Published: 10:26, April 1, 2020 | Updated: 05:30, June 6, 2023
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COVID-19 retro medicines bring hope
By Wang Yuke

These seem like desperate times as the coronavirus surges worldwide, but teams of medical researchers are hopeful that effective remedies may be close by. Wang Yuke reports.

In hospitals in every corner of the world, medical workers are fighting to save lives devastated by COVID-19, while in labs, researchers frantically search for remedies, fearing the day the surge takes hold and leaves death and economic ruin in its path.

The search for a drug that will dispatch COVID-19 is in high gear. Drugs are already in human trials, which means they’re close to approval, and then they can be used to treat the disease.

The Hong Kong vaccine is based on a flu-virus technology. The technology has been around for years and is widely used to combat flu epidemics. ... So the system is well established and safe

Chen Honglin, professor of the Department of Microbiology at the University of Hong Kong

Other researchers are ramping up efforts to discover new vaccines in the race to prevent the surge from getting even worse.

Already, there are two promising developments. One was produced by a Chinese biological lab, the other by a US pharmaceutical company. Both are in clinical trials already.

As of March 20, another 42 possible vaccines are in pre-clinical trials, according to the World Health Organization. It is hoped that these promising treatments will put an end to the virus down the line.

Humans have experienced plagues from ancient times but the scourge taking place these days — COVID-19 — is more contagious, more transmissible and more dangerous, said Zhang Hongbing, a scientist from Peking Union Medical College, Chinese Academy of Medical Sciences. What’s worse, “some patients have no symptoms. Some show only mild symptoms in the early stages of infection. All of these, whether they are entirely asymptomatic or showing only mild flu symptoms, are carriers, spreading the disease among more and more people.” Then comes the surge in reported cases.

The major damage from COVID-19 is to the lungs. The immune system overreacts to a point that can have fatal consequences. The patient actually drowns when their lungs become inflamed and then are inundated with fluid. When the lungs cease functioning, the patient can’t get oxygen, can’t breathe, or can’t exhale carbon dioxide.

Common sense tells us that people with a robust immunity have a better chance of survival. However, overreaction of the natural immune system is responsible for many of the fatalities from COVID-19. Clinically, that reaction is known as a “cytokine storm”, said Zhang. Cytokines are a type of molecule produced from cells in the immune system. Under normal conditions, they control the inflammation that comes with an immune reaction to any foreign invader. White blood cells and other immune cells rise up in defense and invade the virus, attacking viruses with everything they’ve got. When the immune system reacts too aggressively, an abundance of immune cells attack and kill the infection, but also ravage healthy lung tissue.

Hundreds of drugs are being examined all over the world to fight the coronavirus. It is of some comfort to know there are signs of hope.

Chen Honglin (left) and his fellow researchers pose for a group photo at the lab. (PHOTO PROVIDED TO CHINA DAILY)

Repurposed old drugs

Researchers are looking again at some drugs already proved effective in fighting a swath of infections, like seasonal flu, malaria, AIDS, SARS and MERS. Denis Kainov and other European-based scientists have reviewed several existing antiviral drugs to explore their potential for treating COVID-19. “Drug repurposing is a strategy for generating additional uses from an existing drug,” Kainov said. In sum, drugs already on the market may have untapped potential for treating other diseases.

Kainov, an associate professor of clinical and molecular medicine at the Norwegian University of Science and Technology, believes “repurposing has significant advantages over new drug discovery and development.” Existing drugs are proven and certified to human treatment.

Dan Barouch, professor of medicine at Harvard Medical School, said, “It can take years to develop a new drug. There are drugs in the market that are available right now, and that can be reproduced quickly, if they prove effective against a new infection.”

Repurposed drugs are a standard line of research any time new infectious diseases pose new threats to human life and treatments are in urgent need. In the case of COVID-19, the rationale is that the medications under study already have been shown to stop the replication of viruses in host cells. Viruses have to reproduce in its host, or they die. If replication is blocked, the virus cannot survive and the host gets better.

Remdesivir, developed by Gilead Sciences, a US research-based biopharmaceutical company is one of the most promising avenues of current inquiry. The drug was tested on animals against SARS-CoV and MERS-CoV. Remdesivir also showed promising results during clinical trials at the height of the Ebola outbreak. The drug is an antiviral in the class called, “nucleotide analogues”. A nucleotide analogue simulates the normal building blocks of deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) — two molecules that carry genetic information.

In the case of COVID-19, the drug interferes with reproduction, causing the coronavirus to reproduce faulty RNA. If the virus is unable to reproduce, the patient is likely to get better through an intravenous drip. Researchers suspect the drug intervention may alleviate a patient’s labored breathing and reduce the risk of multiple organ failure. Nevertheless, its affordability has recently become the subject of controversy after it was reported that Gilead refused to guarantee the drug would be affordable to all.

Just how the drug works can be difficult to fathom. Zhang explains it by using an example of the Chinese folk tale Monkeys Catch the Moon. In the tale, the monkeys hang from tree branch in a chain, hoping to catch the moon, which is reflected in a well down below. The one at the top hangs onto the tail of the one below, one after another. If one monkey doesn’t have a tail to hold on to, the chain is broken. It’s a good metaphor for how the drug works — stopping the coronavirus from replicating.

Another direction of research is the protease inhibitor, applied in AbbVie’s Kaletra, which was originally used for treating HIV. The drug also proved effective against SARS-CoV and MERS-CoV.

The idea behind protease inhibitor is to suppress the virus’s ability to produce an enzyme or protease — a component the virus requires to multiply in the host cells. During viral reproduction, proteins are produced. The role of the protease is to break down large proteins into individual units, each of which plays a part in viral reproduction. The drug inhibits that process, depriving the virus of the molecules it needs to reproduce.

It’s like a group of workers under a team leader who hands out assignments to finish a project. If the team leader is off, having a late lunch, anarchy spreads throughout the team, and the job doesn’t get done.

Researchers conduct experiments on candidate vaccines in the State Key Laboratory at the University of Hong Kong. (PHOTO PROVIDED TO CHINA DAILY)

Nipping it in the bud

Medicines potentially could cure COVID-19. A vaccine, however, would kill the infection on contact. It is commonly believed that vaccines save countless lives every year. The smallpox virus has been completely uprooted, and the incidences of polio and measles have been drastically reduced.

Anthony Fauci, the director of the US National Institute of Allergy and Infectious Diseases, told the media in March that with any luck, the first vaccine for public use may be ready in 18 months.

Yu Chengbo, a front-line doctor in Wuhan, considers Fauci’s time frame conservative. Even he agrees finding a vaccine for clinical use requires many, many steps. Seventeen major organizations in China have turned their attention to COVID-19 vaccine research and development.

Since viruses mutate frequently, there is some concern that the new coronavirus could mutate, so that by the time researchers develop a vaccine for today’s virus, it would have changed completely and all the work would be wasted. Yu doesn’t think that’s very likely because there is a low probability of radical mutation at that level. “When the viral genome sequence alters by 8 percent, the nature of the original virus changes, and a vaccine that might work on the earlier stage of the virus might not work on the current virus. But the chance of the SARS-CoV-2, the official name for the coronavirus that caused COVID-19, mutating that much is small.”

Barouch has led his team toward a DNA vaccine, targeting the current coronavirus. “The work is in progress. … We hope there will be concrete clinical data in several months, and expect to start clinical trials this fall.”

They also started collaborating in February with the Chinese Center for Disease Control and Prevention on the DNA vaccine.

Researchers conduct experiments on candidate vaccines in the State Key Laboratory at the University of Hong Kong. (PHOTO PROVIDED TO CHINA DAILY)

A different avenue 

While the development of single-strand messenger RNA vaccines is gaining a global spotlight, some scientists propose obtaining antibodies by extracting blood from recovered patients. The serum harvested from previously recovered patients has virus-fighting antibodies that may help other people acquire immunity from the infection.

That avenue of research may offer new clues about solutions to eradicate the novel coronavirus. The topic, however, is a matter of some dispute among medical researchers. While the idea is theoretically viable, it may not prove feasible clinically, Barouch argues. The approach hangs on the fact that survivors of infectious diseases develop antibodies against the viruses, and the antibodies protect them from contracting the infections again. So, the theory goes, if we transfuse blood from a recovered patient to a healthy individual, he or she will acquire immunity from the infection. It would also benefit those already infected, slowing the progression of the symptoms.

The idea has been around for more than a century. During the Ebola outbreak, researchers tried the same thing and it didn’t work in the trial phase, Barouch said. “The reason was unknown, but it’s likely because the level of antibodies was too low,” he said.

Blood transfusions always present risks, added Zhang. The blood product obtained from recovered patients “may have contamination, such as residue of the virus, or even another virus like HIV. In that case, we must purify the blood sample before using it. That is labor-intensive and expensive.”

The limited supply of serum used for the treatment is another issue, Zhang said.

A potential side effect of some vaccines is that it can initiate the “cytokine storm”, exacerbating the inflammation that comes as part of the patient’s immune response. Researchers from the University of Hong Kong (HKU) are developing a vaccine that can curtail the overreaction by the immune system. There are a range of advantages about this Hong Kong-made vaccine, said Chen Honglin, professor of the Department of Microbiology at HKU.

The Hong Kong vaccine is based on a flu-virus technology. The technology has been around for years and is widely used to combat flu epidemics, especially in the US, Canada and Europe, Chen said. “So the system is well established and safe. That’s why it only took us a couple of weeks to develop the vaccine seed,” he said.

It can be administered as a nasal spray, so it’s easy to administer. The vaccine development is one of several research efforts to eradicate COVID-19 by the State Key Laboratory for Emerging Infectious Diseases at HKU. They secured seed funding from the Coalition for Epidemic Preparedness Innovations (CEPI), an innovative partnership between public, private, philanthropic, and civil organizations, launched at Davos in 2017, to develop vaccines to stop future epidemics.

The funding is proceeding on a milestone basis, according to He Yiwu, who led the research team.

“Instead of giving a big chunk of money all at once, CEPI has granted $620,000 for preclinical studies. We’re striving to accomplish Phase One studies by July as we promised, in order to obtain the funding for the next round of trials.”

CureVac, a Germany-based biomedicine company, also received CEPI funding worth $8.3 million. It announced that its COVID-19 vaccine is expected to be mass-produced for clinical use in fall this year.

Despite some speculation that COVID-19 will not die easily and may become cyclical, some scientists believe that it will be in full retreat by summer, like its predecessor, SARS. Whether it stays or goes, we need to know, at least, that we are prepared to deal with it for the future.

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