The rapid development and delivery of a vaccine against the new coronavirus seems like a medical miracle, but not to the scientists who spent years pushing boundaries to solve the unsolvable.
Among them is Wang Nianshuang, a former research associate with the University of Texas at Austin, who studied coronaviruses for eight years before his continuous hard work was rewarded with the pivotal design of a synthetic spike protein.
Wang’s design is at the heart of the mRNA vaccines developed by Moderna and Pfizer-BioNTech, as well as two others under development by Johnson & Johnson and Novavax. It was available so quickly because of his previous research, which went largely unnoticed at the time.
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“I will feel pretty good when I finally take the Covid-19 jab, and be very confident about its quality,” said Wang, who now works at Regeneron Pharmaceuticals in the US. “My wife is just glad that I finally made it because it has been not an easy path. My four-year-old daughter thinks I am a hero who fights off the coronavirus.”
Wang was born into a rural family in the eastern province of Shandong and supported himself through high school, before he was admitted in 2005 to the Ocean University of China. He arrived for his studies in the bustling port city of Qingdao, ignorant of the basic skills of urban survival – the coins needed for bus fares, how to use bank cards, and the existence of social media.
But he shone academically and in 2009 Wang was exempted from the entrance exams to the prestigious Tsinghua University in Beijing, where he worked towards his doctorate in the structural biology centre. In 2013, he began the research that would ultimately contribute to the Covid-19 vaccines.
Wang and his research partner Zhang Linqi, a professor with Tsinghua’s medical school, reported the first human monoclonal antibody to exhibit strong neutralisation activity against the coronavirus responsible for Middle Eastern respiratory syndrome (Mers).
The experience paved the way for his post-doctorate appointment at Dartmouth College in the US, where he joined professor Jason McLellan and his team who were working on a concept to design a vaccine for Mers, based on the structure of key proteins found in coronaviruses.
In essence, all vaccines work in the same way: by training the body to recognise and react to a virus without getting infected, so that an immune response can be activated quickly when exposed to the real virus.
Conventional vaccine technologies use killed or attenuated viruses. But the mRNA vaccines currently being rolled out in the US use a new technology which deals only with the genetic code of a key part of the new coronavirus.
Coronaviruses – including Sars-CoV-2 which causes Covid-19 – derive their name from the distinctive spike proteins on their surface, which look like crowns. These spikes are able to lock on to proteins on the surface of human cells in a process called membrane fusion.
The spike protein changes its shape before and after the process – from a smaller, mushroom-like form that first makes contact with the human cell, to a rod-like form that initiates entry and can then take over the invaded cell, causing the illness.
The shape of the protein mattered, as McLellan knew from his work with the National Institute of Health’s Vaccine Research Centre seven years earlier. The immune system needed to be able to recognise the protein spike in its pre-fusion shape – before infection occurred – if a vaccine was to be effective.
Wang was given the task of locking the spike protein in its pre-fusion shape, so that vaccines based on the structure could deliver the information to the body’s immune system. He spent a tremendous effort on the project, with little result.
Things started to improve when he switched his attention to the spike protein for HKU1, a mild strain of coronavirus responsible for the common flu, which is more stable than the Mers spike protein.
After more than 100 painstaking attempts, Wang was finally able to engineer the Mers spike protein into a stabilised state by making small genetic mutations to its encoding gene sequence. “It is like putting a steel splint on the spike protein to stabilise it in the pre-fusion configuration,” he said.
Wang was also confident the technique could be applied to different coronaviruses – “including new coronaviruses” – which all have very similar spike proteins. But, after completing his work in 2016, Wang’s paper was rejected five times by major science journals.
It was finally published in 2017 by Proceedings of the National Academy of Sciences and it would take a further three years – and the emergence of a new coronavirus – before the value of Wang’s work was fully appreciated by the vaccine industry.
On January 11, the genome sequence of a new coronavirus circulating in the central Chinese city of Wuhan was published by Shanghai professor Zhang Yongzhen at the open access virological.org website.
Zhang, from the Shanghai Public Health Clinical Centre, had run the sequence from a viral sample taken from a patient with the mysterious new illness in Wuhan and found a new strain of coronavirus with about 80 per cent similarity to Sars, a fatal contagion prevalent in China in 2003 and also caused by a coronavirus.
At that stage, the Chinese authorities had only confirmed dozens of cases and launched an official probe into reports by doctors in Wuhan of a ‘Sars-like’ illness they had not seen before. Meanwhile, coughing patients were crowding into local hospitals.
Having identified more than 2,000 viruses during his career, Zhang feared the new coronavirus would wreak havoc in the busy travel season before the Lunar New Year holiday. He filed a report calling for immediate action to China’s National Health Commission on January 5 – the same day he finished the genomic sequencing.
After five days with no response, Zhang published. The authorities officially released the information a day later, but the world’s scientists had already leapt into action, armed with the genetic code that would help them fight the new virus.
Wang, by this stage a research associate at the University of Texas at Austin, and his colleagues were among them, and their past success in coronavirus research gave them a head start. “It took me a weekend to design more than a dozen genome codes for the spike protein – including ones that created mutations that would lock it into the pre-fusion shape,” Wang said.
“The finished sequence was shared with our partner, the National Institutes of Health, to advance vaccine development.” Together with NIH, the team filed a joint patent application for the stabilised spike protein – the key ingredient of the new technology vaccines.
Wang also worked with other members of the team on protein purification and structure determination. They reconstructed the molecular structure of a stabilised spike protein and were the first to publish the structure of the Sars-CoV-2 spike protein, in the journal Science on February 19.
“The lab delivered the construct encoding stabilised spike protein to more than 100 laboratories around the world and advanced vaccines and drug development targeting spike proteins,” Wang said.
Vaccine developers, including Moderna and Pfizer/ BioNTech, incorporated the sequence of the stabilised spike protein into their Covid-19 vaccines. These use messenger RNA (mRNA) – simple bits of genetic code which instruct cells to make things – in this case, the spike protein in its pre-fusion state.
Use of the stabilised protein is not limited to mRNA vaccines. Johnson & Johnson’s vaccine delivers the synthetic spike protein designed by Wang using an adenovirus as a vector, while Novavax is using it to develop a recombinant subunit vaccine.
Zhang Linqi – who Wang worked for back at Tsinghua when they identified monoclonal antibodies – is also developing a vaccine based on adenovirus technology, which uses adenovirus found in chimpanzees to deliver spike protein, and is applying for approval to start human trials in China.
“The introduction of proline mutations can be applied to various coronaviruses. Its application in other viruses needs further verification,” Wang said. “However, the concept of structure-based vaccine design is brand new and not limited to creating proline mutation. The concept has great potential in design of vaccines against other infectious diseases.”
Zhang hailed Wang’s design and the work of McLellan’s team – and their embrace by the vaccine industry – as the realisation of an “avant-garde concept”.
“It’s a landmark. It’s a conceptual breakthrough that we have been hoping to see, a new age in vaccine development.” Zhang said the industry had been slow to adopt the new technology because of its uncertainties, including how long the development of new vaccines might take.
Wang was practically unknown and had experienced both ups and downs in the US, until his design was incorporated into the Covid-19 vaccines. Yet throughout his career he has remained rooted in scientific research, hoping to translate his findings into medical advances, no matter the difficulties.
“One basic quality of a scientist is to withstand loneliness and stand up to challenges. More importantly, it is to draw lessons from repeated trial and error. Only someone who really loves that can stick to the job,” he said.
That Wang has no shortage of that quality is partly thanks to his parents. They did not finish primary school, but gave their son tremendous support when he struggled with his lessons.
“They always told me to take it slow, learn the lesson and everything would be all right. The result does not matter that much,” Wang said. “That always calmed me down and I came to learn that all setbacks are growth.”
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