SARS-CoV-2, new and familiar.

SARS-CoV-2, the coronavirus that is the cause of COVID-19, is new but also familiar. What we have seen in the past 3 years is virology and immunology in real time unfolding.

SARS-CoV-2 has behaved much as we expected it to behave. The route of infection, the cells its infects, its transmission, replication, in large part its evolutionary path, its selection criteria, the epidemiology, the way the immune system detects it and responds, the antibodies that bind it and wane, the T cell response that stays, the reinfections, how to detect it, and how to target it with a vaccine, did not hold much mystery. We knew much, expected most, but certainly not everything was and is understood!

Let´s start with some statements to avoid confusion:

1. Pathogens, such as viruses, parasites, fungi, or bacteria, can cause disease and kill people
2. Getting infected with a pathogen is never "good"
3. Infections can result in damage, including to organs and immunity
4. There are many poorly understood ways infections can cause problems
5. The result of an infection is person-dependent and can range from asymptomatic to severe illness and death
6. Endemic does not mean mild or "nothing to worry about"​
7. Seasonal also does not mean mild, nor does it exclude transmission at other times.

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We know a lot about viruses and immunity. What we have seen happening in the past three years is infection and immunity in real time. Not only that, but we have also seen much of what was predicted from decades of study of viruses and the immune system. SARS-CoV-2 has confirmed a lot of the things we know. That does not mean there were totally no surprises, it does not mean we should not have studied it and it certainly does not mean we know all there is to know. There are major gaps in some things. But overall, SARS-CoV-2 and the immune response were textbook.

This will need explanation and quantification.

Let´s start with the virus. Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2), the cause of coronavirus disease 2019 (COVID-19) is a strain of coronavirus. Coronaviruses are not new; they are enveloped positive-sense single-stranded RNA viruses with a large genome. Many strains are found in many hosts. Hosts include bats, farm animals, pets and yes, humans. The name, corona, comes from the Latin for crown, thanks to their distinctive crown-like look.

The original observation, the discovery of human coronaviruses, happened in 1960 by June Almeida and David Tyrrell, after developing novel culture methods enabling the propagation of this respiratory virus. That is over 60 years ago, and much has been discovered since. But the earliest descriptions of coronavirus disease are over 100 years ago, in the 1920s, of respiratory disease in chickens, infectious bronchitis virus (IBV).

The first corona cold virus was named 229E, OC43 followed with NL63 and HKU1 later discoveries, and together making up the 4 human coronaviruses that give common colds. However, as stated above, do not think too lightly of these viruses. You are exposed in early life to these, when your immune system makes a strong innate response (interferons, IFNs) protecting most of us against these viruses. This will enable the generation of memory B and T cells over time, providing life-long immune protection. Yet, as so often, in old age many systems start to fail. Our immune system is no exception and the risk these viruses cause can be life threatening. These coronaviruses are seasonal and have characteristic annual waves.
Although common, its contribution to mortality in children and the elderly is much less known. Much of their molecular workings, the proteins they use, are known. That includes Spike proteins, critical for all these viruses to gain cell entry. The Spike of NL63 has the specificity for our host receptor ACE2. Their detection and identification, yes, using PCR.
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Coronavirus infection results in hijacking the host cell protein and metabolic machinery, eventually causing cell stress and cell death. Hence, HCoV-229E, -OC43, -NL63, and -HKU1 are considered pathogens, causing upper, and lower, respiratory tract disease and responsible for up to 15%–30% of common colds in adults. In addition, enteric coronaviruses also exist and can cause gastroenteritis and intestinal infections.

Of course, most well-known are the SARS and MERS coronavirus outbreaks in 2002 and 2013. These provided a renewed impulse to more detailed investigations into coronaviruses, their pathophysiology, and the design of the first vaccines. In other words, a lot of knowledge about how these viruses operate. Do we know everything? No, of course not. Is every coronavirus the same? Also not, each has their own characteristics. But, in broad terms, the scientific community, especially virologists, know a lot about viruses and coronaviruses.

SARS-CoV-2 is hence not an unknown entity. i.e. it is a coronavirus. We know a lot about coronaviruses. This general knowledge has been held up very well. The virus mutates, some recombination is possible, it has abilities to reduce immune detection (reduced expression of HLA-1, reduction of detection by innate receptors and IFN production), but it does not escape detection. It does not go latent (long-term infections in immunocompromised does happen), it does not integrate in our genome, it does not attack or kill B or T cells, etc. Yet, that does not mean it was not dangerous, or that we knew everything.

​It was new on another level.

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So, SARS-CoV-2 is not an exception compared with other coronaviruses.
Its infection in children is often, but certainly not always, mild. IFN responses are strong and the adaptive response is not relied upon as much, but certainly starts to participate and will provide, over several exposures, good immunity. Infection of vulnerable people, those with reduced immune responses, can have severe consequences. These include the elderly. But with an immunologically new virus, we are all vulnerable.

SARS-CoV-2 caused many victims, not only via mortality but also long-term damage (LongCOVID) to our tissues and systems.

Some explanation required again. People are diverse, a complex interplay between the host, its health status, much is genetic, and the pathogen can give wide-ranging outcomes. These include long-term problems, associated with many infections, referred to as "idiopathic" or in plain English; "we are clueless what causes it". They are the consequence of the host - pathogen interaction and a variable that is not understood. This is a knowledge gap, but not SARS-CoV-2 specific. However, we are now very much confronted with a new wave of long-term consequences, due to the COVID-19 pandemic, and it would be great if progress can be made to understand this much better, identify the risk factors and, in the best case, find treatments if not cures.

But be aware. This is a complex issue, which takes time and resources. Also be aware this is not SARS-CoV-2-specific. SARS-CoV-2 has no magical properties, does not do something particularly scary that other pathogens, especially coronaviruses do not do. Sure, we only recently could establish, it was suspected for a long time, that EBV infection can indeed cause multiple sclerosis; that measles can wipe out some of your B cell memory cells. i.e. we discover new aspects; we are better and better at doing this with recent technologies. There are things about SARS-CoV-2 we do not know much about. But, for most things it is a textbook virus. Hence, it is better not to get infected, but, after obtaining immunity and not having underlying conditions that make you particularly vulnerable, infection will be overcome, mostly without additional consequences. Again, like most infections. Every autumn and winter, you will be infected with many pathogenic viruses. SARS-CoV-2 will highly likely become one of them. It is also true that from all the other viruses and infections of causes we do not know everything there either.



Yet, all those victims and the substantial amounts of long-term consequences,  SARS-CoV-2 is a new virus, a new virus to our immune systems.

Although I have argued that we know a lot about SARS-CoV-2, that knowledge is in books, papers, the internet and in the collective brains of scientists. Our immune system does not have that knowledge. Yet, it is not clueless either. This needs again more explanation.

Our innate system has many receptors that are inherited from generation to generation and can detect and recognize conserved elements of pathogens. This, conserved elements, means structures our own cells do not make. Some sugar or fat groups, the way DNA is packaged or the presence of RNA where it should not be. Our innate system, although never, ever having seen SARS-CoV-2 before, will detect it and, importantly, will identify it as an RNA virus we need to deal with as quickly as possible.

Depending on the dose you received, your age, your genes, you may even deal with the SARS-CoV-2 infection and be asymptomatic. For the vast majority, it will require more reaction. This is normal for these types of viruses. They are extremely fast and can overwhelm our innate immune system. Also, with the 4 common cold HCoVs, you experience symptoms, and you need more than your innate system.

Here is where you need the adaptive part of your immune system. Textbooks will have a strict divide of innate and adaptive immunity. That is for educational purposes, the two arms are very intertwined. Of course, B cells (that make antibodies) and T cells play their specific role in fighting infection. But they also support and strengthen the cells of the innate system. e.g., antibodies bind to the virus, making it easier to detect and for cells to "eat" it. Both B and T cells do not make use of inherited receptors but uniquely make new ones. Each T or B cell has generated a unique receptor, collectively the billions of cells will really be able to recognize anything, no matter how new or strange.
T cells will boost those eating cells (macrophages) so they work harder en better. Of course, B cells also make neutralizing antibodies, these can even prevent infection. Other antibodies target infected cells for cell death (ADCC, NK cells). The generation of antibodies is a complex process we know a great deal about, and ideally also requires the help of T cells. T cells in their turn can kill infected cells, thereby limiting the spread of the virus. All this is indeed textbook.

It is also textbook that we can prime the adaptive response using vaccines. That Spike protein is important, it is the only protein against which neutralization of infection is possible. This is the reason that vaccination was considered so important. To allow a much improved innate and adaptive response against infection with SARS-CoV-2. Without this, some people would be asymptomatic, several would get severely ill, and some would die. With vaccine-induced immunity, the same B and T cells acquired after infection, this disease spectrum shifts towards much less severe disease and mortality. The data shows, textbook, that it worked. 

No, this does not mean that nobody gets severely ill, remember that there are always some people susceptible: due to disease, medicine, old age, or genetics, and we have been at the beginning of this immunity build up. It just happens very much less and will end up being in line with other infections. It is just that SARS-CoV-2 is studied in such detail that we may not realize there are many other infections doing something remarkably similar but are not assessed at the same level of detail and many therefore appear less frequently.

No, it also does not mean you will not get infected. This is something that is difficult for many people to understand. You will be regularly infected. That is again, textbook. SARS-CoV-2 behaves just like other coronaviruses, very much like other respiratory viruses: it must be quick and adapt to our immune responses. Every virus will have to infect to replicate and remain in the population. SARS-CoV-2 is not different. It has the main selection criteria to do so: speed, location, and mutations. Speed is important: it will infect and start replicating very vastly, with, like other respiratory viruses, symptoms of inflammation within days. This contrasts with measle virus, which has an incubation time of a good week (8-10 days to complete its life cycle of replication deep inside our bodies). Once immunity has been gained, it will respond very swiftly, well within a week, so you may not notice that you have been infected, and viral load has remained low, without giving any symptoms. For respiratory viruses, your response may be very quick, quick enough to avoid viral dissemination from the upper airways to the lungs or other organs (chance of severe disease), but the infection will have taken hold, just on the surfaces of your upper respiratory tract and you can transmit viable new virus particles.
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Secondly, it is an RNA virus. Mutational space is not as broad as influenza, which relies on two proteins, NA, and HA, but much more than measles virus. Initially, the virus adapted to us humans, beter binding to ACE2, infection, speed, and some interference with innate responses (all predicted). But there will be an optimum reached. The gear change in infection and speed of the Delta variant was an unexpected one; requiring a third vaccine dose to ensure more optimal immune responses. Secondly is the mutation selection to reduce neutralizing antibodies, a difference with measles that has much less space to do so. This will give the virus more potential hosts and time to infect. This cannot be stopped, although the mutational space here will subdue a bit as well. There are areas within Spike that are not easy to alter due to functional and structural needs. It also cannot be stopped due to the nature of our own response: antibodies wane. They always do, no matter the vaccine or infection. On the short-term vaccines can prevent infection, reduce the chance over the mid-term, but they cannot stop it. You need constant vast amounts of antibodies to prevent respiratory virus infection and transmission. But you can prevent severe disease.

Because SARS-CoV-2 was new to our bodies: the immune response can be severe, such as cytokine storms. The response compares here well with a new strain of influenza. The acute response can be damaging to self in severe cases. Similarly, a temporal sensitivity to co-infections, bacteria, or fungi, can be seen. This is again to be expected to the naive immune status of adults, never having seen SARS-CoV-2 before.

There is yet another layer of complexity, mucosal immunity. Although B cells cannot continue to pump out substantial amounts of antibodies systemically, if all B cells would do that your blood with be a thick syrup, at the body´s surfaces, they can do this for much longer. But the cells that do this, plasma cells, will also die. There are specialized T cells, which can integrate at the site of infection, called tissue resident memory T (Trm) cells that can give immediate protection against infection. Without memory T and B cells, without immunity, the virus can be too quick to control and reach all organs in the body, with severe damage and pathology, therefore.
This means that hybrid immunity, vaccination, and infection, offers the best protection against infection, around 8 months. The 8 months infection protection is not dissimilar to our protection against other respiratory HCoVs, and, once immunity is synchronized, dictates a more seasonal pattern of SARS-CoV-2 infection. Again, that is textbook, but does not mean it cannot change from year to year, e.g., the RSV wave was in the summer of 2022, not that it cannot transmit out of season! We monitor SARS-CoV-2 a lot, e.g., via wastewater, which we do not do for other infections, which are around throughout the year, just at low transmission levels. 

There was no seasonal pattern for SARS-CoV-2; it was new for our immune systems. It could infect so many people with so much ease, it did not need more optimal conditions for infection. Yet, there was a gap between the March/April outbreak, and the subsequent autumn outbreak, the second peak caused by Alpha variant, causing many victims prior to vaccine roll out. There was a summer peak caused by Delta, with relative limited impact in counties' already with a high vaccination grade, but severe in others (e.g., India). Subsequently, there was the Omicron outbreak at the end of 2022, followed by rapid selection of subvariants later in 2022, such as BA.5. It has remained quiet since, in part due to less testing. Although wastewater analysis shows more distinct peaks, hospital records show the huge clinical impact of immunity.

In summary, SARS-CoV-2 is not an unfamiliar virus as far as our knowledge is concerned. It was a new virus for our immune system, but also that phase has passed. SARS-CoV-2 is adopting to a seasonal pattern, from the start in 2020, but due to its immune-novelty, and measures taken, that pattern is a bit more distorted yet. SARS-CoV-2 has gone endemic, we will be regularly infected. As we had written in 2020. It is important to note that "endemic" or "seasonal" does not imply dangerous or mild. It is and remains a pathogen that can cause damage and death. Seasonal also does not imply it cannot transmit out of season, the same as RSV, Influenza, etc.

In many aspects the virus and its response to it have been textbook. This also concerns its detection (PCR, antigen tests), its countermeasures (distancing, masks, testing, quarantine). For any following pandemic, all will be part of the playbook. 

Infections will remain; the virus will mutate, and our antibodies will wane. Every infection will boost immunity, new epitopes will become part of our immune memory: we will immunologically mature. Infection is unlikely every year, but every 3-4 years is quite possible, with asymptomatic or mild disease the most likely outcomes.
We have gained long-term, immunological memory to the virus, the same as we do against other pathogens. This was achieved with vaccination and infection. Continued infection may still strengthen this further. For other respiratory infections, we would have been infected several times before we reach adulthood. Adults now exposed to SARS-CoV-2 have not had the opportunity to build up immunity from an early age, so damage from a new pathogen was expected and vaccination has been an incredible help to avoid more. With vaccination we are like adolescents, with additional infections we will be immunologically speaking, adults again. This takes some time, nothing much more can be done about it.

There is a gap in our knowledge, for other pathogens as well, how SARS-CoV-2 can cause debilitating damage in some people with long-term consequences. We know too little about how this works, how to prevent, how to treat and heal. A new frontier of research that hopefully will bring understanding and solutions. 


In line with this, the WHO SAGE advice is that adults without underlying conditions should have three vaccine dosages. The elderly and vulnerable may need an annual booster to reduce infection chance and increase the memory pool. 
The role of children is a little more contentious: It is likely that they develop particularly good immunity and undergo SARS-CoV-2 infections well: just like all the other infections, thereby building up immunity. This is less clear in older children (>5 years), that should have two dosages of the vaccine to catch up on memory cell development. The next generation will be fine getting infected and building up immunity without the need of vaccination. But like for influenza and soon RSV, it would be right to offer the vaccine to those who want it and those vulnerable groups that need it.