COVID-19 and mRNA vaccines: the first large-scale testing of a new method

On January 10, 2020, Chinese researchers released the RNA sequence of the new coronavirus (later the WHO named it Severe Acute Respiratory Syndrome-Coronavirus-2, or SARS-CoV-2). Immediately, scientists studying genetic vaccines turned their attention to the new pathogen that caused the coronavirus disease-2019 (COVID-19), SARS-CoV-2. They know that a fast-reacting genetic platform can shorten valuable development time from weeks to months, which is crucial during a pandemic.

They are right. Only 66 days later, when the first clinical trial of the SARS-CoV-2 vaccine was conducted in the United States, volunteers were vaccinated with the mRNA vaccine (mRNA-1273) provided by the biotechnology company Moderna and the National Institute of Allergy and Infectious Diseases (NIAID). ).

On July 27, based on the encouraging early results of mRNA vaccines, both Moderna mRNA-1273 and another candidate mRNA vaccine BNT162b2 from BioNTech/Pfizer in Germany entered Phase 3 trials, and a total of 60,000 volunteers will be recruited. . Dr. Francis Collins, director of the National Institutes of Health (NIH), said at a press conference that day that this milestone was "significantly faster than the usual vaccine preparation." NIH officials said that results could be obtained as early as this fall.

Although the speed is unprecedented, the mRNA vaccine has not been clinically proven. There is currently no commercial mRNA vaccine used, and until now, it has not been tested in large-scale human trials. With COVID-19, all this will change. Experts said in an interview that if this technology becomes popular, the epidemic will help introduce a new "plug-and-play" method of vaccinology.

Genetic advantages

Current antiviral vaccine design can be divided into two camps: protein-based or gene-based.

Protein-based vaccines deliver antigens that stimulate the immune system to the body. This category includes fully inactivated (killed) vaccines in polio and influenza vaccines, and subunit vaccines and viroid particles in hepatitis B and human papillomavirus vaccines.

Gene-based vaccines have different characteristics. They carry the genetic instructions of the host cell to make antigens, which are more able to mimic natural infections. In the case of coronavirus, the target antigen is the surface spike protein (Spike protein) used by the virus to bind and fuse with human cells. Paul Offit (MD), a professor of vaccinology at the University of Pennsylvania, said: “You are not giving them protein, but giving them genetic material, and then instructing them how to make this spike protein, so that they produce Hope to have a protective antibody response.” He explained in the JAMA live broadcast in June. This method of

is not completely unfamiliar. In live attenuated vaccines, such as measles, mumps, and rubella vaccines, the weakened virus integrates its genetic instructions into the host cell, causing the body to produce copies of the virus that cause antibodies and T cell responses. In new gene-based designs (viral vectors, DNA and mRNA vaccines), scientists synthesize and insert genetic instructions for pathogens of interest to induce immune responses. The

virus vector technology can transmit genetic information through a less harmful virus (usually the adenovirus that causes the common cold). This virus is sometimes engineered so that it cannot replicate in the host. DNA and mRNA vaccine designs can provide naked nucleic acids or, more recently, encapsulate them in carrier nanoparticles. In each general platform, the same production and purification methods and manufacturing equipment can be used to produce vaccines against different diseases.

When COVID-19 just appeared, these highly adaptable technologies were waiting. Dr. Louis Picker, deputy director of the Institute of Vaccines and Gene Therapy at Oregon Health and Science University, said: "The people who jump right into this step are those who sit there and can do the vaccine platform." The basics they have to doThe above is just figuring out which part of the virus they will put in the vaccine and then using it. "

benefited from the research on severe acute respiratory syndrome coronavirus (SARS) that began in 2002, and then the Middle East respiratory syndrome coronavirus (MERS) research that emerged ten years later. Scientists know that Initial attention was focused on the spike protein of the new coronavirus. They also know which genetic modifications can stabilize the spikes in its "pre-fusion" configuration (important for a strong and safe antibody response), and which Genetic modification can make mRNA less inflammatory and therefore safer. They also learned how to purify mRNA to remove contaminants, and how to protect it from degradation in the body by encapsulating it in lipid carrier molecules. These have been The delivery vector used with therapeutic small interfering RNA also helps mRNA to cross cell membranes and may even have an immunostimulatory adjuvant effect. According to Dr. Barney Graham, associate director of the

NIAID Vaccine Research Center, many of these innovations have only recently been realized. He said: "In the past ten years, vaccinology has undergone fundamental changes. "I have been doing this kind of work for a long time, and the things that can be done now, the technologies available, the way we can understand things in great detail is really amazing to me. "

is different from traditional vaccines. mRNA vaccines are not grown in eggs or cells. This is a time-consuming and expensive process. Essentially, these vaccines are just chemicals that are catalyzed in test tubes or tanks. They are not produced on a large scale, but this makes it easier to develop them quickly (at least in theory) on a large scale.

Drew Weissman, MD, a researcher on mRNA vaccines at the Perelman School of Medicine at the University of Pennsylvania, said: “We are publishing SARS- RNA was prepared within a week of the CoV-2 sequence. "This speed has driven development: According to Weissman, both groups are currently testing nucleic acid-based vaccines in phase 3 trials, and both groups have obtained his team’s mRNA preparation license from the university. .Why is

mRNA?

As of the end of August, 30 potential vaccines against COVID-19 are in clinical trials, and another 139 are in preclinical development, including candidate vaccines based on genes and proteins. But genetic methods have Potential immunological advantages. In addition to eliciting antibodies and CD4 + helper T cells, they also recruit CD8 + cytotoxic T cells, also known as killer T cells, through the major histocompatibility I (MHC I) pathway.

According to Dr. Otto Young, an infectious disease researcher and clinician at the David Geffen School of Medicine at the University of California, Los Angeles, if human cells produce this protein themselves, human cells can only be on their surface through this pathway. This viral protein appears. He said: "If you just inject a protein or inject a dead virus, it will not enter the pathway and will not be displayed in this way, so it will not stimulate T cells. "

has obvious advantages even in gene-based platforms. When removing the viral vector, both DNA and mRNA vaccines eliminate the pre-existing immune risk against it, which may limit effectiveness. Yang said: "If Your immune system clears the vector before it actually enters the cell, that is a big problem. "This immunity may also be more common in certain geographic regions than in other geographic regions, so that the effectiveness of the vector vaccine depends more or less on the region. The existing immunity of

can explain why it is in the phase 1 clinical trial. , The non-replicating viral vector COVID-19 candidate vaccine from CanSino Biologics Inc and several Chinese institutions caused low levels of neutralizing antibodies. The pre-existing neutralizing antibody against the vector, namely human adenovirus 5 (called Ad5), It is as high as 69% in the United States and 80% in Africa. Offit said in a live broadcast in August more than ten years ago that it needs further attention that men with Ad5 immunity are receiving experimental Ad5 vectors. The risk of HIV infection increases after the HIV vaccine.

To solve these problems, ChAdOx1 nCoV-19 (a type from AstraZeneca and OxfordThe non-replicating viral vector candidate in the university’s phase 3 trial used an adenovirus that infects chimpanzees rather than humans. However, it is possible that the existing immunity that cross-reacts to human adenovirus will still reduce the response.

According to Weisman, mRNA vaccines also have advantages over DNA vaccines. In DNA vaccines, genetic material must first enter the nucleus of the host cell. From there, mRNA is created, and the mRNA enters the cytoplasm from the nucleus to form proteins in the cytoplasm. However, genetic information can only enter the nucleus during cell division, making the process inefficient.

researchers are trying to use electrical pulses to solve this problem to increase the uptake of DNA into cells during vaccination. However, the mRNA platform just bypasses this step. Weissman said: "When encountering RNA, 95% of cells will absorb RNA and produce protein, so this is a very effective process." The

proof is in the pudding (the proof lies in the evidence)

4 All COVID-19 vaccine developers that have published clinical trial data use non-replicating adenovirus or mRNA platforms. The US government is betting on some of these new technologies. Under the auspices of the "Operation Lightning Speed" vaccine development program, the US government has purchased hundreds of millions of doses of Johnson & Johnson’s ChAdOx1 nCoV-19, modern mRNA-1273, Pfizer’s BNT162b2 and a research non-replicating Type virus vector vaccine. Whether or when it is approved, the dose is ready for use.

Now everyone is concerned about safety and effectiveness. Although non-replicating viral vector vaccines are relatively new, they have been extensively studied in HIV and other disease trials. Janssen's new Ebola vaccine protocol uses two different non-replicating viral vectors and was approved in Europe in July.

However, the same level of clinical testing has not been conducted on mRNA vaccines. Researchers have studied mRNA-based therapeutic antibodies and therapeutic cancer vaccines based on research. But less than three years ago, the German company CureVac and academic collaborators published the first phase results of the first preventive mRNA vaccine clinical trial for anti-rabies.

Since then, potential mRNA vaccines against rabies, influenza, Zika virus and some other viruses have been studied in small early trials, many of which are still in progress. In both rabies and flu trials, the candidates stimulated promising but lower-than-expected neutralizing antibodies. Some moderate and severe injection site or systemic reactions have been reported, although serious incidents rarely occur.

So far, in the early COVID-19 trials, the results of the mRNA platform are encouraging. Dr. Kathryn Edwards (Kathryn Edwards), the scientific director of the Vanderbilt vaccine research program, said: "Of course, these vaccines look like they are producing the immune response we need, and there are no serious adverse reactions." But , She continued, “The real evidence for pudding will be the phase 3 trial, where we will see if the vaccine can really prevent disease.” The US Food and Drug Administration stated that the COVID-19 vaccine requires at least 50% of the efficacy to obtain Approved.

tolerance may be another issue. Edwards said: "People must know that they may have some local reactions about a day or so after the vaccine injection, or they may feel a little unwell," Edwards said. She and others said that like any new drug, the Phase 3 study may also show more serious safety risks, and there may be unexpected adverse effects in the future. In a media briefing on July 27, Collins talked about some concerns: “Yes, we are developing very fast. But, no, we will not sacrifice safety or efficacy.” Experts say that several factors prove it. The safety of mRNA vaccines. First, mRNA does not cause infection. It also does not enter the nucleus, so it is believed that the chance of integrating it into human DNA is very low. In addition, the human body can decompose mRNA and its lipid carriers within a few hours, thereby alleviating people's concerns about long-term danger.

However, this rapid degradation raises questions about the protection period of mRNA vaccines. Researchers in Hong Kong have recently become more worried about the durability of the vaccine’s protection. He confirmed that a man with SARS-CoV-2 was later re-infected, despite his secondCases are asymptomatic. Yang and colleagues found that antibodies in patients with mild COVID-19 disappeared quickly. Yang pointed out that the current candidate's 2-dose treatment regimen may help overcome this, and their cell-mediated immunity should bring more appeal.

Offfit is a member of the National Institutes of Health (NIH) Accelerated COVID-19 Treatment Intervention and Vaccine Working Group. He said that it is not possible to know the protection period of any COVID-19 vaccine until the product is approved and put into use. How long will it last? But, as Picker said, even a safe and effective vaccine for a limited time is enough to "break the foundation of an epidemic."

surpasses COVID-19

If an mRNA vaccine works, its impact may far exceed COVID-19. Success can pave the way for the platform to be widely used for emerging pathogens and established pathogens.

Johns Hopkins University Health Safety Center senior scholar Amesh Adalja, MD, said: "We have indeed made great progress in vaccine development, which is expected to change the way vaccines are handled in the future."

scientists said that mRNA may enable this stability The vaccine without freezing or refrigeration. Chinese researchers recently showed that a potential mRNA-based SARS-CoV-2 vaccine can be stored at room temperature for at least one week.

Weissman is trying to develop a more effective second-generation mRNA vaccine, which can be used once. He also looks at the universal coronavirus vaccine using the gene platform. He said: "We have had three coronavirus epidemics in the past 20 years." "The next time this happens, we will have produced a vaccine that is ready to be shipped and used quickly to prevent a pandemic. Spread.”

Before COVID-19, his team had been studying mRNA flu vaccines and drug candidates for genital herpes and HIV. The flu virus changes with the seasons, making it an excellent candidate for a rapid "vaccine on demand" platform.

In Weisman's view, mRNA may be truly transformative. In an upcoming study, he said that he combined mRNA with 20 antigens against different diseases in the same vaccine. All 20 species elicited a good response in mice. He said that in theory, children may be vaccinated twice a day to cover their more than 50 vaccines.

His philosophy is not isolated. The author of a recent review article wrote that mRNA vaccines “can target multiple antigens at the same time, and pathogens will have a wide range of uses for multiple diseases, reducing the number and frequency of vaccination, and reducing the burden on medical staff.”

A large part depends on the success or failure of the mRNA COVID-19 vaccine, and high hopes are placed. Yang said: "I think this is an opportunity for the technology to shine."

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