[IBS 통신]Types and characteristics of vaccines

The Institute of Basic Science (IBS) publishes a series of’Corona 19 Science Report 2’to seek scientific understanding of SARS-CoV-2 and ways to overcome it, following last year. In this series, we will focus on research trends and issues related to the development of vaccines and treatments, as well as viral mutations that have recently aroused global interest. We hope that the front-line knowledge and information delivered by IBS scientists and domestic experts will help end coronavirus infection-19 (COVID-19, hereinafter referred to as COVID-19). <코로나19 과학 리포트2 바로가기>

◆ What types of vaccines help prevent COVID-19?

After recovering from an infectious disease, the human body gains immunity against invasion of pathogens in the future through’immunological memory’. Even if you don’t necessarily get sick, you can learn immune function by using a vaccine.

The vaccine must meet two conditions. First, it should not cause infectious diseases for the pathogen. This is because vaccines for immunity’priority learning’ should not be the cause of infection. Second, antibodies that neutralize or inhibit pathogens must be produced in plasma cells (special cells that make immune antibodies by transforming B lymphocytes) and induce activation of T cells that attack the pathogen.

To induce these two conditions, the existing vaccines used a method that attenuates, deforms, or inactivates the pathogen, or uses only a part of it to produce an effect similar to an infection. However, with the recent advances in biotechnology, vaccine development strategies have also become much more diverse. They use only antigen fragments from pathogens, or use mRNA (messenger RNA) or viral vectors corresponding to the’antigen blueprint’ as vaccines like these developed Corona 19 vaccines. This was explained in detail in Corona 19 Science Report 2 Vol.3.

As such, various vaccines are used today, depending on the characteristics of the disease, immune patterns, and convenience of development. This is because basic science has made so much progress. In particular, with the COVID-19 vaccine, which has become a turning point in human history, we can expect to develop a vaccine that goes beyond the existing limits. In this report, we would like to introduce various types of vaccines and COVID-19 vaccines that are currently commercially available or in clinical development.

◆ Live Attenuated Vaccine

The components of the live attenuated vaccine are living pathogens that have been modified or weakened pathogenicity. Modified pathogens, when administered to the human body, do not cause disease, or cause only limited infections and mild symptoms. It is mainly used to make vaccines against bacteria rather than viruses. Because the mechanism is very similar to natural infection, it induces a strong, long-lasting immune response. Attenuated chemical vaccines are being used for diseases such as measles, mumps, rubella, rotavirus, smallpox, chickenpox, and yellow fever. There is no attenuated chemical vaccine being developed for Corona 19.

◆ Inactivated Vaccine

The dead vaccine uses chemicals such as heat, radiation, and formaldehyde that inactivate (or kill) pathogens that make it impossible to multiply. Therefore, even if the vaccine is injected, it cannot cause disease or be activated. Unlike live vaccines, it has high stability because it does not use live pathogens, but has a relatively low immune response and a short duration. For this reason, several doses are sometimes given to enhance the effectiveness of the vaccine and maintain it for a long time. Dead vaccines are used for diseases such as hepatitis A, flu, polio, and rabies.

The COVID-19 vaccine being developed by China’s state-owned pharmaceutical companies, Sino Pharm Wuhan, Sino Pharm Beijing, and Sino Baek, is a four vaccine and is currently in phase 3 clinical trials. Currently, the vaccine is limited only in China. Some claim that a phase 3 clinical trial of about 12,000 people in Brazil showed 78% of preventive efficacy. However, it is too early to judge its efficacy as scientific evidence has not been disclosed. There are also reports that India has achieved high preventive effects through its independent development and vaccination, but statistics and evidence are still unclear.

◆ Protein Subunit Vaccine

If live vaccines and dead vaccines use all pathogens, subunit protein vaccines use specific protein fragments (peptides) and polysaccharides that make up the shell or cell membrane of the pathogen as the main components. The protein used at this time is generally mass-produced and purified using genetic recombination technology. The subunit protein vaccine has few side effects and is safe, but because it shows a low immune response, it induces a high immune response by administering an adjuvant together. It is used for influenza, whooping cough, and malaria vaccines.

Corona 19 vaccine developed by a domestic company, SK Bioscience, and currently undergoing phase 1 clinical trials, is a subunit protein vaccine. SK Bioscience developed a vaccine using only the spike protein on the surface of Sascoronavirus-2 as an antigen. Overseas, NovaVax’s COVID-19 vaccine’NVX-CoV2373′ is a subunit protein vaccine. Currently, it is leading the way by undergoing phase 3 clinical trials. NVX-CoV2373 has the advantage of avoiding allergic reactions as it is surrounded by plant-derived saponins.

◆ Virus Like Particle (VLP)

Virus-like particles are particles that consist only of the outer protein shell of a virus without genetic information. Some viral proteins spontaneously assemble to form virus-like particles with a structure similar to that of the original virus, but because there is no viral genetic material, infection and propagation are impossible. The most well-known virus-like particle vaccine is the cervical cancer vaccine (Servarix, Gardasil) that targets human papillomavirus (HPV).

◆ Toxoid Vaccine

Some bacteria cause disease not from the bacteria themselves, but from the toxins they produce. Therefore, when immunity to toxins is formed, it has the same effect as preventing diseases. Like four vaccines, these toxins inactivated using heat and chemicals are called toxoids or denatured toxins. Unlike toxins, toxoids trigger an immune response without causing disease. Tetanus and diphtheria vaccines are representative toxoid vaccines.

◆ DNA vaccine and mRNA vaccine

Nucleic acid vaccines such as DNA vaccines and mRNA vaccines work by delivering genetic material that contains information corresponding to the antigen of the pathogen. When the genetic material information is injected into the human body through vaccine administration, it is synthesized into the antigenic protein of the pathogen in the cell. In other words, it serves as a blueprint for making the protein of the pathogen. It selects a part that can be a good antigen in the protein composition that makes up the pathogen, and transfers the DNA or mRNA containing the genetic information of the part through a medium. Compared to existing vaccines, this method has the advantages that ▲the development period is short, ▲can induce a long-term immune response, and ▲the vaccine production is also fast because DNA or mRNA synthesis is easy.

The DNA vaccine uses a plasmid with a circular structure. After inserting the nucleotide sequence corresponding to the antigen to be produced into the plasmid, mass amplification and purification from bacteria are then administered to the human body. Plasmid DNA enters the nucleus of cells that make up human tissues and becomes mRNA through a process called transcription. The mRNA that has moved from the nucleus to the cytoplasm is translated into amino acids according to the base sequence in the ribosome to biosynthesize antigenic proteins.

In other words, the antigen of the pathogen was not directly administered, but it produced the same effect as administered by biosynthesizing within cells using genetic material. It has been developed 25 years ago, but until now, only DNA vaccines targeting animals have been commercialized. Vaccines for humans are still in clinical trials. It is pointed out that the administered individual produces less antigen, resulting in low immune response and prevention efficacy. In Korea, Genewon Life Sciences (Clinical Phase 1/2a), Genexin, Inovio-International Vaccine Research Center are developing a COVID-19 vaccine using this method.

DNA vaccines need to enter cells and are transcribed into mRNA. It is the concept of mRNA vaccine that omits this process itself. Until now, there has been a problem that the structural stability of mRNA is very weak compared to DNA, so it is rapidly degraded. However, improved bio, physical, and chemical understanding of RNA and the development of genetic engineering solved this problem. Through various modifications of the base, the stability of mRNA can be greatly improved.

mRNA vaccines have been studied for 15 years. However, the concept has not been proven because there have been no successful cases of clinical trials. Pfizer’s successful development of an mRNA-based Corona 19 vaccine has started to change a lot. We will cover this in detail in a follow-up report.

In order for DNA vaccines and mRNA vaccines to become protein antigens, they must use the biosynthetic function inside the cell. Therefore, the DNA vaccine must be inserted into the nucleus inside the cell, and the mRNA vaccine must enter the cytoplasm. Currently, technologies to effectively deliver these vaccines to the cell nucleus and cytoplasm, respectively, are being actively researched. Pfizer and Modena used lipid nanoparticles. It seems that there is an important know-how for the composition of lipid nanoparticles. However, polyethylene glycol, a component of lipid nanoparticles, can cause side effects of allergic reactions in a small number of people.

◆ Virus Vector Vaccine

The virus vector vaccine is a method of delivering the antigenic genetic information of a pathogen by packaging (vector) with a different kind of adenovirus or lentivirus shell than the pathogen. In other words, the outer (vector) and genus (antigen gene) of the vaccine are different from the original pathogen. The viral vector used at this time cannot be replicated and is not pathogenic.

The Corona 19 vaccine developed by AstraZeneca is a representative example. The vaccine was developed by inserting a gene corresponding to the spike protein of Sascoronavirus-2 into a vector modified from chimpanzee adenovirus. Various companies, including AstraZeneca, Gamaleya in Russia, Cansino in China, Johnson & Johnson in the US (Phase 3 clinical), and Celid-LG Chemical (Phase 1 clinical trials) in Korea, are developing virus vector-based Corona 19 vaccines. There are reports that this has a preventive effect of 60 to 90%.

Vaccine development that was unprecedented and successful, and future vaccinations should be judged correctly.
Among the COVID-19 vaccines developed so far, the mRNA vaccine seems to have the best preventive effect and stability. However, there are interim results that the efficacy of other types of Corona 19 vaccines are also quite high, so further analysis should be observed. All variables such as side effects, cost, method of transport and storage, duration of antibody, and efficiency of strain should be considered comprehensively. Therefore, it is expected that we will have to wait 2-3 years to determine which vaccine is the best.

Despite the situation in vaccine development, hasty opinions and judgments are disturbing the world. For example, opinions have already been made to have flexibility in the interval, frequency, and dose of vaccination according to the circumstances of each country. Experts warn that in this case the best preventive effect cannot be obtained. There are also opinions to see indirect effects through other vaccinations. Targeted vaccines that have already been developed with advanced life science technology and COVID-19 vaccines that have successfully passed phase 3 clinical trials are available to all of us within this year. There is no reason to receive another vaccine in this situation. Some medical groups refuse to receive vaccination, which is not reasonable. This is because there is no vaccine without side effects.

Vaccine development takes about 10 years and costs close to 5 trillion won. After the first report of Corona 19 patients in China, the sequence of Sascoronavirus-2 was revealed on January 1, 2020. After the virus sequence was identified, Modena selected the sequence of the part that is likely to act as an antigen. And within 2 days, the base sequence of the mRNA-1273 vaccine was determined and introduced into vaccine development. It was only 63 days after the sequence was revealed that it entered the clinical trial.

On December 11, 2020, Pfizer’s vaccine was approved for emergency use by the Food and Drug Administration (FDA) for the first time. In about 11 months, mankind has acquired a weapon to win the war against Corona 19. In the past, the SARS vaccine candidate of the National Institute for Allergic Diseases (NIAID) took 20 months to enter the phase 1 clinical trial. Considering this, the development of the Corona 19 vaccine took place at an unprecedented speed.

◆ The reason why global pharmaceutical companies are actively developing COVID-19 vaccine

Before the Corona 19 pandemic, global pharmaceutical companies did not actively engage in vaccine development. In a word, it was not a profitable business. While existing vaccines have high development risks and costs, most of the demand was oriented to developing countries, where the financial burden was insufficient. This has acted as an ethical constraint making it difficult to set a high price for the developed vaccine. Also, due to the nature of infectious diseases, there was only one or two demands per individual. In short, it was difficult to generate a return on investment due to the market structure.

However, the situation of the Corona 19 pandemic was completely different. First of all, a huge amount of capital of over 15 trillion won (9,4472 billion won in countries around the world, 2.18 trillion won for non-profit organizations, and 3.7789 trillion won for global pharmaceutical companies) was invested in vaccine development. The total cost currently under development will exceed 20-30 trillion won. As the concept of’pandemic’ implies, there has been a demand for vaccines targeting all humans. In addition, phases 1 and 3 clinical trials are concurrently conducted to reduce development time, and vaccine management and approval agencies in each country have unprecedentedly reduced the approval stage and process. In particular, on May 15, 2020, the U.S. government implemented unlimited financial and administrative support for vaccine development, distribution, and vaccination through Operation Warp Speed, and saw the fruits of that. Finally, innovative concept vaccines such as mRNA vaccines appeared, raising the level of existing science and technology to the next level.

However, there are also challenges to be solved. For the development of next-generation vaccines, scientists and specialists have ▲ minimizing side effects, ▲ phase 3 clinical trials without placebo (ethical issues for placebo test subjects), ▲ rapid manufacturing and supply through local production, ▲ safe and convenient storage and transportation, ▲ variants It is emphasized that there is a need to simplify the approval process for the production and manufacture of vaccine modifications and ▲ develop a universal vaccine.

◆ What should we learn from our experience in developing a COVID-19 vaccine?

The rapid development of the Corona 19 vaccine in developed countries has many implications for us. To develop a vaccine for infectious diseases in a short period of time ① Scientists from universities and research institutes with original technology and knowledge, ② Pharmaceutical companies with experience in vaccine development, production, and clinical trials, ③ The Centers for Disease Control and Prevention, responsible for managing and approving vaccine development, and ④ Phase 3 clinical trials Medical staff specializing in infectious diseases who can conduct and analyze the test, and ⑤ government and inter-ministerial support groups, etc., should set a direction and proceed together from the first stage. In other words, the organic linkage of industry, academia, research, and government is important, and financial support for large-scale clinical trials is essential. If any of these agents had not functioned properly, vaccines in the US and Europe would not have been developed at this rapid rate.

Domestic pharmaceutical and venture companies, research institutes, and universities are also accelerating the development of the COVID-19 vaccine, but they are currently in phase 1 or 1/2a clinical trials. This is because the vaccine production and commercialization system has been established, but the vaccine development and clinical trial experience and infrastructure for new infectious diseases are insufficient. At this opportunity, the aforementioned actors must gather together to promote the vaccine development process. In doing so, it is necessary to establish a comprehensive vaccine development system and use it as an opportunity to accumulate skills and experiences. Above all, it is essential to establish a control tower and secure capabilities. The control tower of vaccine development should be able to support and coordinate the entire process from the discovery of vaccine candidates to preclinical, clinical, and production.

A new epidemic inevitably challenges humanity again. One mistake is a sickness boss, but two mistakes on the battlefield are unacceptable. We must prepare for the next war properly by using the Corona 19 pandemic as a teacher on the other hand.