On October 5th, Beijing time, the Karolinska Institutet in Stockholm announced that the 2020 Nobel Prize in Physiology or Medicine will be awarded to American virologist Harvey Ort, British biologist Michael Horton and American virologist Charles Rice in recognition of their discovery of the hepatitis C virus.
Prior to the work of the above three scientists, significant progress had been made in the discovery of hepatitis A and hepatitis B viruses, but most blood-borne hepatitis cases remained unexplained. The discovery of the hepatitis C virus revealed the causes of chronic hepatitis cases other than hepatitis A and B, and made blood testing and new drug development possible, thus saving millions of lives.
The Nobel Prize official press release states that the discovery of the hepatitis C virus is a milestone achievement in the continuous fight against hepatitis C. Thanks to their discovery, we can now perform highly sensitive blood tests for this virus. These tests have basically eliminated post-transfusion hepatitis in many parts of the world, greatly improving global health. Their discovery also enabled the rapid development of antiviral drugs for hepatitis C. WHO data shows that antiviral drugs can cure more than 95% of people with hepatitis C infection, thereby reducing the risk of death from liver cancer and cirrhosis.
Hepatitis C was cured for the first time in history, bringing hope to the eradication of hepatitis C virus worldwide. However, in order to achieve this goal, the world will still need to promote the provision of blood testing and antiviral drugs. Currently, the accessibility of diagnosis and treatment is still low. According to the WHO, in 2017, of the 71 million people infected with hepatitis C virus worldwide, an estimated 19% (13.1 million people) knew their diagnosis. Among those diagnosed with chronic hepatitis C infection, as of the end of 2017, about 5 million people had received direct antiviral treatment. “There is still a lot of work to be done if the world is to achieve the 80% hepatitis C virus treatment target by 2030.”
Hepatitis C virus (HCV) blood sample was positive.
Global health problem: hepatitis
Hepatitis is a phenomenon that describes liver inflammation. The word “Hepatitis” is derived from ancient Greek, “hêpar” stands for “liver”, and “-itis” stands for “inflammation”. Although alcoholism, environmental toxins and autoimmune diseases are also important causes, they are mainly caused by viral infections.
There are two main forms of hepatitis. One is acute hepatitis caused by the hepatitis A virus, which is spread through contaminated water or food. The other is caused by hepatitis B virus or hepatitis C virus (this year’s Nobel Prize). This blood-borne hepatitis is usually a chronic disease that can develop into cirrhosis and liver cancer.
In the 1940s, scientists believed that there were two main types of infectious hepatitis. The first is hepatitis A (hepatitis A), which is spread through contaminated water or food and usually has no long-term effects on patients. The second type is spread through blood and body fluids, which is more threatening to human health, causing a chronic disease and developing into cirrhosis and liver cancer.
It is worth noting that the second type of hepatitis has an incubation period. Healthy people may be infected silently for many years before serious complications occur. Hematogenous hepatitis has a high morbidity and mortality rate, causing more than 1 million deaths worldwide every year, making it a global health problem comparable to HIV infection and tuberculosis.
Just as in the early stage of the new crown pneumonia epidemic, Chinese scientists quickly found the new coronavirus (SARS-CoV-2). For any infectious disease, the key to identifying the pathogen is to find the source of the “true culprit”, that is, to identify the pathogen.
In the 1960s, American scientist Baruch Blumberg, discoverer of the Hepatitis B virus, determined that one of the blood-borne hepatitis was caused by a virus later called hepatitis B virus. This discovery led to Development of diagnostic tests and effective vaccines.
At that time, Oort, who worked at the National Institutes of Health (NIH), was studying the incidence of hepatitis in blood transfusion patients. Although blood testing for the newly discovered hepatitis B virus has reduced the number of transfusion-related hepatitis cases, Oort and colleagues still proved the worrying fact that a large number of cases still exist. During this period, testing for hepatitis A virus infection has also been invented. Obviously, hepatitis A is not the cause of these unknown cases.
Many people undergoing blood transfusions develop chronic hepatitis due to an unknown source of infection, which has caused great concern. Oort and his colleagues discovered that the blood of these hepatitis patients may transmit the disease to chimpanzees, which are the only susceptible host besides humans. Subsequent research also showed that this unknown source of infection has virus characteristics. This mysterious disease was later called “non-A, non-B” hepatitis.
Discovery of hepatitis C virus
Identifying this new virus has become a top priority. Scientists have used all traditional virus capture techniques, but this mysterious virus has escaped human separation from them for more than 10 years.
Horton, who worked at the pharmaceutical company Chiron at the time, undertook the arduous work required to isolate the viral gene sequence. Horton and his colleagues collected a set of DNA fragments from nucleic acids found in the blood of an infected chimpanzee. Most of these fragments came from the chimpanzee’s own genome, but the researchers speculated that some of the fragments might come from this unknown. Virus. Assuming that the blood of a hepatitis patient contains virus antibodies, the researchers used the patient’s serum to identify cloned viral DNA fragments that encode viral proteins. After a comprehensive screening, they found a positive clone.
Further research showed that the clone came from a new RNA virus belonging to the flavivirus family, named hepatitis C virus. The presence of antibodies in patients with chronic hepatitis strongly suggests that this virus is a previously unknown pathogen.
The discovery of the hepatitis C virus was decisive, but a key part of the puzzle was missed: can hepatitis be caused by a virus alone? To answer this question, scientists must investigate whether the cloned virus can replicate and cause disease.
Rice and other RNA virus teams at Washington University in St. Louis noticed that there is a previously unrecognized region at the end of the hepatitis C virus genome, and they suspect that this region may be important for virus replication.
Rice also observed genetic mutations in isolated virus samples, and speculated that some of them might hinder virus replication. Through genetic engineering, Rice obtained an RNA variant of the hepatitis C virus, which includes newly identified regions of the viral genome. When this RNA was injected into the liver of chimpanzees, the virus was detected in their blood and pathological changes similar to those in humans with chronic diseases were observed.
Rice’s work made the chain of evidence finally pieced together, proving that hepatitis C virus alone can cause unexplained blood transfusion-mediated hepatitis cases.
Where is the difficulty in developing hepatitis C vaccine
Compared with hepatitis A and hepatitis B, there is no effective vaccine for hepatitis C. The reporter interviewed Zhong Jin, a researcher at the Shanghai Pasteur Institute of the Chinese Academy of Sciences, on the reasons why the hepatitis C vaccine is difficult to come out.
Reporter: In the “big family” of hepatitis viruses, hepatitis A, hepatitis B and hepatitis E have long had vaccines. Why has the hepatitis C vaccine not been available?
Zhong Jin: An important reason is the variability of the hepatitis C virus genome. There are 7 different genotypes and as many as 67 subtypes of hepatitis C virus, and the nucleotide difference between genotypes is as high as 30% to 35%. In contrast, the difference between the different genotypes of hepatitis B virus is only about 8%. Moreover, as an RNA virus, the RNA polymerase encoded by hepatitis C virus lacks correction function and has a high mismatch rate. At the same time, this virus has a high tolerance for mutations. The same degree of genetic mutation may make other viruses unable to survive and replicate, but it has no effect on the hepatitis C virus. These factors have caused the hepatitis C virus to become a “various” virus.
The currently marketed hepatitis A, hepatitis B, and hepatitis E preventive vaccines are all monovalent vaccines, which can effectively prevent infection of all genotypes of the virus, but it is difficult to cover all genotypes of hepatitis C virus with one vaccine. Therefore, either find a conservative viral epitope as a vaccine target, or develop a multivalent vaccine like a cervical cancer (HPV) vaccine.
Reporter: When developing vaccines, people are most likely to think of inactivated vaccines and attenuated vaccines. Why did the development of an inactivated or attenuated vaccine against hepatitis C fail?
Zhong Jin: This is about a very mysterious and very special feature of hepatitis C virus. In vitro cell culture of hepatitis C virus is very difficult. Because of this characteristic, after Harvey Alter discovered “non-A, non-B hepatitis” in the 1970s, hepatitis C virus was not successfully isolated for more than a decade. Finally, Horton pioneered the use of molecular biology methods to clone this new virus. It is precisely because of this characteristic that it is difficult for people to rely on cell culture methods to obtain a large number of virus particles to produce inactivated or attenuated vaccines that meet the needs, and it is even more difficult to expand to commercial production scale.
Reporter: Judging from the characteristics of virus infection, is it possible for the hepatitis C vaccine to be successfully developed?
Zhong Jin:The vaccine actually simulates the natural infection process and activates the human immune system. The difficulty of developing a vaccine for a virus is closely related to the natural clearance rate of the virus.
In hepatitis, neither hepatitis A nor hepatitis E can cause chronic infection. After the acute infection period, the patient can eliminate the virus by itself. Among adult hepatitis B patients, only 5% to 10% will become chronically infected. However, only 20%-40% of people infected with hepatitis C virus can clear the virus naturally, and the rest will suffer chronic infections that last for life. This determines that the development of a hepatitis C vaccine is relatively difficult.
Although the development of the hepatitis C vaccine is more difficult than several other hepatitis vaccines, it is far from the “hell-level” difficulty of the AIDS vaccine. As long as some patients can clear the virus naturally, it means that we still have hope to activate the body’s immune potential and fight against this virus.
Hepatitis C virus infection medical concept illustration.
Reporter: In addition to changing, difficult to cultivate, and difficult to remove, does the hepatitis C virus have other characteristics that make the vaccine so “difficult to deliver”?
Zhong Jin: It is true, that is, it is difficult to establish animal infection models. Animal infection models are very important tools for the development of hepatitis C vaccine, but the natural host of hepatitis C virus is very single, and only humans and chimpanzees can infect.
Due to the controversy of animal ethics, the National Institutes of Health announced in 2013 that it would stop using chimpanzees as experimental animals, making relevant animal experiments difficult. At present, people can only use gene-edited mouse models to carry out research work, but these animal models are generally not ideal.
In contrast, because hepatitis E and other viruses can infect many different animals, experimental animal models are easier to establish. Although the hepatitis B virus can only infect humans and chimpanzees, the hepatitis B vaccine was developed earlier, and some animal experiments have been done on chimpanzees. In addition, ducks and other animals can also be infected with viruses similar to human hepatitis B virus, and can also be used for animal experiments.
Reporter: Has there been any breakthrough in the development of hepatitis C vaccine recently? Do we hope to make an ideal hepatitis C vaccine in the future?
Zhong Jin: In 2019, the world’s first clinical trial of hepatitis C vaccine to verify the protection and effectiveness was launched. This is a recombinant chimpanzee adenovirus vector vaccine. The results show that this vaccine does not protect the vaccinated from infection, but it reduces the peak level of hepatitis C virus after the vaccinated is infected, and can also induce a certain immune response. This is a valuable step in the history of hepatitis C vaccine development.
Our laboratory is also doing some work. Based on the insect expression system, we have obtained a trivalent vaccine that can cover nearly 70% of the world’s major hepatitis C virus strains. At present, the immunogenicity of this vaccine is relatively good, and the production and cost issues have also been resolved.
In fact, the development of hepatitis C vaccine is still facing some practical problems. Because the current rate of new hepatitis C infections in China is not very high and the drugs are very successful, the industry is not very interested in hepatitis C vaccine.
My point is that hepatitis C vaccine is still necessary. It is not like the new crown vaccine, which is required for a large number of people around the world. But for those high-risk groups, a safe and effective hepatitis C vaccine is still a guardian worth looking forward to.