The COVID-19 vaccine skipped preclinical animal trials, increasing the risk of failure. In the process of normal drug and vaccine development, we need to screen multiple candidate molecules in the animal model of disease before clinical, and find out the candidate molecules with the best effect and acceptable toxicity in animals for follow-up clinical trials.

A clinical trial of novel coronavirus vaccine began on Monday, and the first volunteer to participate in the trial will receive the experimental vaccine on the same day, a US government official said, according to local media reports. the clinical trial will recruit 45 participants.

It is reported that the vaccine was developed by Moderna Inc, which provided samples of the vaccine to the National Institutes of Health to prepare for final trials to determine whether it can effectively prevent viral infection.

1. Why did this vaccine come out so quickly?

The vaccine that Moderna Inc enters the clinical trial this time is the mRNA vaccine, not the traditional vaccine.

Traditional vaccines inject attenuated or inactivated pathogens, or part of the pathogens ("antigens") into the human body. The human immune system recognizes antigens and then produces antibodies through immune reaction. The risk of traditional vaccine research and development is relatively low, but the screening of attenuated / purified pathogens takes a long time, and the vaccine production process is complicated, so it is not suitable for rapid response to sudden epidemic situation.

MRNA vaccine is a new vaccine technology. What is injected into the human body is not the pathogen itself, but the pathogen-specific mRNA sequence (such as the S protein used by novel coronavirus to bind to the ACE2 receptor). Liposome-encapsulated mRNA can enter muscle cells after intramuscular injection. MRNA is transcribed into pathogen-specific proteins in muscle cells and expressed on MHC1 receptors. Dentritic Cell can recognize the pathogen protein expressed on muscle cells and stimulate immune response to produce antibodies. In other words, by injecting mRNA, human cells can become machines for expression and display.

MRNA vaccine does not need a complicated strain screening process, as long as it involves mRNA sequence, synthesis, liposome encapsulation in a few steps, a small amount of production can be completed in a few weeks, speeding up the next preclinical and postclinical phase. At the same time, the production process of mRNA is simpler than the traditional vaccine, does not need to produce biologics strict production line and equipment requirements, and is suitable for mass production and rapid response to sudden outbreaks.

During the 2016 Zika virus crisis, Moderna Inc, a leader in mRNA technology, partnered with the Defense Advanced Research projects Agency (DARPA) and the Biomedical Advanced Research and Development Administration (BARDA) to launch a research and development program for Zika virus. It took only 10 months from mRNA sequence synthesis to the completion of preclinical animal trials to clinical trial declaration (IND), which can be called the largest in the history of vaccine research and development, and fully reflects the characteristics of rapid response of mRNA vaccines to sudden outbreaks.

During novel coronavirus's outbreak, Moderna Inc, in cooperation with the US National Institutes of Health (NIH), directly skipped the primate experiment that proved the effectiveness of the vaccine (it is rumored that NIH conducted a small-scale mouse experiment). It took only two months from the beginning of the project to the start of the first phase of the clinical trial. It is entirely possible to complete the design and production of the mRNA vaccine in two months (and to counter accusations of US bioweapons conspiracy theories), but saving half a year of primate experiments that prove the effectiveness of the vaccine before clinical practice is a big gamble.

2. Does clinical trials take a long time?

Media reports revealed that the clinical trial of Moderna Inc and COVID-19 vaccine will recruit 45 healthy volunteers and inject twice on the 1st and 29th day. The main clinical end point will be the adverse reactions of the vaccine (short-term adverse reactions will be measured 7 days after injection. And follow-up 394 days to see long-term adverse reactions).

At the same time, the secondary end point of this clinical trial was to check the production of specific antibodies to novel coronavirus in volunteers from 1 to 57 days after vaccination. In other words, this phase 1 clinical trial will also see the effect of COVID-19 vaccine.

The clinical trial is expected to end on June 1. In addition to long-term adverse reactions, other results, including short-term adverse reactions and antibody production, should not surprisingly be announced by September.

3、What is the probability of clinical success?

In short: security is not a big problem, but the effect is risky

If a drug or vaccine is to be put on the market, it needs to be confirmed by clinical trials: safety, and efficacy.

Let's start with security. The safety requirements of the vaccine are very strict, and the main purpose of this phase I clinical trial of Moderna Inc's mRNA vaccine ("main clinical end point") is to prove the safety of the vaccine (short-term and long-term adverse reactions). Although no mRNA vaccine has been approved for sale, Moderna Inc has several vaccines that have been proved to be very safe through phase I or even phase II clinical trials. For example: mRNA-1944 (Chikungunya virus vaccine), there is no obvious adverse reaction in the first clinical phase.

Moderna Inc previously conducted phase I clinical trials of five mRNA vaccines (you can see the summary below), which unanimously proved the acceptable safety of the mRNA vaccine. Therefore, I am confident that the safety of Moderna Inc's COVID-19 vaccine should not be a problem.

Let's see how it works. I am worried about whether Moderna Inc's COVID-19 vaccine is effective (causing vaccinators to produce antibodies to COVID-19 S protein) for two reasons:

First, there is a precedent that mRNA vaccine fails to produce enough antibodies in the first clinical phase. The Zika virus vaccine mRNA-1325, which takes only nine months from synthetic sequence to IND, has been shown to produce antibodies and protect primates from Zika virus infection in animal experiments, but it has not been shown to produce enough antibodies in humans in phase I clinical trials. Moderna Inc went back to the furnace to remake it, re-selected a mRNA sequence mRNA-1893, and re-launched a new phase I clinical trial. The new candidate vaccine, mRNA-1893, is 20 times more effective than the previous mRNA-1325, saving the project, but the loss of time caused by this return to the furnace makes people wonder, why not make more efforts to select the mRNA sequence for the first time?

Moderna Inc's other mRNA virus vaccines have proved satisfactory antibody production in the first clinical phase, but only this rapid response Zika vaccine has failed in the clinical first stage. does it prove that Moderna Inc advances too fast in the rapid response mechanism and does not have the same "slow work" as other vaccine research and development? How likely is COVID-19 's quick response to repeat the same mistake this time? We don't know that.

Second, the COVID-19 vaccine skipped preclinical animal trials, increasing the risk of failure. In the process of normal drug and vaccine development, we need to screen multiple candidate molecules in the animal model of disease before clinical, and find out the candidate molecules with the best effect and acceptable toxicity in animals for follow-up clinical trials. In other words, preclinical trials are often a "funnel" to identify the most successful candidates in the human body in a low-cost way.

This time, because COVID-19 spread too fast around the world, the animal model has not yet been established, human beings have been faced with serious challenges, vaccine research and development is imminent. This time, Moderna Inc's vaccine did not complete a complete animal experiment as usual (rumored to have done only a small-scale mouse experiment, completely skipping the primate experiment that proved the effectiveness of antibodies) and went directly to clinical trials. There are few precedents before. Save half a year, but also inevitably increase the risk of failure.

4. How long will it take for this vaccine to be available?

Normally, vaccine development is a very time-consuming process. After the completion of phase I clinical trials, phase II and phase III clinical trials are generally carried out. The purpose of the Phase II clinical trial is to find the most appropriate dose among hundreds of volunteers and to further evaluate the effectiveness of the vaccine. Phase III clinical trials were conducted in hundreds or even thousands of volunteers to confirm the effectiveness of the vaccine.

For example, Merck's tetravalent HPV vaccine, Gardasil III, was tested in 6463 women over a period of four years and was finally approved by FDA. Merck's follow-up nine-valent HPV vaccine, phase III, was followed up in 14215 women for 6 years. According to Mark Feinberg president and CEO of the International AIDS Vaccine Initiative, the average vaccine development cycle is 10-15 years.

For the imminent COVID-19 crisis, we certainly can not wait 10-15 years. If a vaccine from Moderna Inc or another company can prove effective in a small phase 2 or even phase 1 clinical trial, FDA will be approved quickly due to political and epidemiological pressure. According to Anthony Fauci, "Zhong Nanshan" in the United States, if all goes well, it will take 12 to 18 months for Moderna Inc's vaccine.

Even I boldly estimate that if the vaccine produces antibodies in this phase 1 trial, it is not impossible to get FDA approval in September this year. But the premise must be: phase 1 clinical trial is not only short-term safety is no problem, the effect of producing antibodies must also be good enough. Going back to my previous analysis of this vaccine, I am not too worried about the safety of this vaccine, but it is too early to tell what the final effect will be.

Moderna Inc did not walk alone in this vaccine development. Also on the fast-response mRNA vaccine track, the research and development process of the two German companies CureVac and BioNTech is also orderly. BioNTech today reached an agreement with Fosun Pharmaceutical to jointly develop COVID-19 's mRNA vaccine, and plans to start clinical trials in China, Germany and the United States at the end of April. Inovio Pharmaceuticals also plans to start clinical trials of the DNA vaccine later this year. The eggs are not in one basket, and I have reason to expect that at least one company will have an approved COVID-19 vaccine by this time next year.