Compared with injectable vaccines, oral vaccines have three main advantages: the activated immune response may be stronger; mucosal immunity can be activated; compared with injections, oral methods are much more convenient, popularize vaccination faster, and people's compliance It is more sexual and does not require professional vaccination.

Recently, in a study published in the sub-journal of "Nature", Chinese scholars designed a bacterial-derived oral tumor-like vaccine by genetically engineering Escherichia coli, which was shown in a variety of mouse models of cancer. Antitumor efficacy.

What is an oral tumor vaccine? What are the advantages of oral tumor vaccines and what problems can they solve for patients? A reporter from Science and Technology Daily interviewed Nie Guangjun, one of the leaders of the above-mentioned research team and a researcher at the National Nanoscience Center of the Chinese Academy of Sciences.

Oral vaccines have obvious advantages but are difficult to develop

"The sugar pill vaccine I ate as a child is actually an oral vaccine against polio." Nie Guangjun said that a research paper reported that the oral new crown vaccine currently being developed by scientists has achieved preliminary results in animal experiments.

Compared with injectable vaccines, oral vaccines have three main advantages.

First, the magnitude of the immune response activated by oral vaccines may be stronger. "Injectable vaccines generally can only stimulate immune stimulation through the draining lymph nodes around the injection site, which is relatively limited. The gut actually contains about 70% of the body's immune cells and is one of the largest immune organs in the body. If it can be administered orally, The vaccine method stimulates the immune cells in the intestine, so the activated immune response will be very strong." Nie Guangjun said.

"Theoretically, the greater the number of immune cells stimulated by the vaccine, the stronger the activated immune response will be, and the stronger the protective effect on the body will be in the end. For oral tumor vaccines, the more immune cells activated by the vaccine, The stronger the inhibitory effect on tumor cells, the better the therapeutic effect may be." Nie Guangjun explained.

"Of course, excessive activation of the immune system is also a potential risk, so preclinical research and clinical trials are needed to determine the dose of oral vaccines to ensure that the immune response is within the range that the body can tolerate." Nie Guangjun added.

Secondly, oral vaccines can activate mucosal immunity and stimulate the body to produce a special antibody IgA, which is mainly distributed in mucosal parts, such as the digestive tract and respiratory tract. Nie Guangjun told reporters: "Mucosal immunity is actually a line of defense formed by the body against pathogenic microorganisms. Therefore, it has a stronger preventive effect on pathogenic microorganisms that invade through the intestinal tract or respiratory tract. Mucosal immunity is what injectable vaccines lack."

"However, for oral tumor vaccines, the significance of this mucosal immunity remains to be further studied and explored." Nie Guangjun mentioned.

Furthermore, oral vaccines also have certain advantages in practical application. "Compared with injection, oral method is much more convenient, popularization of vaccination is faster, people's compliance is higher, and it does not require professionals to vaccinate, and the consumption of social resources will be much lower." Nie Guangjun said.

"But oral vaccines are far more difficult to develop than injectable vaccines, and face more challenges," said Nie Guangjun.

According to Nie Guangjun, his research group has long been concerned about the use of nanotechnology and biotechnology to develop new methods for the treatment of tumors. Therefore, in terms of the oral vaccine technology system, they chose tumor vaccines as a breakthrough point.

Making 'bacterial robots' overcome two challenges

Nie Guangjun told reporters that there are two main challenges in the development of oral vaccines: First, vaccines need to overcome the complex digestive tract environment. Stomach acid and various enzymes that digest food may cause the vaccine to be degraded before it reaches the gut. Second, the vaccine needs to pass through the intestinal epithelial barrier. The main components of vaccines are antigens, that is, proteins. Proteins are difficult to effectively penetrate the epithelial barrier, so they cannot activate immune cells distributed under the epithelial barrier.

How to overcome these challenges? The answer is to create "bacterial robots".

Nie Guangjun told reporters that the research team genetically modified Escherichia coli. The genetically modified Escherichia coli can produce and secrete a vesicle with tumor antigens - bacterial outer membrane vesicle (OMV) in the intestine. Like a truck, it will bring the loaded tumor antigens to the vicinity of immune cells under the intestinal epithelial barrier, thereby delivering these tumor antigens to the immune system and activating the anti-tumor immune response in the body. Nie Guangjun's team called the E. coli bacteria that work autonomously in the body according to their design "bacterial robots".

"Bacterial robots" are the core components of oral tumor-like vaccines, which can continuously generate OMVs with tumor antigens in the intestine. On the one hand, it will cause the body's immune response to resist the tumor, but on the other hand, constant immune stimulation will also lead to immune exhaustion and tolerance.

In order to eliminate this hidden danger, the researchers added a "responsive switch" to the tumor antigen gene. With this switch, the "bacterial robot" can only carry out the tumor antigen gene in the presence of arabinose (a sugar substance). expression. In this way, the intestinal behavior of the "bacterial robot" can be controlled by oral arabinose, so that it will not get out of control. In the animal model experiment, the researchers gave the mice some "sugar water" to drink after 24 hours of oral administration of the "bacterial robot".

The use of oral "bacterial robots" to generate OMVs with tumor antigens in situ in the gut not only solves the insurmountable problem of the epithelial barrier, but also overcomes the difficulties brought by the complex digestive tract environment. "Initially, we adopted the way of direct oral administration of OMV, but found that OMV could not reach the intestinal site efficiently, so we considered the way of oral 'bacterial robot'. Because, compared with OMV, E. coli itself is a colony of intestinal flora, The tolerance is higher." Nie Guangjun said.

"However, the survival time of these 'bacterial robots' in the intestine is limited." Nie Guangjun told reporters that according to their observations, after 72 hours of oral administration, these "bacterial robots" will be excreted or degraded; in addition, Without the sugar arabinose, the "bacterial robot" behaves like other symbiotic bacteria in the gut.

"From the perspective of animal experiments, this oral tumor-like vaccine based on 'bacterial robots' has no obvious side effects. The situation in the human body needs further verification." Nie Guangjun said.

Talking about the suitable groups of oral tumor vaccines, Nie Guangjun said: "From the experience of oral polio vaccine, the vast majority of people can receive oral vaccines. Of course, oral polio vaccine is to prevent diseases, and The oral tumor vaccine we are going to do is used to treat diseases, and the user is the patient. We must strictly control the dose of the vaccine according to the patient's tolerance to the vaccine. Whether there are specific groups of people who are not suitable for oral vaccines, Further research is needed to verify it.”

Tumor vaccine is an important means to realize individualized treatment

Wth the development of the times, the concept and means of anti-tumor are constantly improving. The initial surgery, radiotherapy, chemotherapy and other methods are all methods of treatment corresponding to most patients, which belong to "brutal treatment". Later, precision treatment represented by targeted therapy was developed, which is a drug for a small number of patients.

"In the past 10 years, the voice of individualized treatment has been increasing, that is, each patient can correspond to a treatment method." Nie Guangjun believes that tumor vaccine is a very promising individualized treatment. "Because the gene mutations of tumor cells in each patient are different, that is, the tumor antigen information is unique. The tumor vaccine made by using these patients' unique tumor antigens is only applicable to the patient himself, a real individual. Nie Guangjun believes that with the development of antigen identification methods and delivery technology, tumor vaccines will definitely be used in clinical treatment, and relying on technological progress and the corresponding support provided by medical insurance policies, the cost of individualized treatment of tumors will also be greatly increased. reduce.

Nie Guangjun predicts that the clinical application of injectable tumor vaccines will become a reality in the next 2-5 years. "Oral tumor-like vaccine is still a new technology, and it takes time to develop and optimize. We are confident that in the near future, oral tumor-like vaccine can become a killer for mankind to defeat malignant tumors." He said.

Nie Guangjun said that the next work of the research group mainly focuses on two aspects: first, to further improve the oral vaccine system based on "bacterial robots", to verify the effect in more tumor antigens and models, and to accelerate its transformation and implementation; second It is to use "bacterial robots" to try to transport vaccines and even drugs for other diseases, such as vaccines against gastrointestinal pathogenic microorganisms, drugs for enteritis, etc., to further expand its application scope.