Why did it take more than 20 years to discover the hepatitis C virus and only a week to discover the new coronavirus?

The first Nobel Prize in 2020 was awarded to three scientists who discovered the hepatitis C virus over a 20-year history. Thanks to technological advances and the accumulation of previous people, this year’s new coronavirus was “discovered” not so hard. As the world battles the new coronavirus, this year’s Nobel Prize in Physiology or Medicine went to the three discoverers of the hepatitis C virus.

Prior to their work, hepatitis A and B viruses had been detected, but more than 80 per cent of cases of blood-based hepatitis remained “unexplained”. The discovery of the hepatitis C virus has saved millions of lives by revealing the causes of the remaining cases of chronic hepatitis and making it possible to test blood tests and new drugs.

“Discovery” of a pathogenic virus requires a number of conditions to be met.

In an interview with the media, Patrik Ernfors, an expert on the Nobel committee, stressed the importance of the virus being discovered.

“The first step in the fight against viral infectious diseases is to locate the virus that causes the disease.” “To get this done, we’re at the start of developing drugs and vaccines,” he said. “

As the Nobel Committee describes it, the discovery of the hepatitis C virus took scientists decades. This is because identifying the pathogens that cause an epidemic usually meets the following points:

(1) Suspected pathogens shall be found in patients and pathogen nucleic acids may be detected in clinical samples of patients;

(2) The pathogen can be successfully isolated from the patient’s clinical sample;

(3) Isolated pathogens can cause the same disease symptoms after infecting host animals.

Why did it take more than 20 years to discover the hepatitis C virus and only a week to discover the new coronavirus?

Among the discoverers of the virus, Harvey J. Alter’s systematic study of blood transfusion-related hepatitis showed that an unknown virus is a common cause of chronic hepatitis; Michael Houghton isolated a gene for a new virus called hepatitis C virus; and Charles M. Rice provides final evidence that hepatitis C virus alone can cause hepatitis.

The three scientists, and many of the people behind them who have quietly contributed, have achieved this difficult three-step process. Today, the discovery of viruses is no longer so long. Virus hunters can identify hundreds of viruses each year.

New crown virus found at “record rate”

At the end of 2019, there were several cases of “unexplained pneumonia” in Wuhan, after which the pathogen was quickly identified as a “new coronavirus”.

According to Xinhua News Agency, on January 2 this year, after receiving samples of cases sent for examination in Hubei Province, the CDC immediately put in a “relay race”: the extraction of nucleic acids, genetic sequencing, matching analysis … After more than 30 hours of continuous struggle, the genetic code of the virus was finally deciphered in the first time. According to this whole genome sequence, nucleic acid detection reagents were developed quickly.

The second step is virus isolation. The isolation culture of coronavirus is not easy, and the specimen has experienced freezing and long-distance transportation, which increases the difficulty of separation. But it took 5 days, the first time the researchers isolated and identified the new coronavirus, obtained the world’s first photo of the new coronavirus electron mirror, for the rapid identification of the pathogen “one hammer tone.”

On January 12, the CDC, the Chinese Academy of Medical Sciences and the Wuhan Virus Research Institute of the Chinese Academy of Sciences, as designated institutions of the National Health And Health Commission, submitted information on the genome sequence of the new coronavirus to the World Health Organization, which was published and shared in the global influenza sharing database, which provided an important basis for global vaccine research and development, drug research, outbreak control, etc.

“China has identified pathogens in a record short period of time and shared full gene sequence information with the World Health Organization and other countries.” World Health Organization Director-General Tandesser said.

The discovery of hepatitis C virus is really slow compared to the fact that the new coronavirus can be “discovered” quickly. There are obvious reasons for the development of science and technology. Nucleic acid detection, for example, was key to the detection of the new coronavirus, and the most primitive gene sequencing techniques were not developed until the late 1970s.

In 1972, after Harvey Alter proved that a “non-A-non-B” virus was the cause of chronic hepatitis, the separation of the virus was delayed. Until 1989, Michael Houghton and others isolated the nucleic acids of HCV with the latest molecular techniques;

“They’re waiting for the technology to mature,” Dennis Brown, chief scientific officer of the American Physiological Association, told the media. “

“Forgotten” human coronavirus discoverer.

In addition, scientists were able to quickly identify the “true killer” of the new coronavirus, thanks to familiarity with the virus , the discovery of which is based on previous virological developments, including the HCV virus, which is also known as the RNA virus.

The first time human coronavirus showed its true appearance was in the 1960s, more than half a century after humans knew them.

The first person to “see” a human coronavirus was a woman, British virologist and virus imaging expert June Almeida.

Almeida, who was married to Joan Hart, was born in Glasgow, Scotland, in 1930. Her father, a local bus driver, did not receive much formal schooling herself. At the age of 16, unable to afford university tuition, she got a job as a technician in the Tissue Pathology Laboratory at Glasgow Royal Infirmary. A few years later, the Almeidas immigrated to Toronto, Canada.

At the Ontario Cancer Institute, Almeida not only mastered the techniques of electron microscopy, she also innovatively invented a way to make viral imaging clearer — by using antibodies to aggregate viruses into clusters.

Almeida’s talents were recognised by British scientists, and in 1964 she was lured home to work at St Thomas’s Hospital’s affiliated medical school in London, where She was treated after British Prime Minister Boris Johnson contracted the new coronavirus. After his return, Almeida began working with David Tyrrell, the head of a common cold research office.

Tyrrell’s team, studying samples of nasal lotions from volunteers, found that many, but not all, of the viruses associated with the common cold could be cultured in the lab. Among the many samples was a nasal lotion number B814 from a pupil in the south of England.

Unlike the laryngeal symptoms of a typical cold, B814 can cause an infected person to wilt, and B814 can be in viable due to a fat solvent, which means that the pathogen has a lipid outer membrane, which is also different from a typical cold pathogen.

Tyrrell wondered: Can you see the true face of the virus directly under an electron microscope? They sent some samples to Almeida’s lab, but Tyrell didn’t hold out much hope. After all, the sample was able to cause symptoms in infected volunteers, but was unable to reproduce in the commonly used culture environment. Without the purified virus, electron microscopes are not only rare, but also interfered with by cellular tissue.

Almeida exceeded everyone’s expectations. Using the “negative infection method” she learned in Canada to process samples (to improve image contrast), she managed to see virus particles under a microscope, describing them as “flu-like, but not exactly the same.”

What she saw was actually the first human coronavirus.

Why did it take more than 20 years to discover the hepatitis C virus and only a week to discover the new coronavirus?

Photo Electron microscopy of coronavirus taken by Almeida in 1966 (Source: Wikipedia)

In fact, Almeida has seen similar virus particles before when studying the hepatitis virus in mice and the chicken bronchitis virus.

However, her papers to professional magazines were rejected during the peer review process. The reviewer concluded that the viral images she provided of infected mice and chickens were “nothing more than flu virus particles of poor image quality”.

The paper, based on the findings of the B814 sample, was published in the British Medical Journal in 1965. Images of viral particles seen by Almeida were published two years later in the Journal of General Virology. The name “coronavirus” is also based on microscopic images by researchers such as Tyrrell and Almeida.

Almeida later transferred to the Royal Graduate School of Medicine in London (now imperial college of medicine) to continue her research work, where she was awarded a Doctorate. Her career ended at the Wellcome Institute in the UK, during which time she obtained several patents in the field of viral imaging.

Joan Almeida died in 2007 at the age of 77.

Almeida isn’t a high-profile “No Award-winning” science star, and perhaps few regret it – her photos of rubella and hepatitis B appear in some textbooks, and she’s been involved in discovering a “no threat” cold virus, “that’s all.”

The Nobel Prize winner didn’t make a hepatitis C vaccine.

The 2020 Nobel Prize in Physiology or Medicine was awarded to three scientists who “discovered the hepatitis C virus”, giving the long-understated hepatitis C virus a bad brush.

Many people realize that hepatitis C, which has been detected for more than 30 years, has not yet been on the market.

“In fact, Michael Houghton, one of the three Nobel laureates, has been fighting for years to develop a hepatitis C vaccine, but the revolution has not yet succeeded.”

Zhong Jin, a researcher at the Pasteur Institute in Shanghai, said in an interview with the China Science Daily that the four characteristics of the hepatitis C virus make it difficult for vaccines to come out.

Feature 1: There are many changes.

China Science Journal: In the “family” of hepatitis virus, hepatitis A, hepatitis B and hepatitis E are early vaccine, why is the hepatitis C vaccine delayed?

Zhong Jin: An important reason is the variability of the hepatitis C virus genome.

There are 7 different genotypes and up to 67 subtypes of HCV, with nucleotide differences of up to 30% to 35% between genotypes.

In contrast, the difference between different genotypes of HBV is only about 8%.

As an RNA virus, the RNA polymerase encoded by HCV lacks correction function and has a high mismatch rate.

At the same time, the virus has a high tolerance for mutations.

The same degree of genetic variation may prevent other viruses from surviving and replicating, but has no effect on HCV, which is a “varied” virus.

The current listed preventive vaccines for hepatitis A, B and E are unit-priced vaccines that can effectively prevent infection of all genotypes of the virus.

But the hepatitis C vaccine may not be so simple, a vaccine may be difficult to cover all genotypes of hepatitis C virus.

The idea could be to either find a conservative viral surface as a vaccine target or develop a multi-priced vaccine, as the cervical cancer (HPV) vaccine did.

Feature two: not good training.

China Science Journal: When developing vaccines, the most likely ideas are often inactivated and detoxifying vaccines. Why hasn’t the development of an inactivated or detox vaccine for hepatitis C succeeded?

Zhong Jin: This is about a very mysterious and special feature of the hepatitis C virus.

In-body cell culture of HCV is very difficult.

We look at the new coronavirus, isolated from the patient, can be cultured in a variety of in vitro cells, can also infect a variety of cells in vitro.

But hepatitis C virus can not, in-body infected cells can not do, amplification is even less.

Because of this feature, the hepatitis C virus was not successfully isolated for more than a decade after Harvey James Alter discovered “non-A-non-hepatitis B” in the 1970s.

Finally, Horton pioneered the use of molecular biology to clone the new virus.

It is also because of this characteristic that it is difficult to rely on cell culture methods to obtain large numbers of virus particles, it is difficult to produce inactivated or detoxifying vaccines that meet the needs, and it is more difficult to expand to the scale of commercial production.

Feature 3: Difficult to clear.

China Science Journal: From the characteristics of hepatitis C virus infection, hepatitis C vaccine is likely to be developed successfully?

Zhong Jin: We know that vaccines actually simulate the process of natural infections and activate the body’s 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 E can cause chronic infection, and after the acute infection period, the body can eliminate the virus itself.

Only 5% to 10% of adult hepatitis B patients are converted to chronic infection.

But only 20% to 40% of people infected with HCV naturally remove the virus, and the rest suffer from chronic infections that last for life.

This determines that hepatitis C vaccine research and development is more difficult.

Of course, HCV is far from the trickiest opponent.

The natural clearance rate of HIV is 0.

In the absence of therapeutic intervention, the patient will be poisoned for life.

Therefore, the development of hepatitis C vaccine, although more difficult than several other hepatitis, but far less than the AIDS vaccine as “hell-grade” difficulty.

As long as some patients are able to remove the virus naturally, it means that we still have hope of activating the body’s immune potential to fight the virus.

Feature 4: Lack of model.

China Science Journal: It seems that the hepatitis C virus is indeed a hard one, so there are other reasons why the hepatitis C vaccine is so “difficult to produce”?

Zhong Jin: Really.

Animal infection models are a very important tool for the development of hepatitis C vaccines.

But the natural host of HCV is so single that only humans and chimpanzees can be infected.

Because of the controversy over animal ethics, the U.S. National Institutes of Health announced in 2013 that it would stop using chimpanzees as experimental animals, making animal testing difficult.

At present, people can only use gene-edited mouse models and other research work, but these animal models are generally not ideal.

In contrast, viruses such as hepatitis E are easier to build because they can infect many different animals.

Although the hepatitis B virus can only infect humans and chimpanzees, the hepatitis B vaccine was developed earlier and some animal trials have been carried out on chimpanzees.

In addition, animals such as ducks can also be infected with viruses similar to human hepatitis B virus, can also be used for animal testing.

So do you want to do it?

China Science Journal: At the same time that the development of hepatitis C vaccine is difficult, hepatitis C drug has been a great success, with the special anti-HCV drug sophosphobwe, chronic hepatitis C has been a high cure rate of disease. So is it necessary for us to develop a hepatitis C vaccine?

Zhong Jin: I believe it is necessary.

The cost of drug treatment for hepatitis C is relatively high.

In the U.S., a 12-week standard course costs $70,000 to $150,000, or tens of thousands of yuan even in China.

The areas with high prevalence of hepatitis C are precisely in low-income countries and regions.

In addition, although preventive measures to stop the spread of hepatitis C are gradually being improved, the rate of increase in new cases of hepatitis C in recent years has been rapid.

In China, 48% to 95% of injecting drug users have been found to be infected with HCV, and these populations have a very high risk of repeated infection, which may increase the probability of the virus developing drug-resistant mutations, and even contribute to the emergence of drug-resistant strains.

Or that sentence, to really eliminate an infectious disease, or rely on vaccines.

Do we see hope?

China Science Journal: Has there been a significant breakthrough in the recent development of hepatitis C vaccine? Are we hopeful of making the ideal hepatitis C vaccine in the future?

Zhong Jin: In 2019, the world’s first clinical trial of the protective and effective hepatitis C vaccine, a recombined chimpanzee adenovirus vector vaccine, was conducted.

The results showed that the vaccine did not protect the vaccinator from infection, but it reduced the peak level of HCV after infection, and also induced a certain immune response.

This is a valuable step in the history of hepatitis C vaccine research and development.

Many scientists around the world, including Nobel Laureate Horton, continue to look for ways to break the hepatitis C vaccine. Our lab is doing some work, too.

Based on insect expression systems, we have obtained a trialic vaccine that covers nearly 70% of the world’s major hepatitis C virus strains.

At present, it seems that our vaccine is better immunogenic, and the production and cost problems have been solved.

But we can’t produce vaccines in the lab, and the main problem is how to work with companies to develop standardized production and clinical trials for vaccines.

In fact, hepatitis C vaccine research and development is also facing some practical problems.

Because the current domestic rate of new hepatitis C infection is not very high, the drug is very successful, industrial enterprises on the hepatitis C vaccine interest is not very large.

My view is that the hepatitis C vaccine is still needed, unlike the new crown vaccine, which is needed by a large number of people around the world.

But for those at high risk, a safe and effective hepatitis C vaccine is still a god of protection to look forward to.