Essential (and often neglected) elements of antiviral immunology to understand covid-19 vaccination

To save us from the covid-19 pandemic, the new messiah of technological and industrial religion is "the vaccine". But there are still many questions and much confusion. We too often forget that there are several possible levels of protection that are not at all equivalent, nor as easy to obtain: one can protect against PCR positivity, or against colds and mild forms, against contagion linked to these colds, or only against severe forms of covid-19. It is important to understand that in order to make a PCR negative, given the great sensitivity of this technology, it is necessary to eliminate every last virus, which implies a powerful immune response. We then speak of "sterilising" immunity which is very difficult to obtain over time, especially in tissues which are a little "outside" the body and poorly irrigated by blood supplies, such as elements of upper respiratory tract, as the sinuses. To understand the effectiveness of a vaccine, it is therefore necessary to think about the induced protection in a quantitative way, according to its intensity and its location in the different tissues.

PCR at the heart of anti-covid-19 action: critical consequences

Several recent publications have focused on measuring the duration of covid-19 immunity. It is clear that the covid-19 immune barrier, whether natural, i.e. following an infection, or resulting from vaccination, must last a "certain" amount of time to be of any use. But some researchers say it only lasts a few weeks, others at least 6 months. This is another controversy that risks inflaming and insecuring public opinion, which does not need it.

Let's start by remembering that immune protection is defined in a simple, clinical way: a person who heals quickly without sequelae or who is in contact with the virus without being ill is protected. However, this definition requires agreement on the criteria for establishing that a person is infected, on the one hand, and on the criteria for defining that a person is sick, on the other. Note that to assert protection, the criteria for infection and illness must be different. Moreover, protection cannot simply be present or absent: there can be different "levels" of protection that need to be defined.

Curiously, in defiance of all the fundamental principles of medical analysis and virology, a single criterion has emerged to define both contagiousness, infection and, more implicitly, the disease to be combated: positivity of PCR tests. This choice emerged without further thinking, by the force of circumstances and by the search for simple and applicable solutions. PCR positivity has become the measure of the epidemic in texts and communications, but also in the choice of crisis management actions. It is positivity in PCR that defines what health institutions call a "case" and sometimes even a "patient". It is also PCR positivity which allows the anticipation of epidemic "waves" and triggers exceptional measures such as curfews or lockdowns. Such a choice also makes it possible to summarise the epidemic in a single number. And this number becomes what needs to be fought. A new example of "governance by numbers", a drift analysed by Alain Supiot, professor at ? Collège de France ?.

Until the ubuesque invention this summer of the notion of the "sleeping cluster", i.e. a group of PCR positive but totally asymptomatic individuals. I must admit that this invention, which has never been mentioned for any infectious disease before, leaves me stunned. The "sleeping clusters" were brandished as a threat, whereas one could have imagined the opposite, considering the absence of serious forms over the european summer. One could perfectly consider that a person whose sinus contains such a dangerous virus without showing any clinical signs should be considered very well protected! Aren't these "sleeping clusters" good news, given that no one is sick and even an ideal opportunity to become immune?

Vaccinate against PCR or covid-19?

Unfortunately, it is by using so-called "objective" criteria to avoid insoluble debates that we are up to our necks in this matter. Saturation of labs does not allow desaturation of Intensive Care Units. PCR positivity is not infection, nor contagion, and even less disease. And all tests have their limits with regard to clinical questions: false negatives, as well as false positives. Of course, a test has no false positives or false negatives if we consider that it defines the absolute truth. However, PCR is so sensitive, which makes its magic, that one can easily be positive without being sick (false positive from the clinical point of view) or contagious (false positive from the epidemiological point of view). Some authors have even shown that a PCR can be positive in the absence of infectious virus (false positive from a virological point of view). It is clearly impossible to systematically equate a positive PCR with a disease, an infection, or even contagiousness as it is so commonly practised. A medical interpretation according to the clinical context is required. As surprising as it may seem given the dominant communication, the interpretation of a positive PCR can quite clearly conclude that there is a very strong immune protection: this is obviously the case for a person who is in contact with the virus (in his nose) and who obviously has no symptoms. Once again, when faced with a test result, the clinical examination and the doctor's art remain essential. One can even consider that the clinician expertise, through examination and interrogation will do much better than PCR tests to evaluate disease and contagion risk, both from the point of view of its quality/price ratio and from the point of view of its usefulness in public health. Epidemics have historically been effectively combated by isolating symptomatic individuals, which had the merit of feasibility and simplicity. Moreover, contagion mainly occurs during the symptomatic phase. The anxiety-provoking myth of the highly contagious asymptomatic subject has never been documented.

Despite this, health policy and what it implies in terms of legal liability and professional consequences is based on the exclusive criterion of PCR. With a negative PCR, it is legally permissible to sneeze in the face of the world. With a positive PCR, even for a professional  athlete in top condition and ready to take on an international competition, it's back home, in isolation. And sanctions have even been proposed for those who dare to take to the air despite a positive PCR.

On the basis of positive PCRs, "Ponzi pyramids" of contact cases are launched, which certainly explode the logistics of testing and, by the way, fill the coffers of the laboratories, which did not ask for so much. As in the famous "chains": if you receive this message, send it to ten people, otherwise you'll be cursed. The equivalent here is : If you're PCR positive, name ten contacts in your entourage. And whoever breaks the chain is banned, threatened with the worst kind of trouble. I'll give you the details on the time imposed between the contamination and the test, which is based on the hypothesis that we know who is the source of the transmission and the date of the contamination. When the virus circulates a lot, you can't be sure of the source nor the date. A new masterpiece of absurdity. The creativity of our institutions in the scrupulous application of knowledge understood in an extremely simplistic way is infinite.

The current crisis can also be seen as an epidemic of viruses that we are desperately trying to keep up with the rise in testing capacity. Unfortunately for the advocates of "test-track-isolate" strategy, viruses are multiplying much faster than tests. And the test results keep changing as the virus circulates rapidly: a test that is negative one day will not be negative the next. Fortunately, people who test positive recover and are no longer contagious after a few days: a person who is positive one day is not necessarily positive the next day, nor is he or she contagious. Is it necessary to test each person every day? Such a dynamic sum of changes is impossible to follow with tests .The "test-track-isolate" approach, which is perfectly useful at the very beginning of the epidemic to block a localised outbreak, becomes impractical, absurd and useless when the virus is widely spread in the population. This method is not made for that! This is again the basis of our knowledge in infectiology. I have to admit that it is stunning to see that it is still at the heart of crisis management when the virus is everywhere. Nonsense.

A vaccine against what exactly?

I emphasise covid-19 tests and criteria because this has critical implications for vaccine development. Indeed, in order to bring a vaccine to market, its performance must be demonstrated. And therefore define criteria for success. These criteria must, of course, be measurable and objective. Otherwise, among other technical problems, big pharma risks confusing us or the anti-vaccines groups go wild. Or both. These criteria must also be applicable in the context of a clinical trial.

For example, assessing protection against severe forms, given their relative rarity, would require vaccinating a very large number of people and waiting to see if these forms occur less frequently among those vaccinated. The logistics of such a trial are not straightforward, especially if you are as demanding on performance as you are on safety. The trial must be suspended or abandoned if there are side effects. In a large-scale trial, there are bound to be side effects. The job of vaccine inventors is therefore not the easiest, given the demands of our modern society, which are as legitimate in terms of total performance and safety as they are unrealistic.

While waiting to see the real protection conferred by a vaccine, i.e. against the disease, blood measurements can be taken in tubes. For example, to measure the level of antibodies or other more sophisticated immunological parameters. This is not protection itself, but an experimental approach to protection. This is called an in vitro immunological "correlate" of in vivo protection. The use of the word "correlate" underlines the fact that it is not known whether what is being measured is a "cause" of protection or a simple "correlation". Indeed, one must be sure that these tube (in vitro) measurements do indeed ensure that protection will be effective in infected persons (in vivo). However, this demonstration is only possible if protection is actually observed: if no one is protected, how can it be verified that the tube measurements do indeed correspond to protection? A preclinical animal model can help but it is not enough to put a vaccine on the market.

Will the vaccine arrive soon?

As a result, when testing vaccines, more practical criteria must be used. In the jargon of clinical trials, this is known as "endpoint". (To go further, I recommend Peter Doshi's editorial in the British Medical Journal of October 21st). In the logic followed so far, we see a crazy idea coming: why not use PCR tests? It's easy: let's measure the rate of PCR positivity among vaccinated and unvaccinated people. If the vaccinated have lower rates, that's it! Of course, this does not preclude making other observations and measurements, and analysing the results of the trials on several criteria, but at least we will have a simple and objective criterion for monitoring. In current trials, vaccine performance is measured by comparing the number of people with at least one symptom, even a minor one, AND a positive PCR, in vaccinated versus non-vaccinated people (those who received a non covid placebo vaccine). Before we breathe a sigh of relief, let's look at the consequence of this proposal: we want to vaccinate not only against severe covid disease, but also against mild forms associated with PCR positivity on a sinus swab taken via the nasopharyngeal route. This is justified in the dominant discourse by the need to block not only the serious forms, but also the contagion caused by the benign forms.

At this stage, it is necessary to open the immunology manual. We will learn with interest that the sinus, which belongs to the upper respiratory tract, is a "sanctuary" for the microbes that take refuge there, because immunity is not very effective there. Schematically, we can say that the sinus is a little too "outside" the body to be effectively fought by the immune cells which act mainly "inside" the body. In other words, the sinus is a doorway for viruses, but immunity acts behind the door while viruses are right in front of it. And that's where PCR can detect them. For these reasons, there is no strong immune protection and no lasting vaccine against the common "cold", an infection limited to the upper airways. For the same reasons, there will be no vaccine that can durably prevent a PCR positive "in the nose". An antiviral immunity capable of totally and durably blocking the cold, or a measure as sensitive and external as PCR, has never been observed. This is called "sterilizing immunity" and NO known vaccine is capable of inducing it beyond a few weeks. And this is all the more true as the virus multiplies on a mucous membrane: mucosal immunity exists, but it is not very powerful, not very durable and always difficult to induce.

The poor protection of the mucous membranes of the upper airways against "colds" has important epidemiological consequences since the colds allow transmission of the virus that causes it. A vaccine that does not prevent colds does not prevent contagion either. If we expect vaccination to induce a complete blockage of viral multiplication, without colds or contagion, to finally free us from fear and from many unnecessary injunctions of the health bureaucracy, particularly lockdowns, we risk remaining locked up for some time.

So what do we do?

To begin with, let us take up again the most reassuring fact in this terrible pandemic, so obvious that it is systematically forgotten: protection against severe forms of the disease is observed in all countries, without exception, for a large majority of the population, particularly in the age group of around 2 to 65 years old. This "natural" protection is most likely the result of infections by coronaviruses related to Sars-cov2 , which have been circulating for a long time in the world, particularly among children. This answers in passing the question of the duration of immunity, as we asked in the introduction. According to a simple calculation which I will let you check for yourself, the average duration of protection is 63 years. We do not see how this indisputable epidemiological observation would be compatible with protection lasting a few weeks or months, as some specialists tell us. It should be reminded that the protection mentioned here only concerns severe forms, which correspond to a deeper invasion of the body. If the natural protection against severe forms is so widespread, it is highly likely that this protection will be easily obtained through vaccination. Generally speaking, vaccines do not do any better in terms of protection than immunity resulting from infection.

In order to avoid the current widespread confusion, serious forms and colds should not be mixed up, let alone PCR test positivity without serious symptoms. Severe forms involve deeper and more diffuse damage due to the multiplication of the virus inside the body, especially in the lungs and digestive tract. In the case of colds, as explained above, the virus multiplies exclusively on the mucosal membranes of the upper airways where immunity, particularly the so-called cellular immunity, which is very effective against viruses, cannot act effectively.

This confusion is even reflected in the speeches of some experts who debate the duration of protection or the impact of virus variation. Again, protection against colds is bad no matter what. There is no point in discussing its duration or explaining it by viral variation. On the contrary, the natural protection observed against severe and deep forms is long-lasting and doesn't care about viral variation. As proof, this naturally acquired protection which saves the vast majority of the population, especially children, has been induced by distant cousins of the Sars cov2 virus. This "cross-immunity" clearly indicates that protection can exist despite viral variation.

Repeated infections in the form of a more or less symptomatic and apparent cold are very difficult to avoid. Fortunately, this is not what is saturating our hospitals. In fact, the opposite is true, because catching a simple cold is the equivalent of a vaccination booster. A "re-exposure" from person to person, for an average of 63 years, probably explains the long duration of protection generally observed against serious forms of the disease. It is not by chance that children, who so often have colds due to many viruses, including several coronaviruses, are also the best spared by severe forms of covid-19.

It is therefore unrealistic to try to stop the virus and its spread in the form of colds or positive PCR tests. The virus is already everywhere, so we might as well try to eradicate the rain. Effectiveness and realism require us to refocus on the clinical signs, and to seek above all to avoid the serious forms that saturate our health system and plunge the country into mourning. We must therefore concentrate our efforts on those at risk. Protecting them humanely and effectively, for example by vaccinating them as a priority, as planned, but also by providing them with ffp2 masks or allowing them, if they wish, to isolate themselves at home, is neither punishment nor discrimination. I can't understand what strange twist makes classical preventive medicine applied to high risk groups equivalent to punitive medicine or discrimination. Locking everyone up to protect a minority is only punishing some so as not to discriminate against others. The reactions could be reversed in the case of vaccination: is the priority of distributing vaccines to people at risk negative or positive discrimination? We are not equal in the face of this virus. Solidarity does not mean applying generalised, costly and ineffective blanket measures to everyone, including those at risk, but rather focusing everyone's efforts in the right direction.