The coronavirus disease 2019 (COVID-19) pandemic has affected hundreds of millions of people over the world, with more than 4.5 million deaths. The most striking part of the outbreak is the fact that a majority of those infected show mild or no symptoms, while a significant minority develop severe or critical disease.
Several studies have explored the immunological responses to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), seeking to understand what drives the severity of the disease and what the risk factors are. These provide an overview of the innate and adaptive immune responses.
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Innate immunity to the virus
Cytokines are cellular signaling molecules that mediate many biological and immunological actions. One such is interleukin-6 (IL-6), a pleiotropic cytokine that mediates both innate and adaptive immunity. It helps to direct the differentiation of immune cells, as well as warn of invading pathogens and of ischemic damage.
IL-6 also mediates the growth of plasma cells and their generation of immunoglobulin antibodies. The high levels of IL-6 expression seen in autoimmune or autoinflammatory disorders indicate its role in these conditions as well. Similarly, in COVID-19, IL-6 is expressed at sustained high levels following the entry of the virus into the lung epithelium.
SARS-CoV-2 activates alveolar and circulating macrophages, resulting in a cytokine storm as a result of high IL-6 secretion. This in turn leads to endothelial cell injury and dysfunction, hyper-permeable capillaries, and the clogging of the alveoli with exudative fluid and cells. This is the underlying mechanism of acute respiratory distress syndrome (ARDS).
This has suggested the use of tocilizumab, an IL-6 receptor inhibitor monoclonal antibody, to modulate the severity of ARDS.
Complement activation
Multiple symptoms of severe COVID-19 pneumonia could be due to the activation of complement at a systemic level. They include ARDS and hypercoagulability. The elevated IL-6 levels in these pneumonia patients activate complement, via the C5a-C5a receptor (C5aR) axis.
With symptom severity, all inflammatory markers also progressively rise, from asymptomatic to critical COVID-19. It may be that multiple pathways of complement activation are involved, with the classical and alternative pathways being linked to the most intense phenotype. These pathways are activated by IgG-virus immune complexes.
Inhibition of the C5a/C5aR1 axis may block inflammatory marker release and lung injury, thus producing benefits in these patients. Moreover, patients with COVID-19 pneumonia often develop clotting phenomena due to intense activation of the complement system. This could therefore also be prevented by blocking complement activation.
Another complement activation pathway could be responsible for the occurrence of ARDS in patients infected with this virus. Here, the C1 esterase inhibitor (C1-INH) acts via multiple pathways to regulate the intrinsic complement pathway. It could be useful in treating COVID-19 pneumonia patients, suppressing the crosstalk between the innate immunity and coagulation pathways.
Adaptive immunity - antibodies
This arm of the immune response deals with the coordinated B and T cell response to the virus. Early antibody responses include IgM and IgA, with further IgG secretion within 10 days. This immune response is considered to be protective against infection with the virus as well as provide high-affinity IgG memory B cells.
Antibodies to the receptor-binding domain (RBD) are important in the protective response to the virus and are a favorable prognostic marker. Antibodies that are effective at preventing infection are those that target the RBD and bind the spike trimer.
Initially, T follicular cells activate naïve B cells, which mature into activated B cells. These give rise to B memory cells as well as IgG-generating cells or plasmablasts. These changes occur in the germinal centers of the follicles. Plasmablasts have a short lifespan, which ends this phase of the antibody response. thereafter, reinfection reactivates the memory B cells as well as long-lived plasma cells in the bone marrow, causing a specific antibody response to the RBD.
T cell memory retains the ability to respond to the antigens of the virus, resulting in direct cytotoxic T cell activity to clear the virus as well as promoting B cell responses.
Nonetheless, antibody titers vary between individuals and peak between 50-60 days. They may remain at protective levels for up to 10 months. Too-high IgG antibody responses to the virus may result in severe cytokine release that may lead to systemic inflammation, multi-organ dysfunction, and even death.
Adaptive immunity – T cells
Spike-targeting CD4 T cells are found in over 80% of individuals with SARS-CoV-2 infection, but also in the blood of over one in three healthy donors. In the latter case, these cells reacted to the C-terminal domain epitopes of the spike protein. These cells also cross-react with the spike proteins of human endemic coronaviruses 229E and OC43.
This may mean that the reactive T cells found in these donors were elicited by prior seasonal coronavirus infection. If so, they may explain why children and young adults are less prone to develop a symptomatic infection. This finding is in contrast to neutralizing antibodies to the human coronavirus, that are highly specific to the eliciting strain. Thus, CD4 T cells are key to an effective and durable cross-reactive response to human coronavirus infections, including SARS-CoV-2.
Interferon-alpha (IFN-α) responses are found in most COVID-19 patients. Patients with moderate symptoms who recover successfully show several types of CD4 and CD8 effector T cells as well as natural killer cells, the latter interacting with the FcγR IIIb receptors.
T cells also react to many other viral proteins than the spike, namely, the membrane (M) and nucleoprotein (N) antigens in over a third and almost half of patients, respectively. Not only does this suggest a profile that characterizes protective immunity, but may mean that future vaccines must include additional immunodominant T cell-reactive peptides than just the spike protein.
Conversely, the severe disease was associated with an abnormally strong and sustained immune response. The persistent secretion of IFN-α caused T cell exhaustion and an aberrant T cell receptor repertoire, along with a broad expansion of T cells without NK cell activation. The latter is an important sign of a failure to clear the virus via antibody-dependent cell-mediated cytotoxicity (ADCC).
The rapid increase in the number of cells secreting IFN-α in patients with COVID-19 pneumonia indicates that this agent should be avoided in these cases.
Patients with the highest level of disease severity have the highest CD4 and CD8 T cell response to multiple SARS-CoV-2 antigens. However, both central and effector memory CD8 T cells, reactive to non-spike proteins, are identified in COVID-19 patients. These are probably cross-reactive and indicate the presence of durable immunity.
Perhaps these cells are resident in the respiratory tract to encounter newly invading SARS-CoV-2 viruses, rapidly expanding to trigger an effective immune response. While antibody production can ensure rapidly sterilizing immunity on encountering an antigen, with T cells the antigen has to be presented and the memory response kicked off to begin the process of virus elimination. This also implies that not only is the resulting disease phenotype varied, but individuals without symptomatic infection may carry and transmit the virus until it is cleared by cellular and humoral responses.
Immunocompromised individuals
Some scientists have found a link between the risk of severe disease with human leukocyte antigen (HLA) DQB1*06. This may help detect the presence of immunocompromised people who are unable to cope with the virus but are super-spreaders at risk for poor immune response to the virus and the vaccine.
In the immunocompromised individual, such as those on chemotherapy or immunosuppressive medication, viral shedding may continue for up to two months following infection. A fourth of kidney transplant patients also showed persistent viral shedding though they also developed antibodies that lasted for at least two months. The presence of virus particles in the blood indicates a poor prognosis.
Durability of immunity
A real-time assessment of adaptive immune responses in a sample of patients showed that anti-spike IgG and anti-RBD IgG were detectable at five months after infection. However, no smooth curve could be obtained, showing that the response to SARS-CoV-2 is diverse.
Importantly, memory B cell responses and memory central T cells persisted for an indefinite time, seeming to increase at up to five months after the infection. If this is confirmed, it would mean that the virus elicits a very durable and specific B cell and IgG response. Some viruses, such as the influenza H1N1 virus of 1918, and the smallpox vaccine 60 years ago, continue to elicit B memory cells up to 90 years after infection.
New therapies must be developed based on these findings so that the pandemic can be controlled. Such studies are the best way to understand the immunology of SARS-CoV-2 and to develop better vaccines.
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Further Reading
New SARS-CoV-2 variant JN.1 shows increased transmissibility and immune resistance