Cheer for us
Why do doctors infect healthy people with coronavirus
Polina Loseva, N+1
For links, see the original article – VM.
While millions of people around the world are trying to recover from coronavirus infection, several dozen Englishmen, on the contrary, plan to get sick with it. Recently, a second experiment with targeted infection was launched in the UK. The first one has already borne fruit: three volunteers received a dose of SARS-CoV-2 and recovered safely. Why is this necessary? And why are scientists not satisfied with the millions of potential research subjects who have fallen ill with covid by themselves?
The first proposals to infect someone with coronavirus purposefully sounded back in the spring of 2020 - when it was not even really clear how exactly this infection was transmitted. By the summer, there was already a queue on the 1DaySooner volunteer portal from those who wanted to get infected and contribute to the development of vaccines against a disease that no one knew how to treat. However, it took a whole year before the doctors were allowed to start the experiment. During this year, scientists from different countries managed to publish a dozen polemical articles, argue with each other, weigh the risks and benefits – the history of medicine remembers how such experiments with infections ended in previous centuries.
In 1760, the famous British surgeon John Hunter took a scalpel smeared with purulent secretions of a gonorrhea patient and made a couple of incisions on the penis of a healthy person. This was not his first such experiment: before that, he had already tried to infect several patients through cuts on his back. Hunter somehow believed that gonorrhea and syphilis are different manifestations of the same disease, and thus decided to test his hypothesis. Nothing was known about their pathogens at that time (bacteria were not considered pathogenic, but before the discovery of viruses was still more than a hundred years away), and the experimenter did not come up with another way to transmit the disease.
Evil tongues then said that the penis belonged to Hunter himself and that he himself died of syphilis as a result – although in his notes the surgeon limited himself to the impersonal "experiments were conducted", and doctors are still arguing about his diagnosis. Anyway, after a few months, the owner of the ill-fated sexual organ had chancres, buboes and other symptoms of the disease. Hunter was triumphant – although, as we understand now, in reality he was just "lucky" with the pus donor, and he turned out to be ill not only with gonorrhea, but also with syphilis. But at that time there was no one to suspect a trick.
In more than a hundred years, Louis Pasteur will prove that microbes are to blame for many of our diseases, and Robert Koch will formulate a checklist that could be useful to Hunter. According to Koch's postulates, in order to accuse a microbe of pathogenicity, it is necessary: (1) to find it only in a sick, but not in a healthy organism, then (2) to successfully grow it in culture and (3) infect a healthy organism with it – and only then claim that the culprit has been found. Not knowing anything about microbiology, Hunter immediately started with the third postulate – and therefore received a false positive answer.
Many scientists have ventured to take the third step "according to Koch". For example, his colleagues Pettenkofer and Emmerich checked for themselves whether the cholera vibrio causes cholera – Pettenkofer got off with mild diarrhea, but Emmerich honestly suffered for several days in full. And a young Australian doctor Barry Marshall, who, desperate to infect mice with Helicobacter pylori, drank a culture of bacteria and safely earned a stomach ulcer (twenty years later, however, he was given the Nobel Prize for less risky experiments).
But this is not how the modern scientific process works. To confirm that the SARS-CoV-2 virus causes COVID-19 disease, no one needed to follow Koch's precepts. The connection between the virus and symptoms in the XXI century can be easily established without unnecessary victims. In the case of a new coronavirus, it took about a week: they described the symptoms, excluded other respiratory diseases, isolated the virus from the biomaterial of patients, sequenced its genome, compared it with already known viruses – and found a close relative, the causative agent of SARS. This turned out to be quite enough to decide that the fault of SARS-CoV-2 has been proven.
In the twentieth century, isolated risky experiments gave way to large clinical trials: long, thorough, involving hundreds of people – but no less questionable from an ethical point of view.
This was how, for example, attempts to find a cure for syphilis in Guatemala in the 1940s, almost two centuries after Hunter's experiments. By this time, syphilis had long been learned to distinguish from gonorrhea, and its causative agent was well known, so the participants of the experiment no longer got a dirty scalpel, but a syringe with a pure culture of the treponema bacterium. And penicillin was tested on them, which by that time had proven itself as a panacea for bacterial infections.
Penicillin did not disappoint – they still treat the early stages of syphilis. Some subjects were lucky to complete the full course and recover. But someone, judging by the reports, did not get the medicine – but scientists became concerned about this only a few decades later, when they lifted the old archives.
For such studies, it was convenient to collect homogeneous groups of patients who are not mobile enough, which means they are convenient for observation. The subjects were residents of poor urban neighborhoods, prisoners in prison or patients of a psychiatric clinic. They definitely won't escape from the experiment, and you can also do with them without informed consent – at least, that's what they thought in the 1940s.
After the Nuremberg trials of the Nazis, including doctors, the Nuremberg Code for Human Experiments appeared, in which the first item was the mandatory voluntary consent of the subjects. But the Code is not a law, but only the basis for their creation. New standards entered the scientific community gradually, and laws were written even more slowly. Therefore, the authorities of the state of New York in the 1950s allowed researchers to infect children with hepatitis in psychiatric hospitals - the broad community of physicians found out about it only when their colleagues began to publish in scientific journals. Of course, they were grateful for the data, but the methods have already been condemned. Today, no ethics committee will approve such experiments on forced people.
By the time doctors decided to infect volunteers with coronavirus, hundreds of small clinical trials of drugs and several large ones, where no one specifically infected anyone, had begun and ended. And we already know that most remedies for other diseases (influenza, HIV, malaria) do not give good results, but anti-inflammatory drugs (for example, dexamethasone) can be useful. Anyway, in the midst of a pandemic, there seems to be no shortage of test subjects to test drugs.
Portraying the victim
The covid infection experiment is unlike the experiments of the previous "infectors". There are not many patients in it, literally several dozen. All of them are young (no older than 30), healthy (do not suffer from diabetes, obesity, heart disease) and fully agree to take on the risks of participating in the experiment by locking themselves in the clinic for several dozen days. And the organizers of the experiment, in turn, are ready to pay them for the time spent and cover additional medical expenses.
The first group of "infecters" works at Imperial College London, their research started in February. They select people who have never encountered a coronavirus infection before and inject an aerosol with viral particles into their nose. The second group, from Oxford University, began its work in April – they infect those who have already had covid at least three months ago. In case someone gets seriously ill, the experimenters have monoclonal antibodies from Regeneron - they are approved in the USA for the treatment of mild forms of covid.
To make these experiments possible, doctors had to wait. It was necessary to find out how the severe and mild forms of covid differ, what risk factors they have and which groups of people are more vulnerable. It was necessary to check possible medications and select the most effective ones. And only now researchers can afford to infect people purposefully – with a disease that they have already considered well from all sides and have learned (at least in part) to predict, prevent and treat.
But why, in this case, risk the health of volunteers at all?
The thing is that doctors have studied the phenomenology of covid well, but they still do not know how to calculate it well. For example, they have an approximate idea of how many viral particles can be found in the respiratory tract of a carrier and how much he exhales them when he coughs or speaks, but they do not know how many viral particles are needed to successfully infect a person. And without this knowledge, it is difficult to calculate with what probability a person can get infected at school or on a tram, whether a mask or a respirator will save him, and at what distance he should bypass a coughing passerby.
The recommendations that we rely on now in everyday life are based on assumptions and incomplete data. For example, a distance of 1.5 meters has long been considered the gold standard for infections spread by airborne droplets, but does not allow you to protect yourself from aerosol particles. Experiments with targeted infection can provide a more accurate answer to such questions.
At the first stage of the London study, doctors plan to find out what the minimum number of viral particles is necessary for a person to become a carrier of the coronavirus. After that, it will be possible to check to what extent the epidemiological restrictions currently adopted in different countries correspond to the real risk of infection – and, probably, to correct them.
The second number that we lack to assess individual risks is the number of antibodies to the coronavirus, which protects against infection. If scientists were able to calculate this value, they would immediately find answers to many other questions: who is at risk of getting covid again? Who of the vaccinated can feel safe? Is one vaccination enough instead of two and when will I have to be vaccinated again? The second, Oxford experiment of "infecters" is aimed at this – and that is why only those who have already been ill are selected for it.
Both of these values – the minimum dose of the virus and the minimum titer of antibodies – are not the ultimate goal of experiments, but the beginning of a long journey. This is actually the same thing that is done before preclinical trials – the creation of an "animal model of the disease". Only after it is established that the desired virus infects mice in a certain dose and causes a measurable immune response, it is possible to proceed directly to drug or vaccine trials. The same thing will happen here: if you create a "human model" of covid and learn how to effectively infect volunteers, vaccines and preventive medications can be tested on them.
The Hand of Providence
Of course, it was possible to achieve all this without "human models" – during the year of the pandemic, several companies successfully tested their vaccines and medicines without intentionally infecting anyone. That's just what it took to recruit tens of thousands of people and watch them for several months. It's long, expensive, very difficult to organize, and every next vaccine has to be more difficult.
In fact, most of the money and resources in clinical research are spent on minimizing the role of the case. Since we do not know how much people are at risk of getting infected, and we cannot track when and what dose of the virus they receive in everyday life, we can only increase the sample to exclude the possibility that someone from the subjects accidentally got more or less viral particles. The more people we checked, the higher the chance that our data reflects real statistics in the population, and not a random successful or unsuccessful hit.
But when an experimenter can infect people in a targeted way, he himself takes on the role of chance. He knows exactly who, when and how many viral particles he inhaled – which means he doesn't need to collect such large samples. You can do with literally a few dozen people and a couple of weeks of observation – which is much faster and cheaper.
In this sense, the covid researchers did not discover America. In the same type of experiments (the centers where some of them are conducted are marked on the map below) volunteers can receive a dose of influenza virus or malaria plasmodium, typhoid pathogens or parasite roundworms. hVIVO, which organizes both experiments with covid, specializes in just such studies. And the scientific association HIC-VAC recently tweeted a significant date – researchers finally managed to artificially infect people with streptococcus and cause real pharyngitis.
Of course, not every infection is suitable for such tests. It should be well studied (like malaria), cause rapid and acute symptoms (like cholera) and not leave behind widespread long-lasting consequences (because of this, such an experiment was not allowed to be carried out with the Zika virus). And for her, of course, there must be a known treatment – or at least a way to modify the pathogen so that it causes milder symptoms or does not multiply in the body (as is done with the Dengue virus and schistosomes).
Volunteers who agree to serve as experimental animals call it "the most significant thing in their lives" – and can be rightfully proud of themselves. At the output of such studies, quite tangible products are obtained. For example, recommendations for protection against norovirus on cruise liners appeared based on experiments with human infection (it turned out that infected oysters could serve as its source). They also tested oseltamivir, a common flu medicine, and a cholera vaccine that is administered to Americans before traveling to southern countries.
By the end of the first quarter of the XXI century, we have vaccines for several dozen infectious diseases on our hands – but those that we cannot prevent are ten times more. Therefore, the "infectors" will not be out of work for a long time. Once experiments on humans were considered natural, then they caused condemnation, and now each new project is approved only after long disputes and weighing the risks. But there is a result that can be obtained only by making a person your model object – and therefore experiments continue. And the fact that coronavirus is now involved in them means that we seem to have learned enough to control and treat it – or that we have run out of time and money to start each clinical trial from scratch.
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