“Dormant” for 30 years, gene vaccine technology is in the final testing stage

In September 1992, Deborah fuller went to New York from Wisconsin to attend a scientific conference held at Cold Spring Harbor Laboratory, a non-profit organization. At the meeting, she introduced the new vaccine method that she has been studying. Although it is in the early stage, it has good prospects.

this meeting was actually decided by accident. “When I went, I thought I would be the only one with this new idea, but there were six other people who came up with the same idea,” said Dr. Fuller, who is now a professor of Microbiology at Washington University School of medicine in St. Louis, who is working on a vaccine for the new coronavirus. If other laboratories get the same results, then her results are not accidental.

conference organizers are attracted by this new idea. They rescheduled the meeting to provide conditions for fuller and other participants to present their research at the same meeting on the last day of the conference. The scientists left the meeting ahead of schedule.

this is quite different from the traditional way of vaccine production, but largely retains the original form. The traditional production process is complex and expensive, but the new way is not: it can deal with almost all infectious diseases, and will greatly shorten the time to market of vaccines. “It was a vaccine revolution at the time, and we immediately realized its potential to fight epidemics in the future,” fuller said

now, 30 years later, no so-called gene vaccine has been approved for human diseases. But a few laboratories and companies are still insisting on improving the technology. The emergence of the novel coronavirus pneumonia is a chance for the test stage to enter the final stage of testing. Now, some gene vaccines against the new coronavirus are making progress through clinical trials and becoming leaders in this field. Moderna, inovio pharmaceuticals and Ruikang are all developing gene vaccines.

critics point out that Moderna and inovio have never made any drugs or vaccines before. Before the new coronavirus, the gene vaccine has never carried out large-scale clinical trials against infectious diseases.

if the technology is effective for new coronavirus pneumonia, gene vaccines for other diseases can also be put on the agenda as soon as possible, including new pathogens that may appear in the future. The next outbreak of infectious diseases, the government will be better prepared to use safe and effective vaccine technology to quickly detect, manufacture and promote.

“this may completely change the way other vaccines are made,” Rahul Gupta, M.D., senior vice president and chief medical and health officer of the birth defects foundation, told reporters at a briefing of the national news foundation on August 7. “We may be in the middle of a new technology.”

the working mechanism of all vaccines is to artificially introduce virus antigen, so that the human autoimmune system mistakenly believes that it has been infected and plays its role. The immune system starts to operate and records the characteristics of the invading virus. Therefore, once the real virus invades, the immune system will attack later.

traditional vaccines stimulate this immune response by injecting attenuated or inactivated pathogens into the body. Many of the vaccines used today are made by the traditional methods mentioned above, including those for chickenpox, polio, influenza, rabies, measles, mumps and rubella.

attenuated or attenuated vaccines are very similar to natural infections and can cause a strong and lasting immune system. But because of this, people with low immunity are easy to get sick, which makes it impossible to use the vaccine. On the other hand, the killed or inactivated vaccine can not induce the same intensity of immune response, sometimes need to strengthen the injection dose.

after practical test, the feasible method for vaccine production is to grow pathogens in eggs or animal cells, and then extract them to inactivate or weaken their toxicity. Finally, the vaccine was purified and tested several times. The whole process is laborious.

for example, a flu vaccine requires millions of eggs to make every year, and it may take six months to make. Other vaccines may take years to make and test for safety, while genetic vaccines are expected to be faster and simpler.

“most of the vaccines we developed in the past are really in trouble,” said Dr. William klimstra, a professor of immunology at the University of Pittsburgh. “The way we make vaccines goes back to the 1930s.”

now some vaccines need only one pathogen, not the whole bacteria. This stimulates the immune system to the greatest extent. Both hepatitis B vaccine and HPV vaccine are made in the way described above. Because they contain only some pathogens, these vaccines may be safer, but they usually have to be used in combination with immune adjuvants, and sometimes require a second dose. From the late 1980s to the 1990s, vaccine developers began to use genetic engineering to synthesize proteins instead of original ones.

“we’re starting to think about a simpler way to produce vaccines,” Dr. David Weiner, executive vice president of the Westar Institute and founder of inovio, a non-profit biomedical research institute in Philadelphia, still told the scientific advisory board, which is working with inovio to develop a genetic vaccine for covid-19, “Can we not rely on these complicated machines?”

the gene vaccine does not contain any real pathogen. Instead, it contains a small part of genetic material, which can give instructions to the human body’s own cells for a short time to produce a pathogen. “They can encode information,” Weiner explained. “In this case, the information we’re passing is encoded like a viral protein.”

for the sars-cov-2 virus that causes covid-19, scientists are working hard to study the coronal “spike” protein on the surface of the virus. The virus uses a spike protein to attach to and enter human cells, and the gene vaccine used for covid-19 carries a code that tells cells to make the protein. The vaccine hopes to train the human body to recognize and respond to it.

the adaptability of DNA and RNA vaccines is its charm, which is also the reason why it triggered scientists’ imagination at the 1992 conference. This part of the genetic code can be easily changed, depending on the disease. There is no need to know the genetic code of the real pathogen.

Dr. Margaret Liu, President of the Council of the international society for vaccines, said: “it’s like once you know the formula of ice cream, you can easily make different flavors of ice cream.” At the 1992 conference, she introduced early research on genetic vaccines and helped establish the field.

compared with traditional vaccines, its potential advantages are that DNA and RNA vaccines can be produced faster, and the amount of genetic material required for each dose is less.

Dr. roxna rustomgie, senior vice president of research and development at Sabine Vaccine Institute, a non-profit organization based in Washington, said: “the production of genetic vaccines will definitely be faster. But from a scientific point of view, I’m still not entirely sure of its advantages. We remain skeptical that there will be enough immune response to provide protection. ”

Fuller, Weiner and others have been competing to apply for technology and publish works for this technology since they came home from the conference in 1992. But it’s not easy for scientific journals to accept early papers. When trying to publish research results, reviewers expressed doubts about their effectiveness. But in the end, everyone published the paper.

gene vaccine seems to work well in animal experiments. In 1997, Weiner of the University of Pennsylvania and his colleagues reported that a DNA vaccine they made successfully protected two chimpanzees from HIV infection. But the first human trial of the gene vaccine failed, with no immune response to protect them from disease.

fuller said, “it was a complete failure,” which is a common problem in biomedical research: drugs or vaccines that work in animals often don’t work in humans.

the key problem to be overcome is how to get DNA or RNA vaccines into cells. Both of them face their own challenges, which will take several years to solve. By then, many of the initial passions for genetic vaccines had gone to naught, and many companies had dropped out after the initial trials failed.

fuller and Weiner have always insisted on this field, and the primary research focus is DNA. They know that DNA is more stable than RNA and helps preserve genetic information. But cells can’t easily accept DNA, so scientists need to design small tools that can deliver DNA vaccine particles. One of them is a gene gun created by John Sanford of Cornell University. The gun was originally made for experiments on plants, using helium and gold particles to push genetic material through cell walls. So that we can open up an electronic device that can take DNA and break DNA particles at the same time. Inovio’s covid-19 vaccine uses the device to deliver the vaccine to human skin. In an interview, volunteers involved in the inovio human trial said it was not painful to cut the skin, but it “felt strange.”. With $71 million from the U.S. Department of defense, the small handheld device will expand production. The difficulty with

RNA is that once injected into the body, it breaks down rapidly. Scientists couldn’t make RNA vaccines work until Dr. drew Weisman, an immunologist at the University of Pennsylvania, discovered that RNA could be stabilized by packaging it in tiny fat nanoparticles. Weisman’s technology was attractive, and Moderna, a biotechnology company in Cambridge, Massachusetts, was eventually licensed.

although there is no DNA or RNA vaccine available on the market for human use, a veterinary DNA vaccine was approved in 2005 to protect horses from West Nile virus. Dr Liu said there was evidence that the method could not only be used in experimental animals.

in December 2019, China reported new crown cases. Soon after, in mid January, Chinese researchers published a draft of the virus’s gene sequence on the Internet. With it, companies like Moderna and inovio can start making genetic vaccines.

Scientists immediately realized that this new type of virus looks very similar to the virus they have seen before: the two viruses that cause SARS and mers have similar spike proteins. They know that people who recover from the virus make spike proteins. They believe that vaccines targeting spike proteins can induce a strong enough immune response against the disease.

inovio, Moderna and biontech in Germany are already studying DNA and RNA related drugs, so they can start to take measures quickly.

in a short period of six weeks, Moderna designed, manufactured and shipped the vaccine to the National Institutes of health in the United States, and the initial human safety trials began in mid March. Inovio and biontech, a German company that had worked with Pfizer, quickly completed the design of their gene vaccine and launched it in April