We simply know too little about how the immune system counterattacks COVID-19 infections. Upon careful interpretation of the picture that is emerging, emeritus professor Dirk Bellstedt believes there are reasons for optimism for bringing the disease under control. During a recent online Science Café Stellenbosch talk, he explained how complex our immune system is, and that antibodies are only the first line of defence. In the article below he gives an overview of the functioning of the immune system and how it will builld long-term immunity against the SARS-CoV-2 virus.
Prof Dirk U. Bellstedt is emeritus professor of biochemistry at Stellenbosch University.
What do we know about the human immune system?
Our immune system is incredibly complex. In the fight against the SARS-CoV-2 virus, all aspects of immunity need to be taken into account, not just the antibody response.
Many sub-systems of immunity work together to give total immunity. If plan A does not work, then it's plan B and if that does not work, plan C and so on. Different parts of the immune system work together to eliminate diseases. There is cross talk between these mechanisms, making it even more complex. Different types of disease-forming organisms activate different parts of the immune system, and general comparisons from one type to another cannot be made.
The body can recognize about 10 million different shapes and, depending on certain conditions, will make antibodies that recognize the shape of a corona virus or influenza virus or specific bacteria. In immunology all disease-forming organisms are collectively called an antigen.
We now know that the immune system has two basic branches, namely innate immunity and adaptive immunity. Our innate immunity consists of a set of systems which will fight any foreign organism when it enters the body for the first time. Pathogenic organisms want to use the resources of the body, in other words the building blocks and the energy reserves of the body, to multiply themselves. But in the process they damage the body's tissues. Obviously the body does not want to allow this to continue and fights back. It does so by different mechanisms which are collectively called innate immunity. This includes the mechanism of phagocytosis: when big cells gobble up bacteria to kill them inside the white blood cells (phagocytic macrophages and polymorphonuclear cells are white blood cells); another mechanism consists of a system of proteins which drill holes into organisms thereby causing them to burst (the complement system); then there are also natural killer cells that kill virus-infected cells; and lastly there are mechanisms whereby infected cells give signals to cells next to them to warn them of the threat that they may be infected soon (signalling molecules which are proteins called cytokines).
The second branch of the immune system, called adaptive immunity, leads to a specific acquired immune response and can be sub-divided into so-called cell-mediated immunity and humoral immunity. Let's first look at the innate immune response.
The innate immune response
In the case of a first-time infection with COVID-19, the body tries to use innate immunity to stop it. This innate immunity is what could be referred to as an “emergency response" as it takes place without any previous contact with the disease. Because it is easier to measure dissolved substances such as cytokines and antibodies, most published research thus far has focused on this first response mechanism of the immune system. Research on the immune system's response on a cellular level is much more complex and requires specialised equipment and technical expertise. For this reason, the first results have been published on dissolved substances such as cytokines and antibodies and not on cells such as natural killer cells, B cells and T cells.
From other respiratory virus infections such as influenza, we would expect that cytokines and natural killer cells would be the counterattack by innate immunity against an initial COVID-19 infection. Cytokines, which are dissolved proteins, are produced by cells infected with COVID-19. There are many types of cytokines that can be released by infected cells, but in viral infections, the most important are the interferons. The name interferon derives from “interfering with viral replication". Interferons are released by an infected cell and serve as a warning signal to healthy cells to prepare themselves against viral infection. This allows healthy cells to stop getting infected, which is very important in controlling a viral infection.
Simultaneously other cytokines are released which cause inflammation, resulting in swelling to enable dissolved substances and cells to get to the site of infection, in the case of a COVID-19 sufferer, to the lungs and likely to other organs as well. This inflammatory response, the so-called “cytokine storm", is a double-edged sword: if the inflammation is too severe, it blocks the functions of the lung cells in COVID-19 infections, which means that oxygen can no longer be absorbed into the blood, which can be fatal. It is this almost overreaction of the immune system that many COVID-19 infected patients have died from.
Researchers have thus far established that some patients who had severe disease symptoms produced less interferon in comparison to inflammatory cytokines (Hadjadj et al., 2020, Terrier Nature, https://www.nature.com/articles/d41586-020-00502-w). This finding has had important implications: COVID-19 patients showing severe symptoms of respiratory distress are now treated with drugs such as dexamethasone that reduce inflammation, and others that increase interferon production, which significantly improves treatment.
The second branch of the immune system, called adaptive immunity, leads to a specific acquired immune response and can be sub-divided into so-called cell mediated immunity and humoral immunity. Humoral immunity involves the production of antibodies which are proteins, by so-called B-cells that are found in the red-bone marrow at the tips of the sponge-looking long bones, the breast-bone and other areas. These antibodies are then moved throughout the body by the blood stream, also to between the cells into the tissues, but not into cells.
Antibody-based immunity is called humoral immunity, because “humoral" refers to the blood where they are found. B-cells are like factories making antibodies: some factories produce antibodies against a strain of influenza virus that you got last winter; others make antibodies against a tummy bug that you had two months ago; and if you got COVID-19 and recovered from it, you would have factories making antibodies against COVID-19!
These antibodies move through the body by means of the blood circulation in veins and arteries. If we view the cells of the body as houses, and the blood circulation as a set of roads, this would be a good comparison. The antibodies move out of the arteries and veins to move between the cells of the body, in other words they get off the roads and move between the houses. If a virus enters the body, whether in the blood circulation or between the cells, antibodies will bind to the virus particles, tagging them for destruction. Antibodies therefore play a very important role in pointing out the virus and marking it for destruction.
Cell-mediated immunity is mediated by cells that attack the disease-forming organism. These cells also come from the bone marrow, but are transported to the thymus where they mature to become T cells (T for the thymus gland next to your thyroid gland just under your oesophagus). There are two types of T cells: T-cytotoxic cells and T-helper cells. They are abbreviated as Tc and Th. Corona viruses attack the lung cells, penetrates them and hijack the cells from the inside. Instead of the cell performing its normal functions, it changes into a virus-producing factory, thereby exhausting the cell completely. When all the virus particles are assembled inside the cell, it kills the cell, breaks its cell membrane and the virus particles are released allowing them to spread throughout the body to infect new cells.
While the virus is outside of the cells, antibodies can bind to the virus tagging it for destruction, but once inside the cells the virus can escape the antibodies. The Tc cells of cellular immunity can then recognise virus-infected cells and kill them. The body has a reserve of Tc cells that can recognize about ten million different viruses or intracellular organisms, such as many other viruses and tuberculosis bacteria.
When a lung cell becomes infected with the corona virus, Tc immunity against the virus will be induced. Just as each person's immune system has developed B cells to recognize a vast array of different disease-forming organisms, so also has a vast array of Tc cells been developed, which literally sit and wait for an infection to appear to which they can react. Upon infection with SARS-CoV-2, specific Tc cells are activated and multiplied. These Tc cells will destroy the SARS-CoV-2 infected cells before the virus can start to replicate and infect even more cells. Tc cells are like a “bomb squad" that go in and blow up the cells that have been hijacked to become virus-producing factories. Any virus particles that are still outside the cells will be targeted by the antibodies and destroyed. These two branches of the immune system work together to eliminate the virus. However, this results in severe damage to the infected lungs – the tissue then needs to recover and new cells have to be produced in order for the lungs to be able to absorb sufficient oxygen again.
In all infections Th cells assist the Tc cells and the B-cells that make antibodies to perform their functions better: they are the support team for the immune system's special forces and bomb squad. The Th cells also produce cytokines, such as interferon, which assists with the recovery of virus-infected cells. When infected by a virus such as SARS CoV-2, Th and Tc cells could be expected to play a very important role in combatting infections.
However, when these systems have been successfully employed in combating the virus (or any other infective organism for that matter), the body stops producing antibodies, and by implication also the Th and Tc cells, as it would cost the body far too much energy and foodstuff to continue producing them. However, the factories and the bomb squads are not destroyed - those remain as memory B-cells,Th and Tc cells . When a SARS-CoV-2 re-infection occurs, the large numbers of memory B cells,Th and Tc cells can be reactivated, rapidly producing massive amounts of antibodies and more Th and Tc cells. The re-infection can then be overcome far more quickly and efficiently than after the first infection. This is why vaccinations are given to people. A primary immune response follows after vaccination so that a large reserve of memory B cells and Th and Tc cells is built up, and upon infection by the real disease-forming organism, the secondary immune response can kick in much faster and more efficiently overcome the disease.
Recent reports have suggested that immunity does not last against COVID-19. The drop in antibody levels following COVID-19 infection is being interpreted to mean that immunity against COVID-19 is not long lasting (https://theconversation.com/immunity-to-covid-19-may-not-last-this-threatens-a-vaccine-and-herd-immunity-142556). In a recent article, the incidence of anti-COVID-19 antibodies in Spain was determined to be around 5% of the population (Pollán et al., 2020). This was interpreted to mean that immunity to COVID-19 was low and makes only brief mention that cellular immunity may give protection against COVID-19 infection. This may be because the study was specifically aimed at the determination of antibody levels only, but in an overview by Africa's Medical Digest, Medical Brief (https://www.medicalbrief.co.za/archives/covid-19-herd-immunity-may-be-unachievable-spanish-study-of-61000-people/), this was interpreted as “strengthening evidence that a so-called herd immunity to COVID-19 is “unachievable"". Although it is not written as such, by stating that the immunity against COVID-19 is not long lasting it implies that cell mediated immunity by Th and Tc cells also does not last for long. In the Medical Brief article, the cautionary statement made by Pollan et al. (2020) and I quote “However, cellular immunity, which was not evaluated here, might also play a role in protecting against SARS-CoV-2 reinfection." was not considered and shows how quickly misinterpretations can be made. If cell mediated immunity mediated by Th and Tc cells would not last for long, then you could theoretically get a new infection, just as bad as the first, a short while after the first.
In my opinion, when getting re-infected with SARS-CoV-2 or any other disease forming organism for that matter, the memory B-cells and the memory Th and Tc cells should then be re-activated and the levels of antibodies and Th and Tc cells should go up rapidly again. Due to the fact that there are the B cell antibody factories and reserve Th and Tc cells that are ready and waiting, they kick in very quickly, and the fight back against the SARS-CoV-2 or any other disease forming organisms, is very, very rapid and is stronger than the response after the first infection.
In my opinion, the interpretation that the drop in antibody levels following COVID-19 infections means that the total immunity against COVID-19 is not long lasting, is therefore not justified. Such statements are misleading both for doctors and for the general public. Antibody levels drop after any infection once the disease-forming organism has been combatted and killed successfully, in some infections more rapidly than in others, but the memory B-cells and the memory Th and Tc cells are present as in an infection with any other disease-forming organism, and can be activated rapidly again.
Recent research findings on cellular immunity
In recent weeks, results about cellular immunity have finally appeared in the scientific press. Grifoni et al. (2020) compared the cellular immunity against SARS-CoV-2 of 20 recovered patients that had been infected 20 to 35 days before in comparison to 20 uninfected individuals (samples collected between 2015 and 2018). Most of the recovered patients possessed antibodies against parts of the SARS CoV-2 virus in comparison to negative controls. Cellular immunity assessments of the recovered patients showed a high level of responses of Th and Tc cells against SARS-CoV-2. What was interesting was that a certain percentage of the uninfected individuals also showed cellular immunity against SARS-CoV-2. This was interpreted to mean that they possessed immunity possibly as a result of previous infections by mild strains of corona viruses.
In a study by Le Bert et al. (2020) both Th and Tc cellular immunity was assessed. In 36 people that had recently recovered from COVID-19 they could show that Th and Tc cellular immunity, that recognized the virus, was significantly raised. This would limit spread and multiplication of the virus after infection. They then analysed patients that had survived the first SARS CoV-1 outbreak in 2003 and determined that even 17 years later they still possessed Th and Tc cells that recognized SARS CoV-2. The researchers interpreted this to mean that long lasting immunity against corona viruses therefore certainly can be achieved.
Finally, the researchers assessed the cellular immunity of individuals that were not infected with SARS CoV-1 or SARS CoV-2 and found that over 50% possessed cellular immunity against both of these variants of corona virus as well as corona virus types that produce common cold symptoms. Both studies show firstly that cellular immunity is definitely induced by infection, the second study showed that the cellular immunity is long lasting and both studies showed that a percentage of the population (in Singapore in this instance) possesses immunity to SARS CoV-2. This would explain why some individuals only get very mild infections without symptoms. These individuals already have memory cells that will overcome infections very rapidly. These studies present conclusive evidence that SARS CoV-2 induces cellular immunity in infected patients.
It therefore appears that the majority of individuals will be perfectly capable of giving a good adaptive immune response in the form of antibodies and Th and Tc cells after a SARS-CoV-2infection including a secondary immune response following a re-infection. If the immune system was not able to build up adaptive immunity with memory, there would be no recoveries from the disease. However, we see that there are many recoveries now, so the bulk of the human population must be capable of developing adaptive immunity against SARS-CoV-2.
This is how the immune system has protected all vertebrates over millions of years, from fishes to mammals, and being infected with this virus is just another disease-forming organism once again. However, this does not mean COVID-19 is not a severe disease. COVID-19 has a distinctly higher mortality rate than flu, and the damage caused by a COVID-19 infection appears to be severe. Only time will tell whether individuals that have been infected will suffer from long-term effects. Why there is perhaps not fast and full recovery and fatigue after infection is because of the damage the virus infection has caused, not because of a lack of adaptive immunity. Many of the body's own cells would have been killed in the lungs and other tissues and they have to regenerate and this costs the body a lot of energy and foodstuffs, including proteins and vitamins. It appears that the damage caused by a COVID-19 infection is far greater than say that caused by a normal flu infection. Not only are lung cells injured and killed but also cells of the nervous system and other organs are, so recovery from a COVID-19 infection may take much longer.
Finding a vaccine
A vaccine will contain "parts" of the virus and not the whole virus because if it was introduced as a vaccine it would cause infection and disease. The disease-forming ability of the virus needs to be removed, but a vaccine must still induce adaptive immunity that specifically identifies COVID-19 and induce the formation of antibodies and activate Th and Tc cells. This is not so easy to achieve.
Often a vaccine therefore consists of non-infective “parts" of the virus. The "parts" of the virus can be its proteins, but if those were injected, only antibodies would be made against them, because the immune system does not recognize those free proteins as occurring inside cells and the Tc cells are not activated to multiply. Such a vaccine would also be ineffective because this would not stop the virus from getting into the cells and using the cells as virus-producing factories. This is where DNA vaccines, about which a lot is currently written in the press, can be valuable. After being injected with a DNA vaccine, the vaccine DNA penetrates the cells and temporarily causes those cells to produce virus proteins. The Th and Tc cells then recognize these cells as though they were virally infected cells and the body starts multiplying the Th and Tc cells that can recognize virally infected cells. If a SARS-CoV-2infection would occur after this, they would immediately kill the first SARS-CoV-2 infected cell and stop the viral multiplication.
A vaccine that results in antibody production by B cells and activation of Th and Tc cells would therefore be an effective vaccine. The vaccines that are currently being developed are aimed at inducing both. Thus, the vaccine would mimic a natural infection, and induce antibody production and production of Th and Tc cells, but not cause disease. This is precisely the objective of any vaccine, to give long-lasting protection, but does not induce disease.
Adaptive immunity against a vaccine could be very effective and long lasting. It is not the SARS-CoV-2 virus which decides whether a vaccine would work well, it is the actual design of the vaccine, and whether it activates both B cells and Tc cells, which will determine how effective it will be. It is refreshing to see that journalists are now gaining insights into the complexities of the immune system (https://elemental.medium.com/what-to-make-of-research-suggesting-immunity-to-covid-19-is-short-lived-8f0a92ecce51) and are now writing, and I quote: “Over the course of the pandemic, many science experts and communicators (myself included) have written about immunity solely as it relates to antibodies, but the reality is actually much more complex than that". In the title of that article the author warns “Be careful not to jump to conclusions" and it is precisely that which is needed at the moment, not articles that induce fear and anxiety in readers who are already stressed by the pandemic and lockdowns.
This is very complex because of the complexity of the immune system, but it is this complexity that has saved all vertebrates over millions of years. The induction of adaptive immunity either follows a natural infection of SARS-CoV-2 or can be induced by a vaccine. It is the adaptive immune response that gives long-lasting immunity, and if we refer to this in the context of the human population, it gives herd immunity. The term "herd immunity" is used to describe which percentage of the population possesses immunity, in other words has shown this secondary adaptive immune response, and typically, the disease will not spread once levels of 80% herd immunity have been reached. The chain of infection is broken when there are literally too many people that have adaptive immunity, and therefore can no longer be infected, for the disease to be able to jump from one person to the next. At present, limiting the spread is only a temporary measure, it is this control through vaccination which will result in herd immunity that is required to finally bring the disease under control.
The recently acquired knowledge that both arms of the adaptive immune response, antibody formation and cellular immunity in the form of Th and Tc cells, can be induced by natural infection and by vaccination, gives us hope that this is achievable.
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