The article is from the public number: create (ID: xingshu100) , author: Huang Yicheng.
Ebola virus is known as “one of the most dangerous viruses in the world” due to its lethality of 50 to 90%.
Ebola research dates back to the 1980s and 1990s, but the vaccine was actually approved in 2019.
Scientists have witnessed many intangible constraints over the years: vaccine development costs are billions of dollars, pharmaceutical manufacturers have no enthusiasm for R & D cooperation, and because the epidemic has only sporadic emergence, there is almost no opportunity to carry out experimental vaccines Rigorous testing.
Here is how the Ebola vaccine was born after various twists and turns.
In 2015, in the outpatient lounge of the Liberia Hospital, health workers wearing protective clothing talked to people waiting for treatment
In the spring of 2014, when the Ebola epidemic swept through West Africa, a scientist named Gary Kobinger (Gary Kobinger) Watching news from Canada.
Köbinger is the head of the Special Pathogens Division at the National Microbiology Laboratory in Winnipeg, Canada. His team has contributed significantly to Ebola and other viral hemorrhagic fever work. Kobinger himself has led the development of an effective Ebola therapy.
Winnipeg Laboratories has been studying the Ebola vaccine for many years, and it is currently very effective in animal models. The laboratory even produces human vaccines, hoping to conduct human tests. But Until April 2014, the research has not achieved substantial results. The vaccine has never actually been used in an outbreak, and no major pharmaceutical company has expressed interest in developing it.
With the rapid spread of Ebola in Guinea, a country with no regulatory experience, Kobinger has contacted the World Health Organization to provide vaccines.
WHO, however, rejected the proposal.
“They thought it was too early to advance,” Kobinger recalled. He was told that Guinea lacks the infrastructure to use experimental vaccines.
“That’s true,” he added.
But The reality is that it is unlikely that the virus will only stay in West Africa, and it will eventually erupt.
Köbinger’s predecessor, Dr. Heinz Feldmann (Dr. Heinz Feldmann) said: “The big change changed the game Rules and remind people that this alien virus may pose a real threat to regional public health. “
By 2014, Feldman had long since given up hope: The vaccine called “rVSVZEBOV” in countless studies he published might never have been made.
Structure of Ebola virus
1990s: inspiration from Germany
In the early 1990s, a Yale University scientist named John Rose (John Rose) tried to find an animal virus VSV (Viral stomatitis virus) as a method of vaccine delivery system. Although the virus can infect people, it does not make people sick. The immune system responds quickly to the virus, and the levels of antibodies it induces are surprisingly high.
Ross believes that if the virus can contain genes from viruses such as influenza or HIV, it will be an important step in vaccine development.
But he and his lab students have tried for about six years, and have not yet succeeded in adding genes from other viruses to VSV. He recalled that a good student decided to leave his laboratory because she concluded that the job would never succeed.
In 1994, Rose heard that German researchers successfully modified the rabies virus. Using the German method, he can modify the VSV virus within a few months.
Rose recalled: “This opened up a whole new field of VSV research for us.”
To see if the system works, his research team added protein from the influenza virus to VSV and injected it into mice. “The neutralizing antibody reacts very quickly,” he said, “mice are fully protected after one injection.”
Rose’s lab later used VSV as an implementation of avian influenza, influenza A virus, SARS, Zika, and other pathogens.Testing the core of the vaccine, the results are all effective.
But without the highly secure laboratories needed to handle Ebola, researchers are unable to study the world’s most dangerous virus. Nonetheless, Rose believes that, theoretically, the VSV Ebola vaccine will soon appear.
John Rose’s Lab at Yale
Yale filed a patent for Ross’ VSV structure and licensed it to Wyeth Pharmaceuticals.
It is estimated that Rose has shared his VSV structure with at least 100 laboratories around the world. One of these laboratories is located in Marburg, Germany.
When a scientist named Hans-Dieter Klenk (Hans-Dieter Klenk) came in the 1980s Prior to Marburg, Marlborough Labs had not conducted research on Ebola. Kroenke decided to change all that.
With Rose’s virus, Klenk’s team can study individual Ebola genes by putting them on VSV. The advantage of this method is that it can work at a lower level of biological control than previous Ebola-related research, and the process is faster and cheaper.
Even so, there is some discussion about whether the VSV hybrid virus can be made into an Ebola vaccine. But since this group does not have a highly sealed laboratory for animal research, it cannot test this theory.
From Marburg to Winnipeg
In Canada across the Atlantic, a new national microbiology laboratory is under construction.
The laboratoryIncludes Biosafety Level 4 facilities with the necessary conditions to study Ebola. Feldman was recruited to lead a special pathogen group there. When leaving Germany in 1999, he asked Kroenke if he could continue to use the VSV structure, and Kroenke agreed.
“It became the ‘Canada Vaccine’ in the future. But in fact, it originated in Marburg,” Kronke said.
Feldman recalled that when he was in Marburg, he hadn’t even thought about using Rose’s VSV structure as a vaccine. “We don’t have a vaccine plan. We are not interested in vaccines,” he said. “We are actually using it as a model system for studying glycoproteins.”
After moving to a Canadian laboratory, Feldman and his collaborators, Tom Gaspard of the U.S. Army’s Institute of Infectious Disease Medicine (Tom Geisbert) I heard Dr. Gary Nabel, then the head of the National Institutes of Health’s Vaccine Research Center, (Dr. Gary Nabel) < / span> A speech about Ebola. The latter believes that glycoproteins are the cause of severe damage when Ebola infects animals and humans.
Feldman and Ebola expert Gaspard believe Nabel is wrong, and they can use the VSV structure to prove it.
In Winnipeg, Feldman’s team infected mice with the VSV virus containing Ebola glycoprotein. If Nabel’s theory is correct, exposure to this protein will kill mice.
However the cute rodents are safe.
After the fact, the research team decided to expose the mice to Ebola and see what happens. As a result, all mice infected with the glycoprotein-bearing VSV virus were completely protected from the disease, and all mice not exposed to the VSV virus died.
Feldman said, “I think this is the beginning of the vaccine project.”
In 2003, a shocking new disease-known as severe acute respiratory syndrome (SARS) – China broke out and spread to Vietnam, Singapore and Canada. The Canadian Laboratory’s Special Pathogens Group also joined the study to try to determine what caused the new disease and how to control it.
With the cooperation of Winnipeg’s team, Gaisbert agreed to replicate mouse studies in non-human primates, which is considered to be the best animal model for human infection with Ebola.
Like the rats before, monkeys exposed to rVSV-ZEBOV for the first time survived what should have been a deadly Ebola attack.
In 2005, a paper on this research was published in Natural Medicine, which showed that a modified VSV vector containing Ebola glycoprotein is not only safe, but also can be used as a basis for an effective vaccine .
Scientifically, this is exciting. However, the project is actually difficult to start: it is estimated that the cost of vaccine development is about $ 1 billion. The pharmaceutical industry is not interested in producing a product that prevents diseases that only occur in poor countries. At the time, Ebola had killed approximately 1,300 people in the nearly 30 years since its discovery.
“Yes, this is exciting, but what can this excitement bring you?” Feldman said. “You went to the bar next door, had a beer, and went on working.”
In 2008, Feldman left Winnipeg to become the leader of the virology program at the National Institutes of Health’s Rocky Mountain Laboratory in Mont Hamilton.
Mobile biological control device for monitoring a German researcher infected with Ebola virus
An accident and two factors
In March 2009, there was a sudden crisis.
A German researcher pierced his finger with a needle while using Ebola virus in a mouse laboratory. The needle penetrated three layers of gloves, and although the wound did not bleed, her skin was pierced.
She was taken to the University of Hamburg Medical Center, USEbola researchers from Canada and Canada have diagnosed her, and experts have concluded that she should be offered the VSV vaccine.
48 hours after the accident, the unidentified woman was vaccinated.
The next day, she has a fever. Fever caused by live virus vaccines such as rVSV-ZEBOV is not uncommon, and this is actually a sign that immune stem cells have been activated. But fever may also be the first symptom of an Ebola infection. Unable to know what kind of situation they were facing, the doctors who monitored the researchers transferred her to a specially-built biological isolation treatment room.
After the fever subsided, the woman did not show symptoms specific to Ebola. It is unknown whether the vaccine stopped the infection or if she was not infected. Feldman and other researchers believe the latter is more likely.
But the important thing is that the use of the vaccine has not had a negative impact, which has prompted an important decision for policymakers who are struggling to deploy rVSV-ZEBOV in an emergency.
If two factors are not in place, Ervebo will never be produced: one is funding, and the other is talent.
Funding is a $ 2 million grant to Winnipeg Labs. Although this grant is only a drop in the bucket for scientific research, it did not come easily. Feldman and Steven Jones have done many animal experiments in the laboratory, and they have repeatedly applied for funding from the US government. But their applications have been repeatedly rejected.
This grant was provided by a Canadian defense project that also funded research on tools to combat bioterrorism.
Talent refers to Judy Alimonti (Judie Alimonti) , a humble immunologist and laboratory scientist .
“Judy spent two years alone on this job,” Kobinger said. “She is fully committed.”
After obtaining a patent for the vaccine system and a license from Wyeth Pharmaceuticals to use its platform to produce Ebola and other viral hemorrhagic fever vaccines, Winnipeg Laboratories looked for a number of pharmaceutical companies to seek cooperation for vaccine development partner. But the only one I ’m interested in is a company called “BioProtection Systems” (BioProtection Systems Corp.) , a biotechnology company engaged in cancer vaccine research.
Heinz Feldman (left) and Gary Kobinger are testing Ebola virus
This interest has nothing to do with Ebola or even infectious disease vaccines. In effect, the company is looking for assets to increase its portfolio to generate capital investments. “For them, it’s just a decision to enhance their portfolio, making it easier for them to get funding to do other work that interests them.”
Passion has fallen into a deal.
The company was later acquired by a pharmaceutical company called Lumos Pharma, and development of the Ebola vaccine was put on hold.
Outbreak, try experimental vaccines and therapies
The Ebola crisis in West Africa then broke out.
The outbreak started at the end of 2013 and is developing as quickly as every previous Ebola outbreak. At first, the patient was diagnosed with malaria or other illnesses, and then health workers became ill before judging that it was Ebola.
WHO reports that on March 23, 2014, a “rapidly developing” Ebola outbreak occurred in southeastern Guinea. At that time, there were 49 cases and 29 deaths, more than half of the previously known Ebola outbreak. The following day, the statistical results increased to 86 cases and 59 deaths.
Within a week, cases were reported in the capital of Guinea, the first time Ebola has appeared in a city. By the end of March, Guinea’s neighbor Liberia is also investigating potential cases.
Kobinger’s proposal to WHO upon his return to Canada was rejected. He heard that a few weeks later, GlaxoSmithKline, which was working on an Ebola vaccine,The department also provided the vaccine to WHO and was rejected.
Nevertheless, Kobinger sees the bright side: “This has planted the seeds of the vaccine.”
As Ebola spread from Guinea to Liberia and Sierra Leone, there is an acronym called MSF (the French acronym “MSF” ) ‘s organization has been warning WHO that the situation on the ground is rapidly deteriorating. With the help of Kobinger, MSF has begun to promote the use of the VSV vaccine.
On August 8, 2014, WHO declared the epidemic a global health emergency. A few days later, the Canadian government announced that it would donate the vaccine to WHO.
This is a critical moment, but it creates a difficult question: Is the vaccine safe to use? What is the proper dose? How can human trials be performed during epidemic transmission?
Person suspected of Ebola virus is lying on the ground after the arrival of a doctor’s borderless ambulance
In Africa, the use of untested drugs or vaccines is considered unethical because Africa lacks clinical safeguards and people still remember the 1996 scandal in which Pfizer used meningitis drugs to kill 11 children.
As the crisis continues to grow, a WHO meeting has concluded that, given the particular threats faced, experimental vaccines and therapies can be tried in a “forced immoral” way.
The meeting also decided that in order to use a donated Canadian vaccine, clinical trials must first assess its safety and determine the appropriate dose. But everyone knew in their hearts that there was no suitable institution to undertake this work.
Mary-Paul Kinney (Marie-Paule Kieny) was then the head of WHO’s push for the development of drugs and vaccines for diseases such as Ebola. Gini recalled:” So when we said, ‘ When we should do clinical trials in Africa, they were completely lost. “
So, WHO set out to find a more experienced pharmaceutical company to cooperate or buy a vaccine.
This shortlist is not long. Merck has been discussing how to help deal with the outbreak, and the vaccine seems to be appropriate.
“We have understood how to scale the production of carriers in the system and we know how to manage the entire production process. We have a lot of know-how that complements what we have already done,” said Merck Strategic Communications, Global Public Policy and Dr. Julie Gerberding, Executive Vice President and Chief Patient of Population Health, said (Dr. Julie Gerberding) .
Merck said at the time: “From the exploratory discussions that started in early October to the decision on vaccine authorization in mid-November, this rate is unprecedented in the company’s internal decision-making because people recognize the urgency of vaccines.”
Merck announced on November 21, 2014 that it agreed to pay a $ 50 million license fee.
rVSV ZEBOV Ebola vaccine
In the same month, when researchers reached an agreement on the appropriate dose of the vaccine, Kobinger made a heartbreaking discovery: it was a vaccine used in a trial donated by the Canadian government, and now a key feature of the vaccine has been Was changed.
Feldman believes that this change has no effect on the effectiveness of the vaccine. “Frankly, it doesn’t matter scientifically,” Kobinger agreed. “But from a regulatory perspectiveLook, this is important. “
Köbinger quickly sent an email to the US Food and Drug Administration informing him of his findings.
“But I never received a reply,” he said, and the first phase of human trials had already begun.
Nevertheless, Kobinger urgently sent some vaccines to Feldman so that he could test the vaccines in primates to ensure that the changes did not affect the efficacy of the vaccine. As it turned out, it didn’t.
Finally, it succeeded
Evaluation of rapid clinical trials in 10 countries
Dr. Abdourahman Diallo (Dr. Abdourahmane Diallo ) is a public health officer working for the Ministry of Health of Guinea Dr. Xue is also one of those who responded to WHO’s appeal. He recalled that his colleagues were excited about the prospects for the study. Diallo said by email, “The only thing we want is to evaluate whether the vaccine is effective, because if possible, we want to contribute to finding a solution.”
After the vaccination, transmission seems to have slowed down. “But this is certainly not evidence,” said WHO’s Gini. “It’s just a feeling.”
A woman is vaccinated at a health centre in Conakry
In June, the trial’s data and safety monitoring committee concluded that the vaccine was working.
10 days after vaccination (time required for the immune system to respond to the vaccine) does not appear in the early vaccination population Case.
The Data and Safety Monitoring Committee recommends that health workers vaccinate anyone who has been exposed to Ebola as soon as possible.
On July 31, 2015, less than a year after the Canadian government donated the vaccine, The Lancet published the results of the trial. The trial found that the vaccine was 100% effective. The Lancet described the experiment as “an amazing scientific and logistical achievement.”
A girl receives Ebola vaccine in Beni, Democratic Republic of the Congo in July 2019
Despite the limited number of samples, this result is enough to convince Merck to continue advancing vaccines. Company executive Rick Bright (Rick Bright) estimates that Merck has spent about $ 175 million to support vaccine production and validation.
Ebola outbreak in the Democratic Republic of the Congo in spring 2018. Eight days after the outbreak was announced, the country agreed to use the vaccine under a “compassionate use” agreement, and as of now, more than 260,000 people have been vaccinated.
“I’m really proud of it,” Rose said of the role that vaccines play in it. “We work day and night, and now we finally succeed.”
On November 11, 2019, Ervebo was approved by the European Commission. This is the first time that the certification body has obtained any permit from a regulatory body.
The vaccine was approved in the United States on December 21.
Postscript
The Ebola vaccine is a major advance in human history against infectious diseases.
In fact, the development of any vaccine is not easy. This is a feat built on the hard work of countless scientific researchers and medical workers in many countries around the world for years, decades, and even decades.
This article pays tribute to the front-line researchers and medical workers.
The article is from the public number: create (ID: xingshu100) , author: Huang Yicheng.