The new crown epidemic is the same as other pandemics in history that come and go quietly. If nothing happens, it will eventually be subdued by humans and be subdued by vaccines and drugs. This usually means that under a setting with limited resources and time constraints , To develop a variety of safe and effective vaccines, specific drugs, and appropriate treatment plans for the current epidemic viruses.
In February 2021, the British government approved the launch of a human challenge test for the new crown virus. The purpose is to determine the minimum amount of virus that causes infection and the response of the human immune system to the virus, thereby revealing the attack of the new crown virus on the human body. Details provide clues and basis for the development of new crown vaccines and specific drugs.
You must know yourself and your opponent on the battlefield, and the same is true for dealing with viruses, as explained by Chris Chiu, an infectious disease expert at Imperial College London who presided over the operation of the project.
Human challenge is one of many medical research methods. It has a history of more than two hundred years. It once played a key role in the treatment and vaccine development of malaria, typhoid fever, cholera, and influenza. It was once criticized and is still controversial.
What is a human challenge?
The human challenge is simply to infect healthy volunteers with a virus in a well-designed environment and observe the infection and immune response.
The questions to be answered by this type of experiment are usually extremely difficult to find under normal conditions, or require a lot of time and various resources.
In the New Crown Human Challenge Test in London, volunteers selected through various evaluations talked, signed an informed consent contract, and were admitted to the isolation ward of the hospital. Three days later, they injected liquid containing live virus from their nostrils. Then he was hospitalized for observation for at least two weeks. After the observation period is over, if the virus test is negative, you can be discharged home, but you need to undergo a one-year follow-up observation.
This experiment attempts to answer three main questions:
1) How much virus is required to infect the human body at least? 2) What is the initial response of the human immune system to the virus? 3) Who will get sick after being infected, and who will not?
Having mastered these key “secrets” of the new crown virus, the hope of subduing it is even greater.
Why do human challenge tests?
Because this tool has unique advantages, it also has the advantages of high speed and high efficiency.
To grasp the situation of the first “war” with the human immune system after the virus invades, the human challenge test has a unique advantage. Dr. Kerang Qiu from Imperial College explained to the BBC Chinese website:
“Before the onset of symptoms, it is difficult for people to determine whether they are infected with the virus. When the symptoms appear, the incubation period has passed. The infection actually occurred at some time before that, and it is impossible to see the virus invade the human body when the symptoms appear. The initial conditions at the time, including the number of viruses and the human response triggered.”
This “initial state of virus invasion” information can be used to promote vaccine development, test the safety, efficacy and efficiency of the second and third generation… vaccines; it can also be used for new crown drug testing or for development Upgraded version of virus detection method.
Taking the new coronavirus as an example, the virus currently used for human challenges is the kind that is popular in the summer of 2020. Given time, it may be possible in the future to use this method to detect whether the first-generation vaccine is effective against mutant strains that appear after that.
According to statistics, more than 30,000 volunteers in more than 150 countries around the world have participated in human challenge trials for the development of various new drugs and vaccines.
In terms of vaccine and testing product development, the main advantages of human challenges are small scope, controllable progress, fastest speed, and high efficiency.
The traditional method of measuring vaccine efficacy is that when the vaccine is developed to the clinical trial stage, it is necessary to find thousands of volunteers for each candidate vaccine to participate in the test, and let them return to the society after the injection of the vaccine, follow up and observe, and wait for some of them to be infected with the virus. , And compare it with the infection rate of the unvaccinated group.
In this process, there will be many uncertain factors, time-consuming, and various risks and accidents.
If it is concluded that this candidate vaccine meets the requirements at both the efficacy and safety levels, it will enter the next stage, otherwise it will be eliminated.
But if a small-scale human challenge test is done in advance, those players who are destined to be eliminated can be put on hold, and the resources saved can be invested in more promising candidate vaccines.
Qiu Kerang said that even if there are already a variety of safe and effective new crown vaccines, no matter the type and quantity, more development and improvement are needed. In addition, the existing vaccines cannot prevent the virus infection and spread. Human challenge tests are very useful in these areas: testing new vaccines, combinations of different vaccines, combinations of different doses, types and intervals, and so on.
“The real advantage is that because we know the infection rate, we can quickly determine whether a vaccine is effective, which has the most development potential. Based on this data, we can adjust the plan in time and give priority to the development of the most promising ones.”
Of course, traditional methods still have an irreplaceable position.
Has a long history
As one of the means to verify the effectiveness of vaccines, human challenge trials have a history of more than two hundred years.
In 1796, Edward Jenner (also translated as Jenner, Edward Jenner) invented the vaccinia smallpox vaccine. One of the key operations was to vaccinate his 8-year-old son and let the virus enter his body. As a result, the child was unharmed, so it was the first in history. The smallpox vaccine was born. After another 200 years, human smallpox disappeared.
For more than a hundred years after the birth of the smallpox vaccine, cholera, influenza, malaria, yellow fever, hepatitis, Gordon’s fever…every new virus appeared, and corresponding vaccines and specific medicines came into being, many of which were obtained. Boosting the challenge of the human body.
More importantly, in this process, voluntary, informed and safe have become the most important prerequisites for human trials.
Yellow fever and informed consent
In 1898, a yellow fever epidemic broke out during the war between the United States and Spain in Cuba. The number of soldiers who died of yellow fever exceeded 13 times the number of soldiers who died of severe injuries. The following year, the U.S. military set up a committee to study how yellow fever is spread and how to prevent and immunize it. The pathologist Walter Reed is responsible for it.
In order to verify that mosquito bites are the means of transmission of the virus, the research team designed a human challenge test in which mosquitoes who have bitten patients bite healthy volunteers, and after they develop symptoms, they extract pathogenic microorganisms from their blood samples.
In 1901, the Lead team discovered the yellow fever virus, determined the transmission channel of the virus, and discovered that the blood of the infected person could be made into a vaccine.
The contract states that the signatory is fully aware of the risk of contracting the virus and the care it will receive.
Law, ethics and reality
The Nuremberg Code in 1947 and the Declaration of Helsinki in 1964 became the international rules governing human testing after World War II.
The full name of the “Declaration of Helsinki” is the “Declaration of Helsinki of the World Medical Congress”. It sets out the ethical principles of medical research involving human subjects. It is an ethical principle and restrictive conditions for biomedical research involving human subjects. It is compared with the “Nuremberg Code”. More comprehensive, specific and complete.
The declaration has been revised seven times since its publication, the most recent being in October 2013. The declaration stated that “the primary purpose of medical research is to generate new knowledge, but this goal can never override the rights and interests of the target individual.”
But the reality is far from the vision.
McCain Morty said that in 1966, American anesthesiologist Henry Beecher published an article with landmark significance, exposing a large number of anti-ethical and anti-international rules of human experimentation, and cited 22 examples. , Including the scandal of using mentally handicapped children to test hepatitis, using deception to prevent syphilis patients from receiving treatment in order to observe the changes in the virus in reality, and so on.
Beecher believes that to ensure that human trials comply with ethical and legal rules, volunteers’ informed consent is essential and above all else.
Affected by the successive exposure of scandals, human challenge experiments fell into a low ebb in the 1970s. However, with the improvement of ethical compliance and legal restrictions, human challenge experiments have received attention again in the 21st century.
The human challenge test volunteer website 1daysooner has dedicated a page to introduce some human challenge tests in history.
- In the 1980s and 1990s, the human challenge test of influenza A and B influenza at the University of Virginia School of Medicine in the United States promoted the advent of the antiviral drug oseltamivir (oseltamivir, trade name Tamiflu, gram flu capsules);
- In 2011, the Center for Clinical Vaccinology and Tropical Medicine in Oxford, UK, launched a human challenge test of a typhoid vaccine. The results proved that the vaccine is safe and effective. It was later included in the recommended vaccine list by the World Health Organization (WHO);
- In 2013, a dengue vaccine designed and developed by Johns Hopkins University for NIAID was tested in humans, which provided an important basis for the start of large-scale Phase III clinical trials of this vaccine;
- In 2012-13, the University of Maryland used the human challenge test model to develop a cholera vaccine. That vaccine was approved by the US FDA in 2016.
Why is there still a dispute?
The doctor’s natural responsibility is to save the dead, heal the wounded, and heal the sick to save the lives. Cure is to cure the disease, which is the opposite of getting sick. But the human body’s challenge is to deliberately infect people with viruses and germs. In a sense, it is indeed a deliberate injury, even if it is minor. This is unacceptable in some people’s minds.
Critics questioned, since vaccine development is unprecedented and very successful, is there a need for human challenges?
Since we don’t know much about the long-term symptoms of COVID-19, how can we ensure the safety of the test? Why can’t we wait until we have accumulated more data and learned more about the new coronavirus before we start?
To rise to an ethical level, is it ethical to use methods that seem to be contrary to the professional ethics of doctors for noble medical purposes?
Proponents believe that if the new coronavirus human challenge test can be carried out under the premise of ensuring safety, it will have unique and irreplaceable advantages in many aspects such as pathology, vaccines and new drug development.
Although there have been historical stains of violating ethics and was criticized and neglected by scandals half a century ago, the legal and ethical norms mechanisms are advancing with the times, and today there is a sound supervision and restraint mechanism, and you should not give up because of choking.
More than a century ago, Lieder’s yellow fever challenge trial introduced the informed consent procedure for the first time. Today, this procedure is placed as the most important prerequisite for human trials. The text and details have been improved and upgraded countless times. The safety of volunteers is protected by law. .
From the perspective of the researchers who designed and implemented this project, Qiu Kerang pointed out that from the initial outbreak of the new crown epidemic to the present, there have been billions of new crown infection data from all over the world, and there is sufficient understanding of the virus and risks.
This kind of challenge experiment has entered the actual operation stage from design to layer-by-layer demonstration, evaluation, and review, including volunteer selection, the design of informed consent links, ethical approval and safety measures in the trial process, emergency intervention measures and various specific arrangements. The safety factor should be sufficient.
From the perspective of medical practitioners, Qiu Kerang said that he decided to use this method because it is the best way to achieve research purposes. This is not a question of the need for courage, but of sufficient professional knowledge, practical experience and risk control capabilities.
Any human test is risky, “I always put the safety of volunteers first.”
Judging from the response to the recruitment of volunteers for the London New Crown Human Challenge Test, the public has accepted this method to a considerable extent. Hundreds of people have applied to participate in the challenge test as volunteers after hearing the news, and the planned target is 90 people.
Ofer Raban, professor of Constitution at the University of Oregon and Yuval Dor, professor of biology at the Hebrew University of Jerusalem, believe that human challenges are undoubtedly risky for volunteers, but they are beneficial to humans. Completely ethical.
They wrote in the online media “Dialogue” that in the current reality, the new crown human challenge test is not only morally wrong, “on the contrary, it represents the most noble values of mankind.”