How and why vaccination against one disease can help against another

The SARS ‑ CoV ‑ 2 coronavirus pandemic forced us to improve our knowledge not only about virology and epidemiology, but also about the work of the immune system. The well-established idea that immunity simply protects the body from external threats turned out to be far from always correct. Many victims of COVID-19 are not killed by the coronavirus as such - death is brought by the patient's own leukocytes, which destroy lung tissue, shooting off infected cells, and breed such an inflammatory panic (the so-called "Cytokine stormCytokine release syndrome - Wikipedia"), Which the body is unable to cope with.

Now we have to question one more thesis from the school textbook: the vaccine protects against the pathogen from which it is made.

Vaccines seem to have many side effects - both positive and unwanted - and we can turn some of them to our advantage in the fight against coronavirus.

Kill another

When a stranger enters the body, the immune system needs time to detect it, report it to higher authorities (lymph nodes, bone marrow and spleen) and drive the troops. It would be much more convenient if the army was already on alert. That's what a vaccine is for.

Vaccination is a miniature disease. We infect our body with a pathogen, but it is so weak or passive that the war immunity with him ends with a victory in the first battle, the winners do not suffer losses and then switch to patrolling the territory.

But what happens if there are not one, but two opponents - that is, if soon after the vaccine is administered, another pathogen enters the body?

The fact is that at the very beginning of hostilities, soldiers of innate immunity go on the offensive, who do not differ in great imagination. The tactics of their battle does not depend on who they got as opponents. For example, the antiviral response begins with type 1 interferons, which are proteins that trigger an “emergency” regime in cells. In this mode, the cell slows down the synthesis of its DNA, RNA and proteins so that in the event of its capture, the virus cannot multiply. And if so, it doesn't matter at allCD4 T ‑ Cell ‑ Mediated Heterologous Immunity between Mycobacteria and Poxviruseswho exactly attacks the organism and how many of them - an emergency situation strangles any enterprise.

Therefore, we can assume that if a coronavirus has entered your body, and you have just injected a state of emergency on the occasion of the vaccine war, if not stop, then at least slow down the invasion of a new interventionist. Based on this, the American virologist Konstantin Chumakov, who is evaluating the effectiveness and safety of vaccines in the FDA (American Ministry of Health), suggestedCould an old vaccine be a godsend for new coronavirus? fight the coronavirus with a long-studied, attenuated polio vaccine. In this he inherits his parents - Russian virologists Marina Voroshilova and Mikhail Chumakov - who were involved in the introduction of a live polio vaccine in the USSR in the 50s of the twentieth century.

Mass vaccination not only made it possible for half a century to get rid ofTwo out of three wild poliovirus strains eradicated from two types of polioviruses out of three, but also led to unexpected consequences, not directly related to polio. For example, in the 2000s, African Guinea-Bissau reduced vaccinationsNational Immunization Campaigns with Oral Polio Vaccine Reduce All-Cause Mortality: A Natural Experiment within Seven Randomized Trials the death rate of children by 19 percent - and this in the years when no one was sick with polio in the country. Chinese scientists have noted that children vaccinated against polio are less likely toPre-existing heterologous immunity to poliovirus vaccination may mitigate severity of hand, food and mouth disease caused by EV71 there are infectious inflammations in the mouth and on the limbs. And in Russia, according toCould ‘Innate Immunology’ Save Us From the Coronavirus? Chumakov Jr., the polio vaccination campaign in the 1970s reduced the death rate from seasonal flu by four times. And since the vaccine has proven to be of great help in the fight against other viruses, why not use this weapon again?

The polio vaccine has undeniable advantages: it has been known for a long time, is well studied and is inexpensive. However, there are some subtleties here.

The fact is that there are two vaccines against poliomyelitis. The first is the aforementioned live weakened - her children are dripped into the mouth or fed on a piece of sugar. And the second is inactivated, it is injected into the muscle by injection.

The inactivated one appeared earlier: it is safer, but also less effective. Konstantin Chumakov's parents fought for the introduction of a live vaccine, which gives a stronger immune response, and since then it has been used all over the world. But gradually, as the poliovirus got rid of, countries began to switch back to the inactivated vaccine so as not to put immunocompromised people at risk.

If the live vaccine is started again massively now, there is a chance that people at risk could get hurt. Therefore, even for a long-known vaccine, thorough tests are needed (they are going to be carried out, for example, in RussiaIn Kirov, 1,500 studies of polio vaccine to prevent coronavirus will be conducted). And if such a method of shaking up immunity will become salvation for someone, then only for those who are not yet sick, and those who need emergency protection, first of all, doctors.

Immunity beguiled

But if the idea of ​​a polio vaccine still looks intuitive - in the end, the remedy from one virus can be useful from others - some others seem to be much more strange.

For example, many were inspired when New York scientists calculated that in countries with mass vaccinations against tuberculosis, mortality from coronavirus is lower.Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological studythan in those where the vaccination program was curtailed. If these results were confirmed, it would mean that some countries where tuberculosis has not been defeated and vaccination against it obligatory (for example, Russia), could exhale with relief: if not tuberculosis, then at least the coronavirus will pass through tangent.

But tuberculosis is caused by bacteria - and COVID-19 is caused by viruses.

The article was quickly criticizedBCG Against Coronavirus: Less Hype And More Evidence, Please: the correlation was called insignificant, and the methodology - questionable (among other things, the authors compared countries depending on the average income of the population, which does not always correspond to the quality of medicine). And then Tel Aviv doctors compared the death rate from coronavirus among unvaccinated Israelis and vaccinated migrants and putSARS ‑ CoV ‑ 2 Rates in BCG ‑ Vaccinated and Unvaccinated Young Adults point in this story - the mortality rate did not differ between these groups. You can't breathe out.

Nevertheless, the idea of ​​comparing mortality depending on the history of vaccinations was not born out of the blue. Like the polio vaccine, which is credited with preventing other viral infections, the tuberculosis vaccine also has surprising properties every now and then.

The anti-tuberculosis vaccine is an attenuated strain of bovine tubercle bacillus, Mycobacterium bovis (she is called the bacillus Calmette-Guerin, after the name of her inventors, hence the abbreviation BCG, Bacille Calmette ‑ Guerin). It is related to the human tubercle bacillus - M. tuberculosis.

The first surprising property of BCG is that it does not protect against tuberculosis itself so well.Tuberculosis: in some populations, its efficiency tends to zero at all.

But BCG successfully prevents leprosy caused by other members of the mycobacterium genus. There is an explanation for this effect: related bacteria have similar proteins on the cell surface. And if the body produces antibodies that sit well on one mycobacterium, then with some degree of probability they will stick to the surface of its relative, triggering an immune response.

This phenomenon is called cross-reactivity. And it works not only for antibodies, but also for T-lymphocytes, which suddenly recognize the enemy in cells with unusual molecules and kill them - although the mechanism of their work looks the other way around, remember a specific enemy in order to attack him at the first meeting.

Immunity can thus "confuse" not only related bacteria, but also different virusesCD4 T ‑ Cell ‑ Mediated Heterologous Immunity between Mycobacteria and Poxviruses: HIV and hepatitis, influenza and Epstein-Barr virus, bacteria and unicellular eukaryotesHarnessing the beneficial heterologous effects of vaccination (tetanus and toxoplasma) and even bacteria and viruses: cytomegalovirus and the plague bacillus, HIV and M. tuberculosis.

This leads to the fact that adults sometimes haveHarnessing the beneficial heterologous effects of vaccination immunological memory cells specific to pathogens that their hosts have never been sick with: including HIV, herpes virus and, as it recently turned outTargets of T Cell Responses to SARS ‑ CoV ‑ 2 Coronavirus in Humans with COVID ‑ 19 Disease and Unexposed Individuals, even the SARS ‑ CoV ‑ 2 coronavirus.

One way or another, many researchers have found that the BCG vaccine has the ability to protect not only against mycobacterial infections. For example, in several populations, it decreased two to three timesA small jab - a big effect: nonspecific immunomodulation by vaccines mortality of children from all causes. And this can hardly be attributed to anti-tuberculosis protection: newborns practically do not get sick with it, which means that the vaccine can act in some roundabout way. Gradually, scientists began to suspect that this was not a matter of cross-reactivity - in some cases, the “effect deja vu ", which allows you to cope with a never seen pathogen, worked independently of T- and B-cells from their antibodies. This means that immunological memory has other, previously unknown mechanisms.

Tricks with memory

The classic image of the human immune system is a tree with two branches: innate and acquired (adaptive) immunity. And if each person has his own second and the strength of his response depends on the memory of previous infections, then the first should be the same for all healthy people.

However, there is growing evidence that this is not the case.

Even in plants and invertebrates, which lack the adaptive immune system, from time to time they find signs immunological memory: mosquitoes every time more and more actively try to kill the malaria plasmodium in themselves, and the immunity of crustaceans "Remembers" his parasitic worms. Known examplesHarnessing the beneficial heterologous effects of vaccination and what traces the invasion of the stimulus leaves in the cells of innate immunity: macrophages (eaters of bacteria and cell debris) and neutrophils (the main fighters against bacteria).

These effects are called memory of innate immunity or manifestations of "trained immunity"Trained immunity: A program of innate immune memory in health and disease - in the case of BCG, the trainer, respectively, is the vaccine. In memory of the trial battle with tuberculosis, the body retains not only T- and B-lymphocytes ready to fight the tuberculosis bacillus, but also cells of innate immunity with altered metabolism. For example, some of them begin to release more signaling molecules. Epigenetic shifts are outlined in them: some genes "close" from reading, others, on the contrary, unwind, as a result, the set of secreted substances also changes.

Judging by the fact that some manifestations of immunological memory persistTrained immunity: A program of innate immune memory in health and disease within months or even years after the first "training", changes affect not only adult cells, but also stem cells, which continue to produce activated progenitors. Even "civilians" are trained: the inhabitants of the bone marrow and epithelial tissues, after infection or vaccination, continue to produce more molecules that direct the movement of immune soldiers throughout the body - and it depends on this, for example, how many of them will come running to the lung to fight coronavirus.

We can not always fully predict whether these changes will occur in the case of each specific vaccine, and if they do, then in which direction they will be directed.

Some antigens-irritants cause immunity tolerance, that is, suppress its work. Others, on the other hand, keep the immune system on track and allow it to react more aggressively to other enemies. In some cases, these actions can be combined: the trained immunity will react more strongly to some stimuli, and weaker to others.

In each case, it is necessary to carefully check what kind of memory the antigen leaves behind. Sometimes these effects may not be beneficial to us - for example, one of the flu vaccines turned out to be relatedAntibodies to influenza nucleoprotein cross ‑ react with human hypocretin receptor 2 with autoimmune narcolepsy. And sometimes "vaccine training" can be used to benefit people. For example, BCG is considering usingEffects of Bacille Calmette ‑ Guérin after the first demyelinating event in the CNS at multiple sclerosis and are already experiencingLong-term reduction in hyperglycemia in advanced type 1 diabetes: the value of induced aerobic glycolysis with BCG vaccinations as a remedy for diabetes: vaccination in infancy is not beneficial here, but an emergency vaccine helps to muffle the body's autoimmune attack on the pancreas. The same vaccine is beneficial in other casesTrained immunity: A program of innate immune memory in health and diseaseto enhance the immune response in bladder cancer, leukemia, lymphoma and melanoma.

Now we have the opportunityBCG-induced trained immunity: can it offer protection against COVID-19? take advantage of the newly discovered property of innate immunity and turn its "memory" against the SARS ‑ CoV ‑ 2 virus. It hardly makes sense to count on residues from childhood vaccinations - data on how long the effect of training after BCG remains in the body, vary greatly - from several months to tens of years (although there is even work in which traceMaternal Priming: Bacillus Calmette ‑ Guérin (BCG) Vaccine Scarring in Mothers Enhances the Survival of Their Child With a BCG Vaccine Scar intergenerational effect: children died less often and responded better to the vaccine if they were born to a vaccinated mother). But you can re-vaccinate adults and hope for quick protection (but possibly short-term).

In this case, as in the history of the polio vaccine, there are risks. If the immune system responds too aggressively to the vaccine, a cytokine storm can occur, which the body is not always able to cope with. However, in a similar studyBCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunitywhen BCG was used against yellow fever virusYellow Fever - Wikipedia, this did not happen, and the vaccine worked successfully. But in an epidemic, one cannot be sure that people with weak immunity and the elderly will adequately respond to vaccination. Therefore, while clinical trials of BCG as a prevention of COVID-19 are already beginning around the world, from Denmark to Australia and Uganda, they will be primarily targeted at medical professionals.

Thus, the new coronavirus can act here as an engine of immunological progress. With other drugs to be found for diabetes or cancer, preventive vaccination trials are unlikely to reach such proportions. Now we have a chance to collect a large amount of data on how the vaccines we are used to work in a roundabout way, and to check whether our innate immunological memory is so strong.