wechat_bg

2020-03-06 09:48:13

Update: On March 16, China approved its first experimental vaccine targeting COVID-19 for human trials in healthy individuals, state media reported. The vaccine was developed by researchers at the Academy of Military Medical Sciences of the People's Liberation Army. The early-stage trial is scheduled to run from March 16 to Dec. 31.

In early January, Zhang Linqi started hearing strange reports from the central Chinese province of Hubei. Hospitals in the regional capital, Wuhan, were seeing a spike in pneumonia patients, and doctors were uncertain what was causing it.

As one of China’s leading virologists, the news immediately put Zhang on alert. His years of experience told him that a contagious pathogen could be behind the mysterious wave of infections.

“I really hoped it wasn’t anything particular,” Zhang, a professor at Tsinghua University in Beijing, tells Sixth Tone. “But then I thought: What if it is?”

So when the Chinese government revealed a few days later that the cases in Wuhan were linked to a novel strain of coronavirus — the same family of viruses that can cause SARS — Zhang called his colleague Wang Xinquan, a structural biologist at Tsinghua. They agreed to put aside all their other projects and focus exclusively on the virus. 

In the absence of drastic measures, this will develop into a pandemic.

At the time, the researchers’ decision may have seemed premature — they still had no idea whether the disease was transmissible among humans. But it proved to be a prescient move. “We’re so glad we made that call,” says Zhang.

In just three months, COVID-19 has spread from a single Chinese city to every continent in the world except Antarctica, sickening over 95,000 and killing 3,200 globally as of Thursday. Governments have struggled to contain the elusive disease, with some patients showing no symptoms at all.

As the number of cases outside China climbs, experts fear the worst-case scenario — a pandemic that recurs seasonally — is now a likely outcome.

“In the absence of drastic measures, this will develop into a pandemic,” says Richard Neher, head of research at Biozentrum, the center for molecular life sciences at the University of Basel in Switzerland. “Whether or not we already are in a pandemic is a matter of semantics.”

Scientists are racing to find vaccines, drugs, and antibody treatments capable of combatting the virus, which currently has no known cure.

Developing, testing, and bringing a new drug to the market can take as long as a decade during normal periods. But researchers like Zhang have moved swiftly since the initial outbreak, sharing data to an unprecedented degree and drawing on technologies unavailable during previous health crises.

Responses to past epidemics were often sluggish. When the Zika virus spread across the Americas during the mid-2010s, the outbreak wasn't detected and reported for nearly a year. After SARS emerged in China in late 2002, it took four months for scientists to sequence the virus’s genome.

This time, however, doctors were able to identify SARS-CoV-2 — the virus that causes COVID-19 — within days.

By Jan. 10, a team at Shanghai’s Fudan University had sequenced the virus’s whole genome and uploaded the information to a public database — paving the way for other researchers to begin working on possible treatments.

A transmission electron microscope image shows SARS-CoV-2 — the virus that causes COVID-19 — isolated from a patient in the United States. From NIAID-RML

A transmission electron microscope image shows SARS-CoV-2 — the virus that causes COVID-19 — isolated from a patient in the United States. From NIAID-RML

The genome sequence showed that SARS-CoV-2 invades host cells in a similar way to the SARS virus. Its surface is covered with small, spiky protein structures that can bind to a type of human enzyme. Once docked, the virus can unlock the door to human cells, where it multiplies and spreads.

For researchers, understanding the virus’s entry mechanism is of vital importance, because the most effective way of treating a viral infection is to create a drug or vaccine that can prevent the virus from binding to human cells.

Over the following weeks, teams around the world mapped out the SARS-CoV-2 binding process in minute detail. On Feb. 19, scientists at the University of Texas published 3D models of the virus’s protein spikes in the journal Science, after analyzing it using a cryogenic electron microscope, or cryo-EM, which can analyze molecular structures almost atom-by-atom.

A 3D reconstruction of an RBD-ACE2 complex shows how the new coronavirus binds to human ACE2 enzymes before invading cells. Courtesy of Westlake University

A 3D reconstruction of an RBD-ACE2 complex shows how the new coronavirus binds to human ACE2 enzymes before invading cells. Courtesy of Westlake University

The next day, a team at Westlake University in eastern China’s Zhejiang province published the structure of an RBD-ACE2 complex — a part of the virus’s protein spike bound to the human enzyme. Zhang, Wang, and their colleagues at Tsinghua shared an even more detailed map of the same complex, which they had reconstructed using X-ray crystallography, the same day.

In both cases, the researchers shared their findings immediately rather than waiting weeks to publish in a peer-reviewed journal — a trend that has continued throughout the epidemic. According to a Reuters analysis, 60% of the studies published on COVID-19 are preprints, or manuscripts yet to be peer-reviewed.

“We wanted to share our results as soon as possible — they can help others find a way to block the binding process with antibodies or drugs,” Wang, the Tsinghua biologist, tells Sixth Tone. “Sharing information promptly is critical during this crisis … To fight the virus, we need to mobilize all our forces.”

The structure maps allowed scientists to begin searching for molecules capable of binding to the virus or enzymes — the essential building blocks for a COVID-19 treatment.

First, however, many researchers are testing out existing medications to see if any are effective against SARS-CoV-2. Because it can take years to create and test a new drug from scratch, this could be the quickest way to find a workable treatment.

Various antivirals, including the HIV drug lopinavir, have already been tested on COVID-19 patients, but none have shown definitive results so far.

“It’s highly unlikely that anything off-the-shelf will have good activity against SARS-CoV-2,” David Ho, a professor at New York’s Columbia University, told an online forum for COVID-19 researchers Feb. 26. “On desperate occasions you have to try, but you have be awfully lucky to find one that works.”

Sharing information promptly is critical during this crisis … To fight the virus, we need to mobilize all our forces.

Other teams are combing through giant databases of over 100 billion chemical compounds to identify potential COVID-19 drug candidates. 

Drug discovery is an immensely complex task. The therapeutic compound has to perfectly fit the drug targets — such as the SARS-CoV-2 protein spikes or human ACE2 enzymes — but these structures can have diameters 200,000 times smaller than the period at the end of this sentence.

“Finding the exact drug molecules in an enormous pool of chemicals is like searching for a habitable planet in a universe,” says Lai Lipeng, co-founder of Massachusetts-based biotechnology firm XtalPi.

Lai, however, believes artificial intelligence technology can significantly shorten the drug discovery and development process. XtalPi is using algorithms to trawl through lists of FDA-approved drugs, and it has already identified 38 candidates that could be effective in treating COVID-19.

The firm will soon begin testing the drugs’ efficacy and safety on cells and animals, before moving to clinical trials. Research suggests more than 90% of drug candidates that enter clinical trials will fail before reaching the market. 

“It’s extremely difficult (to find an effective drug), but … we hold the promise of shortening the drug discovery process from three to six years to one to two years,” says Lai.

Researchers have also created potential vaccines against the virus much faster than during previous outbreaks, thanks in part to the extraordinary level of data sharing among teams.

PepGene, a Massachusetts-based biotech firm, is working on a SARS-CoV-2 peptide vaccine — a shot containing synthetic substances designed to trigger a desired immune response and avoid side effects. The company aims to start clinical trials in the second half of 2020.

Chen Tenghui, the company’s founder, tells Sixth Tone that messaging app WeChat has played a surprisingly important role in PepGene’s research and development work since the initial outbreak.

During normal periods, pharmaceutical companies closely guard their research to maintain a competitive advantage. Since January, however, employees at dozens of cutting-edge firms — including XtalPi, antibody developer HiFiBiO Therapeutics, and immunotherapy designer RootPath — have been comparing notes via specially created WeChat groups.

A graphic demonstrates the drug discovery process using molecular modeling. Courtesy of XtalPi

A graphic demonstrates the drug discovery process using molecular modeling. Courtesy of XtalPi

“These chat groups significantly boost the communication efficiency among researchers,” says Chen. “For example, we get to modify our product designs immediately based on a new study that comes out, or find out about opportunities for collaboration right away.”

Many other teams are moving toward clinical trials for their own vaccines. Researchers at Shanghai Jiao Tong University and Fudan University announced Feb. 27 that they have begun animal testing for a SARS-CoV-2 vaccine, while a team at the University of Queensland in Australia claims to be preparing for pre-clinical testing of its first vaccine candidate.

Moderna, a Massachusetts-based biotech firm, announced Feb. 24 that it had delivered its first batch of experimental vaccine to the U.S. National Institutes of Health. The NIH is expected to begin trials in April. Several smaller biotech companies, including Inovio Pharmaceuticals, Novavax, and CureVac, also have vaccines in the pipeline.

(Drug discovery) is like searching for a habitable planet in a universe.

Experts predict it will take 12-18 months for the new vaccines to gain approval due to the time required to complete clinical trials. Zhang, the Tsinghua virologist, says China may expedite the process even more.

“It’s possible we could have a vaccine in six to nine months,” says Zhang. “But it’s hard to predict, because there are many variables, such as the technologies used, whether we have sufficient ingredients and equipment, and if the government ‘green-channels’ the approval.”

Fast-tracking clinical trials can be controversial, as shorter trials give regulators less time to spot potential side effects or other long-term health risks. For Zhang, however, authorities also have to consider the potential benefits of a fast approval process — including protecting frontline health care workers and allaying public fears over the virus.

“Most of the time, vaccines are safe, because the technology has become quite mature,” says Zhang. “Certainly, there may be long-term risks that we can only find out via longer clinical trials. But how long is long enough?”

The first COVID-19 medications to reach patients, however, are likely to be antibody treatments. 

Antibodies are molecules produced by human immune systems to combat viruses, which usually work by blocking the virus from binding to host cells. They can be an effective treatment for patients infected with a virus, as well as a prophylactic for preventing infections.

A graphic visualizes antibodies neutralizing a virus. Remco van der Meer/IC

A graphic visualizes antibodies neutralizing a virus. Remco van der Meer/IC

One of the companies working on a COVID-19 antibody treatment is Regeneron Pharmaceuticals. The New York-based firm is working to harvest antibodies by injecting SARS-CoV-2 into mice that are genetically modified to have human immune systems.

According to Alexandra Bowie, a spokesperson for the company, Regeneron is still uncertain when its antibody therapy will be ready for use on humans. She added that the firm previously developed and started testing Ebola antibodies within six months.

WuXi Biologics, a Shanghai-based biotech company, is collaborating with Vir Biotechnology in California to produce a similar treatment. The two firms expect to begin clinical trials in about three to four months, according to Chris Chen, CEO of WuXi Biologics.

“Using neutralizing antibodies for viral infections is quite safe, because they bind to very specific targets that only exist on the intended viruses,” says Chen, who has no relation to Chen Tenghui.

Yet frontline medics realize even these treatments will only become available after the initial phase of the epidemic is over. 

“As clinicians, we certainly hope a drug or vaccine can be developed as soon as possible, but history and experience tell us that’s impractical,” says Shen Yinzhong, a director at the Shanghai Public Health Clinical Center.

Shen says his team is focusing on saving lives using well-established symptomatic and supportive therapy, such as administering anti-inflammatories and maintaining patients’ oxygen levels. 

“Even if we don’t have a drug or vaccine now, we can still control the epidemic using traditional measures: quarantine, disinfection, and occupational protection,” he adds.

Vaccines will become vital, though, if COVID-19 does develop into a seasonal disease. Chen Xi, an assistant professor of public health at Yale University, tells Sixth Tone the world is paying the price for failing to develop a SARS vaccine in 2003. 

Luo Hongzhi/500px/VCG

Luo Hongzhi/500px/VCG

“A coronavirus vaccine is long overdue from 17 years ago,” says Chen, who isn’t related to Chris Chen or Chen Tenghui. “Even if it (a SARS vaccine) hadn’t worked well on SARS-CoV-2, we would’ve gained so much more experience in how to make one.”

Costly and unlikely to generate immediate returns, companies are often unwilling to invest in vaccine development and the field requires significant financial support from governments and research foundations. 

A coronavirus vaccine is long overdue from 17 years ago.

The first experimental SARS vaccine began clinical trials 20 months after the virus’s genome sequence was confirmed, but by then the epidemic had ended and most studies were abandoned.

Since the emergence of COVID-19, organizations have poured money into vaccine projects once more. Local governments across China have created research funds worth up to 1 billion yuan ($144 million) to support firms pursuing COVID-19 treatments. Jack Ma, founder of tech giant Alibaba, donated 100 million yuan from his Public Welfare Foundation to several research organizations. 

Internationally, the Coalition for Epidemic Preparedness Innovations — a global partnership for supporting vaccine development — has invested over $60 million on SARS-CoV-2 vaccine projects, after receiving backing from the British and Norwegian governments, as well as the Bill and Melinda Gates Foundation.

Chen Xi stresses, however, that investment over the long term is even more important.

“We should learn from the past and continue investing in vaccine and drug development after this epidemic ends,” says Chen. “Then, we’ll be more prepared the next time a coronavirus hits.”

Editor: Dominic Morgan; visuals: Fu Xiaofan and Ding Yining.

(Header image: Fu Xiaofan/Sixth Tone)