A new trope that aims to minimize the seriousness of COVID-19 has been doing the rounds recently – that SARS-CoV-2 is a ‘textbook’ virus that behaves like other common viruses. This trope promotes the views that first, nothing extraordinary has happened with SARS-CoV-2’s establishment in the human population, and second, that uncontrolled transmission is actually beneficial, because it will somehow build immunity and make subsequent reinfections inconsequential. Talking about SARS-CoV-2, one social media commentator stated, “As with other respiratory viruses, symptomatic re-infections tend to sharpen – not weaken, your immunity.”

There are two key issues in such statements. The first is the fundamentally misguided idea of a virus being or not being `textbook’ – viruses objectively exist independent of human textbooks, and if textbooks make false generalizations, then the problem is with the textbooks, i.e. the properties of each novel virus need to be considered on their own, not with a reference to a textbook model. The second is whether infection of SARS-CoV-2 or, indeed, any other virus is a net benefit because it ‘sharpens’ one’s immunity, and whether any ‘textbook’ virus in fact behaves in the claimed way.

It is worth noting that this is not a new assertion. Infection as a conduit for immunity has been made by commentators throughout history, and it is usually raised as an argument to counter any impetus for change. It was raised as a reason not to treat water and has been used by people resistant to mass vaccination campaigns^1,2. Some members of the medical and scientific community, and a significant proportion of the general public, believe exposure to pathogens through infection toughens us and is a net benefit to our health.

They could not be more wrong, and ill-informed statements about infection sharpening immunity show a lack of understanding of what the textbooks actually tell us about infection.

Misunderstanding the Hygiene Hypothesis

First, we need to stress that the canard ‘infections are a good thing’ gains traction in no small part because of a widespread and fundamental misunderstanding of the so called ‘hygiene hypothesis’, which was first formulated several decades ago to explain the apparent rise of immune system dysregulation conditions (allergies, autoimmune disorders, and others) together with advanced industrialization and improved living standards^3-5. The idea is that the immune system needs to be “trained’’ during early development in order to properly develop immune tolerance, and that lack of exposure to microbes is what leads to the increased rates of chronic immune dysregulation seen in the population.

However, this is a very different proposition from the idea that being infected with highly pathogenic viruses is good for you. What the hygiene hypothesis specifically refers to is exposure to bacteria, protozoans and helminths, most of which are normally commensal, or perhaps moderately parasitic components of our microbiomes^6,7. This means exposure is beneficial, neutral or not significantly harmful to humans.

The hygiene hypothesis does not suggest repeated exposure to viruses, especially highly pathogenic ones, is a good thing. The fact that this idea has been so successfully pushed into the public consciousness in the last three years is an example of a very skillful execution of a bait-and-switch tactic⁸.

Coronavirus infections do not in fact ‘build immunity’

The second important consideration is what is in fact understood from decades of research into coronaviruses, the group of viruses to which SARS-CoV-2 belongs⁹. 

Prior to 2020, there were four known endemic human coronaviruses – OC43, NL-63, 229E, and HKU1 – which cause 10% to 15% of common colds^10,11. Since at least the 1970s, we’ve known that infection with these coronaviruses does not lead to lasting protection from reinfection^12-14 - this has been textbook knowledge for decades.

That question was revisited after the start of the pandemic using longitudinal or long-term observations of antibody levels in the same individuals over more than two decades, and the textbook knowledge was confirmed to be true – humans are subjected to regular reinfections by common cold coronaviruses (CCCs)¹⁵. 

In fact, this appears to be a property shared by most respiratory viruses (influenza, parainfluenza, RSV, coronaviruses, and others), likely because of a combination of mucosal immunity (which is what is required to stop a mucosal infection) being shorter-lived¹⁶, and quick antigenic drift or mutation of the virus itself.

Of course, it might be claimed that it is not protection from infection that matters, but protection from severe disease, i.e. people may get reinfected, but it is just a cold, so who cares, right? Implicit in this claim is the assumption that the CCCs would in fact be presenting with severe symptoms if they were to be introduced into an immunologically naive population of adults, and it is only the ‘novelty’ of SARS-CoV-2 that has resulted in the deaths of millions, i.e. if all these people had been infected many times as children, then all subsequent reinfections would be “mild”.

The available data does not support such a conclusion at all.

CCCs are in fact not just colds – they can cause severe pneumonias and exhibit a risk profile very similar to SARS-CoV-2 with age^17-19. The CCCs just pack less of a punch and cause serious adverse outcomes at a much lower rate per infection than SARS-CoV-2. If reinfection strengthened immunity against CCCs, older people would be least affected because they are people who have been infected with diverse variants of these viruses many times in the past.

During the SARS-CoV-1 outbreak of 2003, a cluster of serious symptomatic respiratory infections occurred in a care facility in Canada – 95 of 142 patients exhibited symptoms, and 8 died²⁰. Due to unexpected serological cross-reactivity, there were fears this was a SARS outbreak, but eventually it turned out to be OC43. The numerous past OC43 infections experienced by these patients did not protect them from severe outcomes.

However, most concerning are the properties of SARS-CoV-2 itself. Unlike the CCCs, sarbecoviruses (like SARS-CoV and SARS-CoV-2) have a wide array of accessory proteins that silence the innate and adaptive immune responses in various ways, and in the case of SARS-CoV-2, also have a well documented tendency to trigger immune dysregulation, including in mild cases, through these and additional other mechanisms. Of particular relevance to the question of the future of the pandemic is the observation that children infected with COVID can develop the so-called Multisystem Inflammatory Syndrome in Children (MIS-C), an often severe extreme-inflammation immune dysregulation condition²¹. As far as we can tell, CCCs do not cause this condition. If severity was indeed a consequence of novelty and SARS-CoV-2 was intrinsically similar to the CCCs, we would have seen them cause MIS-C or a similar syndrome in previously unexposed children. 

There is no reason to think that endemic SARS-CoV-2 will become a ‘common cold’ simply through repeated exposure, and without losing its intrinsic pathogenicity, which is clearly much higher than the CCCs. Other viruses such as smallpox and measles have not lost their virulence despite centuries of circulation in humans. Our ability to exist with these pathogens depends on infection acquired immunity, which comes at great cost, or vaccination, and, in the case of viruses such as measles and smallpox, generally protects against infection and lasts decades if not a lifetime.

Infections cause immunosenescence and inflammaging

Immunosenescence refers to the changes in immune function that contribute to the increased susceptibility to disease in older people. Research suggests that immunosenescence is not likely the result of primary aging, but rather is caused by environmental and lifestyle factors, even in healthy older people free of chronic illnesses²².

Serious viral infections are now well understood to accelerate the aging of the immune system, which in turn predisposes people to increased susceptibility to serious outcomes, and SARS-CoV-2 is a particularly nasty virus in this regard. Much of the mechanistic basis for severe illness associated with COVID-19 lies in the hyperactivation of our own immune systems, and this accounts for a substantial skew in the risk profile towards older individuals – as aging is associated with low-grade chronic inflammation (so called “inflammaging”), and an overall exhausted immune system, which is predisposed to such overreaction^23,24. 

In contrast to early studies of people with Long Covid which found increased inflammation and immune activation, a recent study by a team at the University of Utah found cytokine deficiencies in a small group of people with Long Covid which points to immune exhaustion as a possible driver of Long Covid^25,26. It is worth noting that prolonged immune activation could culminate in exhaustion over time^27-29.

As COVID-19 itself seems to cause inflammaging, immunosenescence, and immune exhaustion, and because there are no longer any serious efforts to stop the uncontrolled infection of the population, the possibility of a feed-forward-loop - where there are worsening outcomes over time - is an obviously grave concern, and one that has been extensively discussed in the literature^30-36. 

Various mechanisms underlie this phenomenon. One is telomere shortening. Telomeres – the terminal caps of chromosomes – become shorter as individuals age, and they are believed to play a role in biological aging. Leukocyte telomere length is associated with mortality and many chronic diseases that are thought to be manifestations of age-related functional decline. As a result, telomeres are thought to be reasonable markers for immune system aging^37-39. A leading hypothesis is that telomere attrition is due to inflammation, exposure to infectious agents, and other types of oxidative stress, which damage telomeres and impair their repair mechanisms. Indeed, researchers have been able to induce telomere shortening in mice through exposure to infection³⁸. Chronic viral infection also seems to induce telomere shortening⁴⁰, which may be particularly relevant in the context of persistent infection by SARS-CoV-2.  Poorer outcomes associated with shortened telomeres do not seem to be restricted to respiratory viruses and the senescence of the immune system may be a useful predictor of severity of outcomes in a range of “textbook” diseases⁴¹.

If telomeres aren’t your thing, the aging of the immune system through infection can be measured in other ways. Dendritic cells play a key role in initiating and directing immune responses by recognizing and capturing foreign antigens and presenting them to other immune cells to initiate an immune response. Expression of dendritic cells reduces with age⁴² and age seems to also reduce their effectiveness⁴³. Expression and effectiveness of dendritic cells also reduces with infection^44,45 and such reduction has been seen specifically in the case of SARS-CoV-2^46,47.

Finally, much attention has been devoted to the role of T-cells in the response to and pathogenesis of COVID⁴⁸. T-cell exhaustion is a frequent finding following SARS-CoV-2 infections^49-52. T-cell exhaustion is not universal, and over time, in the presence of chronic infection, certain subsets experience inflation without displaying features of exhaustion⁵³. T-cell aging following SARS-Cov-2 is an even more concerning finding⁵⁴. In order to mount an effective immune response, T-cells need to have a certain amount of proliferative potential and plasticity to be able to differentiate into different functional lineages - they must be malleable and adaptable for the best response - but the capability deteriorates from around 50 years of age and can be measured by changes in composition of naive and effector memory cells in the bone marrow, to the point where it becomes clinically significant from 70 to 100 years of age^55,56. 

One does not need to dive deep into the molecular details of this subject to know that it is a textbook feature of viruses that infection ages the immune system. And aging the immune system is not beneficial to one’s health – in fact it creates a negative feedback loop that makes people more susceptible to infection. So, rather than symptomatic infection sharpening one’s immune system, infection is likely to age the immune system in a way that will make one more susceptible to illness upon reinfection or infection with another pathogen.

To recommend infection as a method of ‘sharpening’ the immune system seems foolhardy in the context of what the literature tells us.

Infections increase the risk of autoimmune disease

Autoimmune diseases are caused by a loss of immunological tolerance for self. The immune system mistakes host for pathogen and attacks it, causing systemic or specific damage to parts of the body. Infection seems to play a role in either inducing or exacerbating predisposition to autoimmunity^57-60 and infection by SARS-CoV-2 in particular has been shown to lead to an increase in autoantibodies⁶¹ and an increase in autoimmune disease⁶². Indeed, early research seems to suggest autoantibody production is not reduced by vaccination⁶³, and if vaccination is a proxy for prior infection, each subsequent reinfection with SARS-CoV-2 may carry with it the risk of developing an autoimmune disease. Approximately 25% of people who develop an autoimmune disease will experience multiple autoimmune syndrome⁶⁴, risking a cascade of autoimmune conditions.

In this context, we believe it is the height of irresponsibility to state that infection ‘sharpens’ the immune response, when in fact infection may carry with it the risk of causing lifelong autoimmune disease.

The immune system is better prepared by vaccines

Another social media commentator recently stated, “The immune system, like the brain, must learn. Immunity doesn't just appear out of thin air. Development of immunity literally REQUIRES exposures.”

This is factually incorrect. The development of adaptive immunity like the T cell repertoire in the thymus requires no exposure to foreign antigen with exposure to self being used for positive and negative selection⁶⁵.

In addition to being factually incorrect, the statement is also poor science communication, because many people will take the ‘requirement’ of exposure to mean infection, and in the context of most governments winding down or restricting their SARS-CoV-2 vaccine programs, it’s hard to see an alternative to infection in many societies. The commentator likely also meant exposure through vaccines, but it is important to be specific; vaccines and not infection are the best way to give the immune system the protective information it requires. This is true in adults⁶⁶ and children⁶⁷, and it seems not only are vaccines quantitatively better, the quality of immune response is improved by higher avidity⁶⁸, a measure of the strength with which antibodies bind.  The benefits of vaccination over infection are not restricted to SARS-CoV-2 but are also true of diseases such as chickenpox, which have traditionally been regarded as mild⁶⁹.

Prominent social media commentators need to take greater care in their messaging, and if they are going to champion infection as a method of ‘sharpening’ the immune response, they must also communicate the risks that accompany each infection. We have outlined some of the long-term risks of SARS-CoV-2 infection here, and even if we set aside some of the more contentious aspects of immune harm, it is clear from what ‘textbook’ immunology tells us about SARS-CoV-2 and other pathogens, that infection should be avoided if at all possible. We believe vaccination is the best way to prepare one’s immune system to reduce the risk of severe acute disease, but that in the absence of sterilizing immunity, breakthrough infections still carry a risk of adverse long-term outcomes and should be avoided. 

SARS-CoV-2 infections may increase the baseline risk upon reinfection

Most of the discussion so far has focused on the role of the immune system in responding to, and mitigating the impacts of SARS-CoV-2 reinfection. But a key question is how the body as a whole will fare against repeated reinfections. The ‘mild endemicity’ model that is being pushed claims that once the pathogen is no longer ‘novel’, its impacts become inconsequential because the immune system is ‘trained’ to prevent worst-case outcomes. This hypothesis relies on framing SARS-CoV-2 as a “textbook” respiratory virus where it joins the ranks of the CCCs, RSV, rhinovirus and so on. 

However, SARS-CoV-2, like SARS-CoV-1, is both a respiratory and a systemic virus, with an extremely broad cell type and tissue tropism covering nearly the whole body. The consequence is that it causes damage to a wide range of human organs and systems. Lungs, hearts, kidneys, cardiovascular systems, and nearly everything else one can think of are well documented to be susceptible to lasting damage as a result of COVID-19^70-73. 

What does that mean for the future? Under the most optimistic ‘mild endemicity’ model, whoever has survived the first infection, without severe sequelae, is set for life and doesn’t have to worry about future infections. Under the less optimistic ‘mild endemicity’ model, it will take a few reinfections to get to that point. 

Most commentators who push ‘mild endemicity’ have pivoted away from the most optimistic scenario because it has already been completely debunked by evidence – reinfections are common⁷⁴, and people do die and get Long COVID as a result of them⁷⁵, and even though the risk of Long COVID reduces by about a third, it is far from zero⁷⁶. So, it is already clear that if you survive the first infection without severe sequelae, you are still at risk - albeit somewhat reduced - of sequelae after subsequent infection.

If each subsequent infection results in additional internal organ and immune system damage⁷⁷, then a different model needs to be considered – a balance between protection from severe outcomes due to the presence of antibodies, and the increased baseline susceptibility to severe outcomes as a result of damage from repeated infections, and the increased risk of infection over time because of the natural processes associated with aging. 

Let’s suppose someone has lost 20% of their lung capacity as a result of previous SARS-CoV-2 infection^78,79. If all else is equal, this person is at higher risk of ventilatory decompensation as well as being at higher risk for developing respiratory infection than someone with 100% intact lung capacity. Similarly, an initial SARS-CoV-2 infection may result in subclinical stage 1 kidney disease⁸⁰, with accelerated progression by repeat infection towards worsening chronic kidney disease and even end-stage kidney disease needing dialysis^81,82. Mild SARS-CoV-2 infection can increase arterial stiffness, which might put people at higher risk of complications from future SARS-CoV-2 infection or long-term vascular complications such as hypertension, stroke, or myocardial infarction^83,84.

At some point the damage accumulated, together with the accelerated immune system aging we discussed earlier plus normal aging processes, can reasonably be expected to outweigh the protective benefits of the memory B and T cells developed from previous infections. As a result, the baseline risk shifts higher - eventually much higher than what it would be at a given age for a first infection. 

Such a process would be expected to result in a dramatically reduced life expectancy and quality of life for much of the population. The excess deaths currently being witnessed around the world already point to a reduction in life expectancy. In the UK, which now includes two pandemic years in its five-year average, excess deaths are currently 7% above expectations⁸⁵ and in Holland, excess mortality is rising in younger age groups⁸⁶. 

It is important to note that some commentators who ridicule the reality of immune harm or aging through infection expect to see relentless and sustained rises in viral, bacterial or fungal infections and in the absence of this phenomena, claim there’s no evidence for infection-induced immune harm. 

However, these commentators fail to acknowledge that studies into variable immune deficiency repeatedly demonstrate that immune compromise manifests in an increased propensity to a variety of autoimmune conditions, cancers and death from diverse causes^87,88. Even in the case of HIV, possibly the most well-known virus to affect the immune system, there are those who believe infection results almost exclusively in increased susceptibility to infection and pneumonia, when in fact the immune damage caused by the virus results in increased cardiac death and disease^89-91, kidney disease⁹², and stroke^93,94 among other diverse elevated risks. 

Infection with a virus does not ‘sharpen’ the immune system, particularly when the virus is shown to in fact cause immune aging and harm. Instead, we should expect the cumulative impact of repeat infection to manifest in diverse illnesses and diseases and to shorten life expectancy.

This is our assessment of the situation based on the best available textbook evidence and it is at odds with the ‘mild endemicity’ hypothesis that underpins the policies of most governments around the world. If the current nonchalant attitudes towards uncontrolled transmission of SARS-CoV-2 remain in place, we will discover which model of endemicity is correct in the coming years. We believe the evidence is already accumulating to suggest this population-scale experiment of mass infection by SARS-CoV-2 will lead to a rejection of the ‘mild endemicity’ hypothesis, but then it will be too late.

If you’d like advice on how to reduce your risk of infection, please click here.