This article is derived from the WeChat public account "Shenghui".
Today, due to "suspected" serious adverse reactions in British test volunteers, AstraZeneca (AZN.US) and the University of Oxford developed the Phase III testing of the Covid-19 vaccine has been temporarily stopped. This is the world's 9 vaccines in clinical trials, and the first Covid-19 vaccine candidate whose Phase III trial has been suspended.
Figure | A total of 9 vaccines have entered clinical trials worldwide, of which only 3 "single vaccines" have entered the late stage of clinical trials ( (Source: New York Times)
Just yesterday, AstraZeneca and eight other leading biotechnology and pharmaceutical companies have just signed a "historical oath"- on potential COVID-19 vaccines We will strictly abide by high-standard ethical requirements and solid and reliable scientific principles in R&D and testing. This statement may be a "reassurance" for the public, or it may be an indirect resistance to intervention by other forces that affect the progress of scientific research: on the eve of the announcement, US President Trump once again "induced labor" the vaccine, saying that the vaccine would Before a very special date" was authorized. This is obviously alluding to the general election on November 3, according to STAT News, a well-known medical and health media in the United States.
Five months ago, the "Operation Warp Speed" was launched. The US government hurled billions of dollars and planned to reduce the vaccine development time, which originally took four years, to about one year. This is considered by the outside world to be the United States. One of the most "ambitious" scientific studies in modern history. Three months ago, AstraZeneca received US$1.2 billion in vaccine research and development funding provided by "Operation Warp Speed" and an order for 300 million doses.
Although it is not uncommon for vaccines to be shelved due to failures in previous trials, it is unclear how long AstraZeneca’s clinical trials will be suspended. However, the use of vaccines to curb the spread is being "eagerly anticipated", so this time shelving and its impact on other vaccines will attract much attention.
Some overseas scholars have pointed out the need to pay special attention to this adverse reaction. At the same time, many well-known professors, experts and scholars at home and abroad have told Shenghui that this incident is normal and should not be over-interpreted. Some netizens appealed on social media: Don't panic! Do your research!
Suspected of serious adverse reactions or motor, sensory, neurological dysfunctionIf the volunteers in the trial have the following symptoms, That can be defined as "suspected serious adverse reactions", 1) need to be hospitalized; 2) produce life-threatening diseases; 2) death. Regarding the specific circumstances of the above-mentioned adverse reactions, AstraZeneca did not disclose other relevant details except for this adverse reaction that appeared in the phase II/III trial in the United Kingdom, but called this possible side effect "a kind of Potential diseases of unknown cause".
Under normal circumstances, Phase III clinical trials will not be suspended due to an adverse reaction. The industry believes that the suspension may be due to extremely serious conditions or there will be a large number of subjects. An adverse reaction occurred.
A spokesperson for AstraZeneca said in a follow-up statement that the company has suspended research on the vaccine project, and researchers are now combing through the database to find similar cases of adverse reactions.
According to clinicaltrials.gov data, this experiment plans to recruit 30,000 subjects. U.S. trials are currently being conducted in 62 locations, but some locations have not yet begun recruitingRecruit participants. But previous phase II/III trials in the UK, Brazil and South Africa have already started. It is not yet clear how many people will be affected, and what measures are being taken by research sites in various regions to deal with the shelving.
Figure | AstraZeneca adenovirus vector vaccine phase III clinical trial Screenshot of trial registration information (Source: clinicaltrials.gov)
It is still unclear how serious and rare the adverse events are, but this discovery may affect the rapid collection of efficacy data from the UK trial. If the above data is missing , AstraZeneca will not be able to apply to the US FDA for emergency use authorization of its candidate vaccine.
The New York Times quoted an anonymous source as saying that the adverse reaction caused by the vaccine may be transverse myelitis (transverse myelitis). Transverse myelitis manifests as paralysis of the limbs below the level of spinal cord lesions, loss of sensation, and dysfunction of the bladder, rectum, and autonomic nerves. The cause of the disease is still unclear. It is generally believed that this disease is an autoimmune reaction caused by viral infection and vaccination of the mental system. However, whether it is a direct virus intrusion remains to be studied, and trauma and excessive fatigue can be the cause.
Figure| MRI manifestations of transverse myelitis (source: Wikipedia)
An insider who asked not to be named said, Participants with suspected adverse reactions had participated in a phase II/III trial in the United Kingdom. The person also said that a volunteer in the British trial had been diagnosed with the disease "rhabdomyositis," an inflammatory syndrome that affects the spinal cord, usually caused by a viral infection. However, whether this disease is directly related to AstraZeneca's vaccine is currently unknown.
Figure | Alejandro Macias, professor and infectious disease expert at the University of Guanajuato in Mexico, said: “We don’t Knowing what adverse reactions forced AstraZeneca to stop testing of its COVID-19 vaccine. But it must be very serious, such as neurological problems (for example, Guillain-Barré syndrome, paralysis) or allergic reactions." Source: Tweet)
At the same time, Alejandro Macias, a professor at the University of Guanajuato in Mexico and an infectious disease expert, once posted the news on Twitter about "suspected The "speculation" of serious adverse reactions coincides with the above-mentioned media revelations and opinions.
Alejandro Macias wrote: “We don’t know what adverse reaction forced AstraZeneca to stop its COVID-19 vaccine trial. But it must be very serious, such as Nervous system problems (e.g. Guillain-Barré syndrome, paralysis) or allergic reactions."
Expert: Stage III problems are normal, but it is necessary to investigate whether they are related to adenoviral vectors
The practice of suspending trials is a normal preventive measure taken in vaccine trials, and it is also a key reason why vaccine clinical trials take a long time. "This is what it means to do Phase II and Phase III trials," said Dr. Phyllis Tien, an infectious disease doctor at the University of California, San Francisco. "We need to evaluate safety. I think it is correct for the safety committee to choose to stop the trial before figuring out whether this is directly related to the vaccine."
The principle of AstraZeneca’s vaccine is to use a Viral vectors deliver coronavirus genes into human cells. In this case, the viral vector is a modified chimpanzee adenovirus that has been modified to make it harmless to humans. The coronavirus component of the vaccine is designed to trigger a protective immune response. If the actual coronavirus tries to infect the vaccinated person, this immune response will be awakened again.
In a paper published in The Lancet in July, AstraZeneca researchers reported that the phase I/II trial of the vaccine was designed to evaluate the safety of the product, and most Participants experienced some mild or moderate side effects, including muscle aches and chills. However, none of the reactions were considered "serious" or "life-threatening", and all reports of side effects subsided during the study. "The vaccine is safe enough to continue further testing." AstraZeneca emphasized.
Why is there such an astonishing flip in the Phase III test? There are other factors that cause this to happen?
In this regard, Duisburg-Essen University School of Medicine Professor Lu Mengji of the Institute of Virology said in an exchange with Shenghui that the current claim that vaccines cause adverse reactions is an over-interpretation. "The current report is that a volunteer who has received the vaccine has spondylitis. It is common for someone to become sick during the clinical trial process. According to the regulations, it must be suspended to find out whether the illness is related to the vaccine." Lu Mengji thinks.
Li Tianquan, founder of Yaozhi.com, believes that there may not be very direct factors. "The probability of serious unquantified reactions is extremely low. In the phase I/II trial, the enrollment rate is relatively small. The expansion of the sample size in the phase III test may expose the problem of serious adverse reactions. The effect of phase III is very low. It is to expand the population to fully verify the safety, so there is no problem with the test results of phase I/II, but the problem appears in phase III. This is normal."
STAT News reported that according to a According to people familiar with the matter, the nature and timing of the adverse reaction is not yet known, but the participants are expected to recover.
And my country's mRNA vaccine research and development company is convinced that the founder of Biology Li Linxian also expressed the same view on Shenghui. Li Linxian believes that "According to the information currently disclosed, we cannot know whether the cause of the above situation is the problem of the vaccine itself, or it is affected by the volunteer's own situation."
Li Tianquan Said, “In the process of drug development, there are usually various issues related to the safety and effectiveness of vaccines, but this also brings us some enlightenment. For vaccine development, safety issues cannot be ignored. We cannot shorten the test time in order to improve efficiency, or even go to large-scale applications before the safety is fully proven."
Lu Mengji also emphasized that I personally think that this news will not affect the vaccine development itself. Negative impact. Due to the global thirst for viral public health events, clinical trials of various vaccines will continue to be carried out step by step. Until it is fully completed and the final conclusion is reached. "
Although the problems in the progress of vaccine trials are normal. However, many experts also emphasized to Shenghui that AstraZeneca’s vaccine candidate is an adenovirus vector vaccine, and the adenovirus itself has a specific band The chain reaction of the coming needs attention.
Jin Dongyan, a professor of virology at the University of Hong Kong, also emphasized to Shenghui, “Up to now, adenovirus has never been approved for use in vaccines. The main reason is that he will Causes serious side effects. "Lu Mengji also said that viral vector vaccines have a strong ability to stimulate immune responses. A strong immune response also means that the human body will respond more strongly, which may easily lead to adverse symptoms.
" Whether it is for AstraZeneca’s Oxford University vaccine candidates or the adenovirus zerg vaccine project currently underway in my country, the problems that the adenovirus vector itself may bring are always clear facts in the industry. From the Phase I/II clinical data released by AstraZeneca, it can be seen that the side effects of the candidate vaccine are very serious. This point does not need to be covered. 1/10 of the volunteers have a fever of more than 40 degrees. It is indeed a serious situation. "Jin Dongyan said.
"As early as the 1990s, there were fatal cases in the US gene therapy tests using adenovirus as a vector. Therefore, the most important thing is that human intervention is needed to optimize various indicators to minimize the side effects of this situation. "Jin Dongyan emphasized.
Therefore, Lu Mengji also believes that "Whether the suspected severe irregular reaction is related to the recombinant adenovirus used in the vaccine must also be investigated. "
At the same time, Lu Mengji also focused on telling Shenghui that the current practice of vaccinating some people when the vaccine has not passed the phase III clinical trial is very risky, especially If the vaccinators cannot accept the supervision of professional medical personnel on a regular basis, unexplained and unexplained cases are prone to occur, which will bring insurmountable obstacles to the promotion of vaccines. Li Tianquan believes that this has also given me a chance.
Vaccine research and development has brought a revelation. "For marketed or quasi-marketing candidate products, very strict standards must be used to monitor its adverse reactions. ”