- New studies on COVID-19 immune response are advancing our understanding of this disease in both symptomatic and asymptomatic cases.
- There is increasing evidence that the differing severity of COVID-19 between individuals is a consequence of a diverse range of immune responses to the virus.
- There is some evidence that antibodies can be detected in recovered patients for up to 2–3 months after symptoms.
- A role for the adaptive cellular immune system, especially T cells, in responding to SARS-CoV-2 infection is emerging.
- There is some evidence reporting T cell reactivity against SARS-CoV-2 in people that have not been previously exposed to this virus. The source and duration of this immunity is unknown.
- A better understanding of the antibody and T cell response to SARS-CoV-2 is key for vaccine development.
- This is part of our rapid response content on COVID-19. The article will be updated as the research progresses. You can view all our reporting on this topic under COVID-19.
In early June the Scientific Advisory Group for Emergencies (SAGE) discussed the latest evidence on SARS-CoV-2 immunology and considered the creation of a UK Coronavirus Immunology Consortium. The proposed role of this Consortium was to coordinate and advance UK-based research on COVID-19 immunity, focusing on five questions:
- The immune system’s role in determining differences between individuals in their susceptibility to infection.
- How the immune system generates protection against the virus, its duration and effectiveness.
- How the immune response contributes to the disease and how therapies might target this.
- Whether previous infection from other coronaviruses confers protection against COVID-19 or contributes to it.
- If SARS-CoV-2 can evade the immune system’s response.
Some answers are emerging. New research is shedding light on COVID-19 immunity and there is increasing evidence that the different levels of severity observed in COVID-19 patients are a consequence of a diverse range of immune responses to the virus. This article will focus on the current understanding of the role of innate and adaptive immunity in COVID-19. This is directly relevant to the development of new COVID-19 therapies and vaccines.
Innate immunity consists of a series of non-specific mechanisms that prevents viruses and bacteria (pathogens) from invading the body. It includes physical barriers, such as the skin, and the cell linings of internal body parts, such as airways and lungs. The innate immune system also consists of several types of specialised cells and signalling chemicals.
Adaptive immunity (also known as ‘acquired’ immunity) describes how the body builds immunological memory – so that if the person is exposed to the same infection again the body’s response is enhanced. This is the basis for immunisation with vaccines. Key features of this adaptive response are that it is specific for the structures on a specific pathogen and that immune memory facilitates an improved response on subsequent encounters. It involves antibodies that bind specifically to the pathogen (produced by a type of white blood cell called B cells), and T cells (another type of white blood cell) that kill infected cells. This type of immunity can be strong or weak, short- or long-lived, and this is a complex result of several factors. It can take up to 3 weeks to develop this type of immunity.
The innate and adaptive immune systems interact with each other in various ways.
Innate immune response
The innate immune system is the ‘first line of defence’ against viruses and bacteria (pathogens). Understanding the innate immune response to SARS-CoV-2 infection can inform the development of COVID-19 therapies. Specialised cells and substances are key to the innate immune response and researchers have found that the levels of these cells and chemicals change after COVID-19 infection.
Changes to cells of the innate immune system
Changes in the numbers of several types of specialised immune cells have been linked to having more severe COVID-19 disease. Dendritic cells are an important cell type of the innate immune system. They pick up and show antigens (foreign proteins) to T cells (part of the adaptive immune system). This activates the T cells, which then start killing any virally-infected cells displaying the same protein. Some studies have reported abnormalities in the numbers of dendritic cells in people with SARS-CoV-2 infection. This could explain why abnormal numbers of T cells are observed in COVID-19 patients (see below), however, more research is needed to better understand this. So far, there is no evidence suggesting that SARS-CoV-2 directly attacks innate immune cells.
Changes to signalling chemicals in the innate immune system
Several studies have found that there is an abnormal release of immune signalling chemicals after SARS-CoV-2 infection. This includes high levels of chemicals called cytokines that cause inflammation. Cytokine release can cause a widespread inflammatory response in the entire body. Activation of the complement system, another signalling mechanism that is part of the innate immune system, may also lead to the abnormal inflammatory response seen in severe COVID-19. COVID-19 treatments targeting cytokines and parts of the complement system are currently undergoing clinical trials.
Innate immune response in asymptomatic cases
Some people can be infected with SARS-CoV-2 and have no symptoms (asymptomatic). So far, few studies have looked at the innate immune response that occurs in asymptomatic cases. According to the data available, infected people who are asymptomatic show a reduced inflammatory response and an increase in natural killer cells, a subgroup of cells in the innate immune system able to recognise and kill virally infected cells.
Taken together, this evidence suggests that defects in the normal innate immune response to infections may have at least a partial role in COVID-19 severity.
Adaptive immune response
Antibodies are produced by B cells in one of two responses:
- The primary immune response is the first response triggered by exposure to a pathogen. Immature (naïve) B cells are stimulated by antigens (proteins of the pathogen seen as foreign to the body), become activated, and start producing antibodies that stick to these antigens. There will be an initial surge of antibodies and then, with time, these antibody levels will decrease as the infection is cleared.
- The secondary immune response occurs during second and subsequent exposures to the same pathogen. Memory B cells are able to recognise the antigens that they have been previously exposed to and start producing antibodies in higher quantities than during the primary response.
B cells produce five classes of antibodies (also known as immunoglobulin or Ig). Two important ones are:
- IgM: the first antibodies produced by naïve B cells during the primary immune response. They are detected at similar levels during the secondary immune response.
- IgG: the major class of antibodies in the blood. They are produced during the primary immune response after IgM and their level increases substantially during the secondary response.
Making SARS-CoV-2 antibodies
Most people infected with SARS-CoV-2 produce antibodies. There is some evidence that higher antibody levels are found in people with more severe disease. Asymptomatic people can produce antibodies as well, but in much lower quantities.
What antibodies do people make when they have COVID-19?
COVID-19 patients produce a diverse range of antibodies targeting different parts of the virus. Some of these antibodies are binding antibodies (they bind to the virus and activate parts of the immune system to enhance the body’s response) and some are neutralising antibodies (they are able to bind and stop the virus). Neutralising SARS-CoV-2 antibodies target different parts of the spike protein, a protein that is found on the virus’s surface. Ensuring the production of neutralising antibodies is key to developing effective vaccines against COVID-19. Another factor to consider is the duration of the antibody response.
How long do antibodies last?
There is some evidence about how long SARS-CoV-2 antibodies persist in the body after an infection. The first report on SARS-CoV-2 antibody levels in 34 hospitalised patients found IgG and IgM up to 6–7 weeks after symptoms began. There was some variability between individuals in how much IgM could be detected by 5 weeks following symptoms. Preliminary analysis (not peer-reviewed) on recovered patients confirmed these individual differences in antibody levels in the 7-week period after infection. A recent study focusing on asymptomatic cases showed that 40% of them have no detectable IgG antibodies within 2–3 months of their infection. Another study (not peer-reviewed) on asymptomatic and mild COVID-19 patients also found that levels of IgG and IgM antibodies decrease in asymptomatic cases after 2 months, but they remain at a more stable level in patients with mild disease. The rapid decay of SARS-CoV-2 antibodies was also reported in 34 patients with mild COVID-19 who were monitored for 4 months. One study focused on the presence of neutralising antibodies and showed that a subset of those are still present in the blood more than 1 month after symptoms began. According to the evidence available so far, antibody levels against SARS-CoV-2 decline faster than those of SARS-CoV.
The primary immune response is characterised by rapidly decreasing antibody levels, while the secondary immune response is characterised by high IgG levels. Currently, no data is available on SARS-CoV-2 secondary immune response and its ability to confer protection against a second SARS-CoV-2 infection.
The role of adaptive cellular immunity in COVID-19
An increasing number of studies are revealing the importance of adaptive cellular immunity (involving B cells and T cells) against SARS-CoV-2 infection. In particular, the role of T cells is emerging. Patients with moderate or severe COVID-19 have reduced levels of T cells in their blood, while milder cases have normal or slightly higher T cell counts. Although some research shows that low levels of T cells in the blood are linked with high inflammatory cytokine levels, the cause and impact of this reduction in T cell numbers needs to be clarified by further studies. A recent study (not peer-reviewed) found that severe cases have a low number of T cells, but a high number of antibodies, suggesting divergent T and B cell responses in those cases. In depth characterisation of the immune response in 125 COVID-19 patients identified three different immune profiles of hospitalised patients, with different levels of B and T cells associated with disease severity. Another similar study performed on a smaller sample confirmed a specific immune profile of severe COVID-19 cases. The role of the adaptive cellular immune system in COVID-19 is another key aspect to consider while developing effective vaccines. According to the evidence available, an ideal candidate should not only be able to evoke an antibody response, but also activate T cells.
Pre-existing immunity to SARS-CoV-2?
There is increasing evidence of T cell reactivity against SARS-CoV-2 in people that have not yet been exposed to this particular virus. Preliminary evidence shows that SARS-CoV-2 can cause a T cell response without antibody production. A similar finding has been described in a study (not peer-reviewed) on T cell immunity in recovered individuals with asymptomatic or mild COVID-19. The source, duration and relevance for COVID-19 of this T cell reactivity is still unknown. One hypothesis is that previous infection from ‘common cold’ coronaviruses could be responsible for the development of T cell immunity, providing a level of protection against SARS-CoV-2. While more research is needed to confirm this, one study showed that patients who had and recovered from SARS in 2003 have long-lasting memory T cells. These cells recognise SARS-CoV (the original SARS virus) 17 years after infection. In addition, they are also able to recognise SARS-CoV-2, strengthening the idea that previous coronavirus infections may lead to some protection. Therefore, ensuring the production of these ‘memory’ T cells could be another crucial aspect of a successful COVID-19 vaccine candidate.
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