Written by: Li Dapeng | Duke University
Originally published: Fanpu2019
Quantum Bit QbitAI Reprinted with permission

The world's first vaccine was created in Britain in the late 18th century. British doctor Edward Jenner noticed that milkmaids who had been infected with the cowpox virus would not be infected with smallpox, so he speculated that the cowpox virus could prevent smallpox. Through experiments, he proved that vaccination with the cowpox virus could effectively prevent smallpox virus infection.

In 1881, Louis Pasteur, a member of the French Academy of Sciences, proposed to name the vaccination preparation "Vaccine" based on the Latin "Variolae vaccinae" (cowpox) in memory of Jenner, and the process "Vaccination" [ 1] .

Over the past two hundred years, scientists have invented vaccines against dozens of infectious diseases, including rabies, tuberculosis, and polio. The earliest vaccines were made by inactivating viruses with formaldehyde, etc., making them infective, and these vaccines are called inactivated vaccines, such as polio (polio virus) vaccines, rabies vaccines, and hepatitis A vaccines.

In addition, viruses or bacteria with weakened virulence are also used as vaccines, such as measles vaccine, rubella vaccine, tuberculosis vaccine (also known as "BCG"), etc., which are called live attenuated vaccines. Although people did not fully understand how vaccines protect the body from pathogens at that time, with the advancement of immunology and microbiology technology, scientists gradually realized that preventive vaccines can prevent diseases by inducing specific immune responses in the body.

Later, the development of molecular biology technology led to the invention of safer subunit vaccines, which are vaccines that use only the active ingredients of a virus or bacteria, usually 1-2 proteins, to induce immune protection in the body. The hepatitis B vaccine and cervical cancer vaccine that we are familiar with are successful examples of subunit vaccines.

The above three types of vaccines cover the vast majority of bacterial and viral vaccines currently on the market. In addition, with the development of genetic engineering technology, new vaccines such as DNA vaccines, mRNA vaccines and viral vector vaccines are gradually emerging, and many promising candidate new vaccines are in the clinical trial stage.

Although people have a deep understanding of vaccines, there are still many infectious diseases that are difficult for humans to conquer. The most challenging ones are the "Big 4" in the field of human infectious diseases: AIDS (HIV), influenza (influenza virus), tuberculosis (M. tuberculosis), and malaria. The US government alone invests billions of dollars each year in research on these four pathogens [2] . However, except for the seasonal influenza vaccine for influenza virus every year, the development of other vaccines is still difficult. With the progress of immunology, genomics and proteomics in recent years, people are trying to answer a question: Why are some vaccines difficult to make, while others are relatively easy?

The key to successful development of classic vaccines

In short, a vaccine that can protect a person for a lifetime with one shot is an ideal vaccine. For example, measles, rubella, and mumps vaccines can provide protection for more than ten years with a single shot.

Among them, the measles vaccine can provide lifelong protection for 96% of recipients [3] . The polio virus vaccine, which is the "sugar pill" that many people took when they were young, has almost achieved the elimination of polio worldwide. Among subunit vaccines, the hepatitis B vaccine is the most classic success story. Its active ingredient is hepatitis B surface antigen (HBsAg). Through three injections of immunization, the effectiveness can reach 80%-100%, and it can provide protection for more than 20 years [4] .

These long-acting virus vaccines often have a common feature, which is to resist the invasion of viruses by inducing the body to produce neutralizing antibodies. This is particularly important for acute infectious diseases.

Specifically, long-acting vaccines can induce the human immune system to produce long-acting plasma cells and memory B cells. Long-acting plasma cells can produce antibodies for a long time; although memory B cells do not directly produce antibodies, they can maintain a "memory" of the virus for a long time. Once a virus invades, memory B cells will be activated to produce plasma cells, thereby secreting a large number of neutralizing antibodies to fight the virus. Neutralizing antibodies can tightly adhere to the surface of the virus and prevent the virus from binding to human cells (Figure 1) ; some neutralizing antibodies can still block the virus from releasing genetic material into the cell even after the virus comes into contact with the cell, thereby preventing viral infection.

△ Figure 1. Schematic diagram of neutralizing antibodies blocking viral infection.

In the picture, red represents the virus, yellow represents the cell, and the yellow protrusions on the cell surface represent the cell surface receptors. During the virus infection process, the virus first binds to the cell surface receptors through the membrane protein (A), then enters the cell through endocytosis (B), and then releases genetic material into the cell (C). When neutralizing antibodies exist in the body, the neutralizing antibodies can bind tightly to the surface of the virus membrane protein, thereby preventing the virus from binding to the cell receptor (D). Image source: Janeway's Immunobiology, Ninth Edition.

A study showed that 88% of the subjects were able to produce high titer antibodies after another injection of hepatitis B vaccine 30 years after immunization, proving that memory B cells induced by hepatitis B vaccine can provide long-term protection [5] . Another classic example is the yellow fever vaccine, YFV-17D, which still had specific antibodies in the body of the vaccine recipients 40 years after a single injection [6] . Currently, the vast majority of viral vaccines on the market protect the human body from viral infection by inducing high titer neutralizing antibodies.

Why can’t we develop vaccines for some viruses?

The first is the technical reason.

In contrast to the classic vaccines mentioned above, if the vaccine cannot induce neutralizing antibodies specific to a certain virus, then the virus will be difficult to prevent through vaccine immunization.

Take AIDS as an example. Although the U.S. National Institutes of Health (NIH) invests approximately US$600 million annually in the development of HIV vaccines[7], current HIV vaccine candidates still have difficulty in inducing neutralizing antibodies in vivo.

First, HIV vaccine candidates tend to induce the body to produce large amounts of "non-neutralizing antibodies," which have no neutralizing activity and are therefore unable to resist virus-infected cells.

Secondly, the structural proteins on the surface of the HIV virus carry a large amount of sugar (approximately equal to the protein's own weight). Even if there are neutralizing antibodies in the human body, it is difficult for them to pass through the numerous barriers and cannot touch the virus.

Finally, B cells that can produce neutralizing antibodies are often mistaken by the body’s immune system as allergic response B cells, thus being strangled in the cradle at an early stage . [8] These technical reasons are often determined by the nature of the virus itself.

The second is economic and sociological reasons.

Vaccines must pass preclinical trials, Phase I, II, and III clinical trials to prove their safety and effectiveness before they can be marketed. Therefore, developing a vaccine requires a lot of financial and human resources. In particular, large-scale Phase III clinical trials often require tens of thousands of subjects, last for 3-5 years, cost approximately US$150 million to US$1.5 billion [9] , and are subject to the risk of failure.

Therefore, if the company is not large enough and there is no government participation and investment, a pharmaceutical company often finds it difficult to bear such high costs and risks. Even if the vaccine passes Phase III clinical trials and is marketed, if the disease is only prevalent in a region, the future market for the vaccine may not be enough to recover the cost.

For example, the Middle East coronavirus (MERS) was only briefly prevalent in the Arabian Peninsula and South Korea [10] . Therefore, although the MERS vaccine has already entered Phase I/II clinical trials and has shown promising results, it is estimated that it may take more than ten years to complete the entire clinical trial and until the vaccine is available on the market [11] .

Why should the new coronavirus vaccine be successfully developed?

On February 10, "a Chinese research team announced that the latest vaccine for the new coronavirus has begun animal testing. This was just two weeks after the Chinese Center for Disease Control and Prevention successfully isolated the first strain of the new coronavirus in China on January 24. The vaccine was jointly designed and developed by the Chinese Center for Disease Control and Prevention, Shanghai Tongji University School of Medicine, and Shanghai Biotechnology Company Sibico. Sibico predicts that if the animal trials go smoothly, the new vaccine will enter human clinical trials as early as April this year. (Yicai Global) " [12] Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health, also announced to the media that NIAID will cooperate with mRNA vaccine giant Moderna and hopes to push the new coronavirus vaccine into clinical trials within three months. [13] Why are scientists from both China and the United States so confident in the development of a vaccine for the new coronavirus?

The above picture shows the SARS virus in a crown-like shape under an electron microscope (a), and a schematic diagram of the SARS virus structure (b). The spike protein (also known as the S protein) can be seen on the surface of the virus in a and is marked in orange in b. The picture is from reference [14]

According to the results recently published by Shi Zhengli's laboratory at the Wuhan Institute of Virology, Chinese Academy of Sciences, the genetic sequence of the new coronavirus is 79.5% similar to that of SARS. Like the SARS virus, it infects cells by binding the viral spike protein (also known as S protein; Figure 2) to the ACE2 receptor on the cell surface [15] . This further shows that the S protein of the new coronavirus and the S protein of the SARS virus have very similar structures.

Therefore, the development of vaccines for the new coronavirus can draw on research on SARS vaccines.

Based on the results of preclinical trials of SARS vaccines, it can be seen that it is not as difficult to develop as HIV vaccines - viral vector vaccines, subunit vaccines and DNA vaccines based on the full-length S protein can all induce SARS neutralizing antibodies in animal models and provide good protection [16] .

If the S protein is further modified to only capture its functional receptor binding region, it is possible to further reduce the toxicity of the vaccine and induce higher quality neutralizing antibodies [17] . The DNA vaccine based on the SARS virus S protein developed by the team of Barney Graham and Gary Nabel of the US NIH Vaccine Research Center (VRC) has also achieved good results in animal experiments and Phase I clinical trials [18-19] .

I believe this is also the reason why scientists from China and the United States are so confident in the development of the new coronavirus vaccine.

In summary, it should not be too difficult to develop a COVID-19 vaccine technically. In addition, the number of current cases is large, and the number of susceptible people is huge, so it is not difficult to recruit enough volunteers to participate in clinical trials. If a candidate vaccine for the COVID-19 can be developed as soon as possible and proven to be effective in animal models, I believe that the country will vigorously promote clinical trials of the vaccine.

However, we still have to keep in mind that even if there is no great technical difficulty and the policy is green light, scientific and rigorous clinical trials cannot be completed in the short term.

A long way to go

In fact, to solve this epidemic, both China and the United States hope that they do not need to use vaccines. We hope that this epidemic will disappear as the weather warms up, just like SARS. However, the southern hemisphere will enter winter at that time, and no one can predict how the new coronavirus will spread and develop.

Therefore, working at full capacity to accelerate preclinical and clinical research on the new coronavirus remains the most beneficial option for the health of all mankind.

Finally, as the examples of smallpox and polio demonstrate, safe and effective vaccines are a powerful tool for eliminating outbreaks and, ultimately, eradicating these viruses from the face of the earth.

However, viruses like SARS, MERS and the new coronavirus exist in nature and have hosts other than humans. Even with a vaccine, we may never be able to eliminate them. Curbing the bad habit of eating wild animals, strengthening market management and quarantine, and raising people's public health awareness are the keys to preventing disasters from happening again.

references:

[1] Pasteur L (1881). “Address on the Germ Theory”. Lancet. 118 (3024): 271–72. doi:10.1016/s0140-6736(02)35739-8.

[2] https://report.nih.gov/categorical_spending.aspx

[3] https://www.immune.org.nz/vaccines/efficiency-effectiveness

[4] https://www.cdc.gov/vaccines/pubs/pinkbook/hepb.html

[5] Bruce MG, Bruden D, Hurlburt D, Zanis C, Thompson G, Rea L, et al. Antibody Levels and Protection After Hepatitis B Vaccine: Results of a 30-Year Follow-up Study and Response to a Booster Dose. J Infect Dis. 2016;214(1):16-22.

[6] Wieten RW, Jonker EF, van Leeuwen EM, Remmerswaal EB, Ten Berge IJ, de Visser AW, et al. A Single 17D Yellow Fever Vaccination Provides Lifelong Immunity; Characterization of Yellow-Fever-Specific Neutralizing Antibody and T-Cell Responses after Vaccination. PLoS One. 2016;11(3):e0149871.

[7] HIV Prevention Research & Development Investments, 2017. https://www.avac.org/sites/default/files/resource-files/HIV_resourceTracking2017.pdf

[8] Haynes BF, Burton DR, Mascola JR. Multiple roles for HIV broadly neutralizing antibodies. Science Translational Medicine. 2019: Vol. 11, Issue 516, eaaz2686

[9] Black S. The costs and effectiveness of large Phase III pre-licensure vaccine clinical trials. Expert Rev Vaccines. 2015;14(12):1543-8.

[10] https://www.cdc.gov/coronavirus/mers/about/index.html

[11] Yong CY, Ong HK, Yeap SK, Ho KL, Tan WS. Recent Advances in the Vaccine Development Against Middle East Respiratory Syndrome-Coronavirus. Front Microbiol. 2019;10:1781.

[12] https://www.yicai.com/news/100497507.html

[13] https://www.sciencemag.org/news/2020/01/scientists-are-moving-record-speed-create-new-coronavirus-vaccines-they-may-come-too

[14] Stadler K, Masignani V, Eickmann M, Becker S, Abrignani S, Klenk HD, et al. SARS—beginning to understand a new virus. Nat Rev Microbiol. 2003;1(3):209-18.

[15] Zhou et al. Discovery of a novel coronavirus associated with the recent pneumonia outbreak in humans and its potential bat origin. bioRxiv. 2020.

[16] Song Z, Xu Y, Bao L, Zhang L, Yu P, Qu Y, et al. From SARS to MERS, Thrusting Coronaviruses into the Spotlight. Viruses. 2019;11(1).

[17] Zhu X, Liu Q, Du L, Lu L, Jiang S. Receptor-binding domain as a target for developing SARS vaccines. J Thorac Dis. 2013;5 Suppl 2:S142-8.

[18] Yang ZY, Kong WP, Huang Y, Roberts A, Murphy BR, Subbarao K, et al. A DNA vaccine induces SARS coronavirus neutralization and protective immunity in mice. Nature. 2004;428(6982):561-4.

[19] Martin JE, Louder MK, Holman LA, Gordon IJ, Enama ME, Larkin BD, et al. A SARS DNA vaccine induces neutralizing antibody and cellular immune responses in healthy adults in a Phase I clinical trial. Vaccine. 2008;26(50):6338-43

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