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Can the United States, China, and Singapore all promote urgently therapies to defeat the new coronavirus?

Can the United States, China, and Singapore all promote urgently therapies to defeat the new coronavirus?

Since the outbreak, the new coronavirus has shown extremely strong ability to spread in humans. Countries are actively looking for effective treatment options and accelerating the development of vaccines. In the absence of vaccines and special drugs, “plasma therapy” began to enter people’s vision.

Not long ago, Duan Kai, the project leader of Wuhan Institute of Biological Products, introduced the situation of plasma therapy during the recovery period. Duan Kai introduced that after recovery of plasma after virus inactivation treatment and multiple safety monitoring qualifications, qualified plasma can be prepared. From February 8th, the first batch of severe and critically ill patients received plasma therapy, and the therapy achieved good results. The National Health and Health Commission fully recognizes and promotes it nationwide. “Plasma therapy for rehabilitated patients” also appeared in the “New Coronavirus Pneumonia Diagnosis and Treatment Program (Trial Version 6)” issued by the Health and Health Commission. At present, there are more than 700 patients who have been treated clinically with plasma in the recovery phase nationwide, showing very good results. This therapy has also gone abroad and is promoted and used in many countries and regions.

On April 12, local time, the Dubai Health Bureau announced that it will start using the plasma of the rehabilitated patients to treat patients with severe new coronary pneumonia in the near future.

At the same time, the Singapore National Center for Infectious Diseases revealed that it has recruited 11 new coronary pneumonia patients to donate blood for clinical treatment of critically ill patients.

On March 1, 2020, the staff of Ningxia Blood Center conducted a preliminary screening test on the plasma donated by the new coronary pneumonia patients.

Previously, the New York Blood Center also collected plasma from new coronary pneumonia rehabilitation personnel, asking donors to have no symptoms for at least 14 days after recovery; the US Food and Drug Administration FDA updated the experimental plan for covid-19 treatment, adding “plasma therapy.

In the response to multiple sudden infectious diseases such as SARS in 2003, A1 N1N1 in 2009, and Ebola in Africa in 2014, plasma therapy in the recovery period has been applied. Why can “plasma therapy” become a special therapy for countries around the world to fight the covid-19 epidemic?

Text | Cui Hexu Observer of Think Tank

1

Global nightmare: epidemics follow

An epidemic, with a high case fatality rate and difficult to cure, has always threatened human society.

From 1735 to 1740, the diphtheria known as the “Angel of Throat” was once popular in New England, killing 80% of children under the age of 10, and was called “a truly terrible plague.”

A hundred years later, the gray membrane of dead cells in the throat still caused a large number of children to suffocate. In the 1980s, in Germany alone, about 100,000 children were infected with the disease each year, and the mortality rate in some places was as high as 50%. Moreover, not only civilians, but also the British royal family are inevitable. In 1878, the daughter of Queen Victoria, Princess Alice and her daughter Princess Mary died of diphtheria.

In 1918, a young man named Albert Gitcher was recruited to join the US military. The patient, who was later confirmed to be the “Spanish flu”, was assigned to work in the kitchen. Within three weeks, 1,000 people in the military camp had symptoms of headache, fever, cough, and even lung blockage, and 38 young soldiers died immediately.

24 out of 36 US military barracks experienced this catastrophe. Not only that, as American transport ships sailed to the European continent, the epidemic crossed the Atlantic Ocean, spreading in France, Italy, and Britain, and even King Alfonso XIII of Spain was sick. In June, the pandemic flu hit Asia.

In recent decades, the Ebola virus has caused no small disaster to humans.

In 1976, an unknown virus attacked 55 villages along the Ebola River. At first, the relevant agencies disregarded the symptoms of headache and fever and used the drug quinine as a treatment for malaria. However, what happened next was unprepared-the fatality rate was close to 90%, and some families were not spared.

The Ebola virus appeared in Gabon in 1994, spread to Uganda, a landlocked country in East Africa in 2000, broke out in the Republic of Congo in 2003, and landed in West Africa in 2014. In West Africa alone, the virus has engulfed more than 11,300 lives in two years, with more than 28,500 confirmed and potentially infected cases.

How terrible is Ebola? The initial symptoms were only headache, fever, muscle pain, sore throat, etc. Some patients died after 48 hours, and the tragedy was unbearable-the virus quickly spread and multiplied in the body, attacking various organs, causing them to die and break down, Internal hemorrhage, Qiqiao bleeding, and then, the infected person vomits the tissues of necrotic organs from the mouth …

Diphtheria, “Spanish flu” and Ebola are just the tip of the iceberg.

In recent years, with the development of tourism and transportation, international and inter-city exchanges have increased, and the spread of epidemics has become faster and more difficult to prevent and control. The previous pandemic took more than 6 months to reach the scope, and the pandemic influenza covered it in less than 6 weeks. The WHO has issued a statement saying that the authorities continue to count each confirmed case is meaningless.

Civilization and viruses are only one flight away.

How to do?

2

R & D vaccine? Not so easy!

When the virus invades, the body’s immune system begins to function, and special cells such as B cells and T cells are called up to “fight against” the virus.

B cell division begins:

Some grow into effector B cells, which we call plasma cells, specializing in the production of antibodies to catch viruses;

Other B cells will grow into memory B cells, responsible for remembering the characteristics of the virus.

If the virus invades again, the “long-remember” B cells will quickly and massively grow into effect B cells to clear the virus.

The effect of the vaccine is to let B cells “long memory” first.

According to the principle of natural immunity, it is the principle of vaccines to obtain specific immunity through artificial methods.

Scientists make vaccines by artificially attenuating and inactivating viruses. This vaccine can simulate the characteristics of the virus, but it is not pathogenic. When injected into the human body, the human immune system mistakes the enemy for the current enemy. When the “enemy” strikes, the immune system can be activated immediately and go into battle with full force.

The world’s first vaccine was born in the UK at the end of the 18th century. British doctor Edward Jenner noticed that milkmaids who had been infected with vaccinia virus did not infect smallpox, so he speculated that vaccinia virus could prevent smallpox. Since 1788, Jenner has been conducting observations and experiments for 8 consecutive years, proving his speculation.

It is easy to talk about it. In fact, vaccine preparation is not simple.

First, the vaccine development process is complicated.

After isolation of a suitable strain of vaccine, it needs to be cultured in cells to a certain amount, and then inactivated.

Next, we will conduct experiments on a series of questions such as whether it can be prevented, whether it is effective, whether it has virulence, and whether it will cause new infections.

In the process of natural infection, there are many difficulties, such as whether the immune system can effectively respond. The results can only be obtained through repeated research, repeated modification procedures, and repeated test results.

Second, the research and development cycle is long.

The clinical experiment is divided into 3 stages:

The Phase I clinical trial initially examines the safety of the human body, and the general subjects are dozens to 100 cases;

Phase Ⅱ mainly conducts vaccine dose studies and preliminary effectiveness evaluations, and examines the safety after further expanding the population. The general number of subjects is hundreds to thousands of cases;

Phase Ⅲ uses a randomized, blinded, placebo-controlled (or control vaccine) design to comprehensively evaluate the vaccine’s effectiveness and safety. The average number of subjects ranges from thousands to tens of thousands.

The duration of all clinical trials generally takes at least 3 to 6 years, or even as long as ten years.

In 1976, the Ebola virus appeared in people’s eyes, but it was not until December 2019 that Ervebo, a related vaccine produced by Merck, was approved for marketing in the United States.

SARS has been in the past 17 years, and no drugs or vaccines of preventive value have appeared.

3

“Heavenly Divine Soldier” has guarded humanity for more than 100 years

The virus does not wait for people, and the long process is an unbearable burden for epidemic patients.

So, how can we quickly and effectively save the lives of infected people from the clutches of the virus?

During the recovery period, the “Heavenly Divine Soldier”, a blood product, has silently guarded humanity for more than 100 years.

In 1890, after the German scientist Emile von Bellin and the Japanese scientist Kitashiri Sairo injected detoxified diphtheria toxin (a protein released by diphtheria bacillus) into animals, a neutralizing toxin was found in animal serum The substance is called an antitoxin, which is what we now call an antibody.

Later, in the pediatric ward of the affiliated clinic of Berlin University, Bellin injected a convalescent blood product into a child with diphtheria. The next day, the child’s condition improved significantly.

Later, this law reduced the mortality rate of diphtheria children in Berlin Children’s Hospital from 18.8% to 13% in 1892.

This move not only won the first Nobel Prize in medicine, but also created a precedent for artificial passive immunity.

In 1918, during the “Spanish flu”, some soldiers and sailors received blood products in the recovery period and achieved good results. A report shows that this treatment can reduce the mortality of severe cases by 50%.

In the 1976 Ebola outbreak in Zaire, an Ebola virus infection laboratory worker recovered completely after infusion of plasma from 2 units of recovered persons. During the Ebola outbreak in Kikwete, Democratic Republic of the Congo in 1995, 8 patients were infused with whole blood from Ebola patients during recovery period, 7 subjects survived, and the case fatality rate was 12.5%. 80%.

In the process of fighting against SARS, blood products in the recovery period also played their role. In 2003, 80 of 1,775 patients in Hong Kong received this treatment, which reduced mortality.

In 2004, Wuhan Institute of Biological Products successfully prepared human SARS immunoglobulin for intravenous injection using the plasma of SARS rehabilitation persons. Can be applied to clinical rescue. “

The case fatality rate is as high as 34.4%, and there is no specific drug treatment for the MERS virus (Middle East Respiratory Syndrome Coronavirus). The International Federation of Severe Respiratory and Emerging Infectious Diseases recommends plasma transfusions for recovered patients as a potential for reducing clinical symptoms of MERS treatment method.

Not only that, it has achieved certain effects in the treatment of measles, hemorrhagic fever in Argentina, influenza, chickenpox, cytomegalovirus infection, parvovirus B19 infection, and the treatment of avian influenza and Ebola virus.

In this new coronary pneumonia epidemic, blood products in the recovery period have also become a “ballast stone” in various countries before vaccines and special drugs are developed.

4

Why is plasma therapy so effective?

As can be seen from the above, whenever an epidemic breaks out, blood products in the recovery period are widely concerned. The reason is not difficult to understand:

One is easy to obtain.

The whole blood leaving the blood vessel is precipitated by centrifugation, and the obtained cell-free liquid is rich in plasma proteins and various antibodies. This antibody is one of the most important weapons for the human body to fight viral infections. The antibody binds to the virus and then “kills” the virus in various forms.

Vaccines are inactivated or inactivated pathogens, and the plasma of recovered persons is a blood preparation containing antibodies. Compared with the cycle and difficulty of developing vaccines, the plasma of rehabilitated persons who can play a passive immune role is more easily obtained.

The second is quick results.

There is no need to go through the incubation period. Once the plasma products are imported, the patient can immediately get immunity. For example, after being bitten by a cobra, quickly injecting anti-cobra serum can neutralize the cobra venom and save lives. However, it has a short duration and is mainly used for the treatment or emergency prevention of diseases.

Take the new coronavirus as an example, the virus binds to a protein called “angiotensin converting enzyme 2 (ACE2)” on the surface of human lung epithelial cells through a “spike protein” shaped like a nail on its own surface, ACE2 The protein subsequently changes its shape and structure, “carrying” the virus into human cells, and uses the cell’s own molecules to synthesize new viruses through chemical reactions.

These new viruses are then released outside the human cells, using the same method to infect the surrounding normal cells, so circulating.

Antibodies are here to break this cycle. For example, neutralizing antibodies are blocked by physical means. It binds the spike protein on the surface of the new coronavirus, blocking the binding of this protein to the human ACE2 protein receptor, thereby blocking the virus from entering the cell, and the virus outside the cell will gradually break down.

In addition to the spike protein, there are envelope proteins and membrane proteins on the surface of the new coronavirus. Antibodies against the latter two proteins are called “non-neutralizing antibodies.” After they bind to the envelope protein or membrane protein on the surface of the new coronavirus, they rely on immune mechanisms to mediate the phagocytosis of virus particles by human immune cells.

After the recovery of most patients with New Coronary Pneumonia, specific antibodies against New Coronavirus will be produced in the body’s blood, and the plasma of the rehabilitated person will be extracted into the patient’s body, that is, the “foreign aid” antibody will be introduced to help the patient to kill and neutralize the virus. Principle.

5

Don’t use it as a “magic medicine”

“Plasma treatment” is performed by extracting the plasma of the healed patients for the screening of related pathogens. After strict blood biosafety testing, virus inactivation, and antiviral activity testing, plasma products are prepared and injected into critically ill patients. The human immune system fights against the new coronavirus.

In principle, after the recovery period plasma is used in critically ill patients, it can promote the virus to turn negative, but this does not mean that it will “show spirit”. Although “plasma therapy” is easier than developing vaccines, there are still some difficulties that must be overcome.

First, the demand for blood products is high.

The composition of blood products is complex, and the presence of high-titer antibodies is unknown. Take plasma, in addition to antibodies, there are water, inorganic salts, nutrients, hormones, uric acid and so on. In order to ensure the therapeutic effect, high titers of antibodies are required in the plasma, as well as “neutralizing” antibodies.

On the one hand, the stability of the antibody content of the rehabilitated patients is still to be discussed. In the absence of viral stimulation, some patients may have antibodies in the blood for a few days, or it may be a few days or weeks.

On the other hand, each infected body produces more than one kind of antibody, and even more than 10 kinds of antibodies. However, only one of them can become a neutralizing antibody, which can prevent the virus from entering the cell.

Even if the antibody concentration stabilizes, if the donor’s plasma high titer is very low in effectiveness, it will be difficult to achieve results. In addition, viral antibodies that are not used in the rehabilitation patients enter the body of the patient being treated, and will also cause adverse reactions in the body.

Second, the requirements for patients and donors are not low.

For example, for the blood required for the new plasma virus “plasma therapy”, donors must meet three conditions:

  • Being diagnosed with new coronavirus infection, discharged from hospital after treatment and recovery, the discharge time can reach more than one week;
  • Age between 18 and 55 years old, no history of cardiovascular disease, diabetes, epidemic, male weight above 50 kg, female weight above 45 kg;
  • Patients with immune system diseases, children, and the elderly are not suitable for donating plasma. Some people with severe infection control are not suitable for donating when the body has not fully recovered. Even after passing a strict donation process, patients may not be applicable. In some critically ill patients, if the virus causes inflammation out of control or severe microcirculation disorder, plasma therapy cannot play a therapeutic role.

Thirdly, this kind of niche therapy cannot benefit the public as much as drug therapy.

The number of new coronary pneumonia patients eligible for donation is limited. Based on the blood donation volume of about 400 ml per cured person, the final collection volume will not be too high, and the number of patients who can be treated is limited.

WHO Director-General Tan Desai announced at the end of March that the WHO research project “Unity Pilot Project” will start clinical trials to compare the efficacy of anti-new coronavirus drugs. Tan Desai said that the WHO “Unity Pilot Project” is a historic trial that will greatly reduce the time required to obtain reliable evidence about the efficacy of drugs. Before the victory of the “Unity Test Project”, as Pan Leiting, a member of the Standing Committee of the Microcirculation and Blood Therapy Committee of the Chinese Society of Microcirculation and a professor of Nankai University, said, “Without vaccines and better treatments, borrow The plasma of the rehabilitated patients can be regarded as the “last line of defense” for the severe patients with new coronary pneumonia.

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