from people with no symptoms.
Does exposure to high levels of the virus make the disease more severe?
People exposed to high doses of the virus, such as doctors, nurses and hospital staff, may experience more severe symptoms if they become infected. In China, healthcare workers who became infected with the new coronavirus appeared to suffer more severe symptoms than other people of their age. The use of personal protective equipment by healthcare workers and physical distancing is vital to limit the spread of the virus.
Does previous exposure to other coronaviruses such as the common cold or SARS1 offer protection against the new coronavirus?
There is little data on whether people are protected from COVID-19 if they were exposed to other types of coronavirus.
What is known about the immune response during disease, and does it vary from person to person?
Many people have a strong and healthy immune response to the new coronavirus which may also give them protection against future infections. The response varies from person to person and is influenced by many factors, including age.
Some people’s immune system overreacts to the virus, causing inappropriate inflammation and fluid build-up which can block airways and overwhelm organs such as the kidneys and liver, potentially leading to multi-organ failure. The ability of doctors to manipulate a patient’s immune response with drugs to prevent this sort of extreme reaction may be vital to prevent death from COVID-19 and is a priority for research.
Can the new coronavirus target the heart, gut and immune cells?
There is no firm evidence that the virus reproduces in tissues other than those found in the body’s airways.
Why are older people, men and people from BAME backgrounds more severely affected?
The immune system, lungs and airways weaken as we age. This helps explain why around 50 per cent of deaths from the disease have occurred in people over 80, and 40 per cent in people aged 60 to 79.
Older people are more likely to suffer from inflammation and have less effective immune reactions to the virus. Studies suggest that older people’s bodies are more likely to get stuck in the early stage of an immune response, which generates a lot of inflammation and tissue damage, rather than moving on to the second stage which is important in clearing away viral infections.
The impact of ageing on the immune system has implications for the development of vaccines for older people because they may respond to them differently. This highlights the importance of developing effective anti-inflammatory and anti-viral drugs in addition to vaccines.
There are early indicators that men may be more likely to get COVID-19 than women, however we need more data about this, and the reasons this could be happening are not understood. Similarly people from a BAME background are also at higher risk of severe disease and death. Again, more research is needed to find out why.
What do we know about patients with one or more pre-existing medical conditions?
Studies are underway to find out more about conditions such as obesity and high blood pressure that increase the risk of a COVID-19 patient developing severe symptoms. Less is known about conditions that affect the lungs such as asthma, or those that suppress immunity, such as pregnancy. There is currently no clear data showing that pregnant women are more at risk from COVID-19.
What can biomarkers tell us about disease?
A biomarker, or biological marker, is a natural feature in the body such as a molecule or gene which reveals something about a person’s health, their chances of developing disease or how well they might respond to treatment.
Easy-to-access biomarkers would be extremely helpful to identify patients who may be at risk of developing severe symptoms. This would allow us to provide early support to prevent them getting worse. Trials are underway of one promising immune system biomarker, called interleukin-6, which may reveal which patients are at risk of an overly energetic and damaging immune response.
Can we tell whether hospitalised patients are still infectious?
Existing tests can show if a patient is still infected with the virus, but not if they can still pass the disease to others. People are likely to stop being infectious a few days before they are clear of the virus. Existing tests for infectiousness take days, involve specialist experts and labs and are not suitable for mass testing of thousands of people.
How can we tell whether someone has been infected by the new coronavirus before?
The immune system produces antibodies to the new coronavirus around seven days after a patient shows symptoms, so an antibody test may reveal whether someone has been infected in the past. Tests of this sort can be used to find out how much of a population has been infected. This type of test can help indicate whether enough people have developed immunity to COVID-19 to stop it spreading through the population, so-called ‘herd immunity’. It is thought that around 80 per cent of the population would need to be immune for this to occur.
How much do antibodies, or other parts of the immune system, provide future protection against COVID-19?
Although the presence of antibodies in the blood can reveal if someone has been infected in the past with the virus, we do not know whether they offer full or partial protection against future infections. Protection may also depend on another part of the immune system, including the response of white blood cells called T-cells, which are not specifically measured by blood tests. This means the idea of an ‘antibody positive passport’, a document that allows people with antibodies to the virus to go back to work as they are presumed to be immune, should be considered with caution.
In addition, 10 to 20 per cent of people who have been infected with COVID-19 have little or no detectable antibody in their blood. However, this does not mean they have no immunity. In other diseases, such as flu, some people who appear to have no antibodies still have immunity through another part of the immune system, anti-viral T-cells. Understanding whether T-cells protect against future infection is key.
What are the important issues for developing useful antibody tests?
Reliable, laboratory-based antibody tests are being used to collect information about COVID-19 infection in the UK, New York and elsewhere. However, we are not at the stage where we can turn these tests into practical, large-scale tests for thousands of people. To be reliable, tests must not give false-positives – results which wrongly suggest people have previously been exposed to the new coronavirus.
How long might immunity last and what do we know about re-infection?
It is still early days when it comes to understanding immunity for COVID-19. We know that people exposed to the related virus SARS1 produced antibodies for at least two years after infection (and in some cases for up to 12 years), but those antibodies became less effective over time. And antibody levels for SARS1 patients were not always stable over the long-term.
There are anecdotal reports from China and South Korea of people testing positive for a second time with COVID-19 after they had apparently recovered from the disease. It is unclear whether the virus remains in the body at undetectable levels before ‘re-emerging’ or whether people were infected for a second time because they had not developed immunity. More research is needed.
What makes a successful vaccine?
Several promising COVID-19 vaccines are being developed, but it is too early to say if they will work to prevent infection and be safe. To help develop an effective vaccine, we need to better understand how our immune system naturally protects us from this virus. New vaccines must be rigorously tested for safety and effectiveness through clinical trials.
What vaccine research is underway?
More than 90 potential vaccines are under investigation around the world, and some are being tested for safety in small scale trials on people. These potential vaccines are all attempting to safely induce a robust, long-lasting immune response to the virus in slightly different ways. Finding the right vaccine to use widely will take time. More studies into how the immune system can protect against COVID-19 are urgently needed.
What are the research priorities?
- What, if any, antibody properties protect against the virus, and what proportion of antibody responses are protective?
- What are the roles of immune cells that form part of the early and late immune response in protective immunity?
- What proportion of people have antibodies to the new coronavirus in their bodies and what proportion of people exposed to the virus have an antibody, or cellular, response?
- How can laboratory antibody tests be turned into reliable mass-produced tests for the public?
- How does the immune system’s reaction to the new coronavirus cause collateral damage to the lung and other organs?
- How can we identify people likely to develop the most severe symptoms using biological markers in their bodies?
- What is the role of antiviral drugs, and treatments which manipulate a patient’s immune system?
- How can we reliably test whether COVID-19 patients are infectious?
- How much is the disease spreading from person to person without them showing symptoms?
- How many people who get the new coronavirus have an immune response that will protect them from getting the virus again in the future?
- How long is natural and vaccine immune protection likely to last?
- What parts of our immune response protect against the virus best, how can this knowledge be used to help develop vaccines, and how effective are vaccines at protecting older people?
- Do genetic differences in people’s immune systems influence how they respond to the new coronavirus, and could this knowledge help us develop new drugs to treat it?