Liquid gold
The inside story of the race to invent a coronavirus vaccine. By Carolyn Y Johnson.
Ian Haydon, a healthy 29-year-old, reported to a medical clinic in Seattle for a momentous blood draw last week. ‘‘Oh yeah,’’ said the nurse taking his blood. ‘‘That is liquid gold.’’
Haydon is an obscure but important participant in an extraordinary medical race. In early April, he was among the first people in the United States to receive an experimental vaccine that could help end the coronavirus crisis. He volunteered to be a test subject knowing the risks and unknowns, but eager to do his part to help end the worst pandemic in a century.
Scientists at the National Institutes of Health (NIH) in Maryland will study blood from Haydon and others for signs that the vaccine triggered an immune response to a pathogen they have never encountered. It would be the first, preliminary signal that the vaccine could provide immunity to Covid-19.
A coronavirus vaccine has become the light at the end of a very long tunnel, the tool that will bring the virus to heel, allowing people to attend sports events, hug friends, celebrate weddings and grieve at funerals.
The goal to deliver a vaccine in 12 to 18 months, often repeated by the US’ top infectious disease scientist, has become the one reassuring refrain during briefings on the crisis. The White House put together a task force called Operation Warp Speed to try to move even faster, making hundreds of millions of doses ready by January.
Bending the rules
With at least 115 vaccine projects in laboratories at companies and research labs, the science is hurtling forward so fast and bending so many rules about how the process usually works that even veteran vaccine developers do not know what to expect.
Scientific steps that typically take place sequentially over years – animal testing, toxicology studies, laboratory experiments, massive human trials, plans to ramp up production – are now moving in fast-forward and in parallel. Experts keep using the word ‘‘unprecedented’’.
It’s a thrilling time in vaccine science, but also an unnerving one. US regulators are firm that they will not sacrifice safety for speed, but some ethicists raise concerns about ‘‘pandemic research exceptionalism’’, in which the demand to hasten a vaccine to market could come at the expense of evidence and fuel the powerful anti-vaccine lobby.
‘‘The 26 years it took us to make the rotavirus vaccine is pretty typical,’’ says Paul Offit, who developed a vaccine for rotavirus, which causes deadly diarrhoea in infants and children. ‘‘If it’s 12 to 18 months, you’re skipping steps. Is that a little risky? Yes it is, but so is getting infected with the virus.’’
On a weekend in early January, scientists at Inovio Pharmaceuticals, a biotech company outside Philadelphia, began designing a vaccine for a mysterious pneumonia that didn’t even have a name. They, like other teams around the world, used the genetic blueprint of the novel coronavirus, shared online by Chinese scientists, as their guide.
It took about three hours to design the vaccine, says Joseph Kim, chief executive of Inovio.
Scientists at NIH had been in talks about partnering with a Massachusetts biotechnology company, Moderna, and immediately began designing another vaccine candidate. By the end of the month, it was in production in a factory filled with robots in a suburb near Boston.
With an array of promising vaccine technologies fuelled by early scientific openness, dozens of vaccine efforts kicked off blindingly quickly in dozens of countries. ‘‘Then the tough work began,’’ Kim says.
Designing a promising vaccine is, in some ways, the easy part. Showing that it is safe and effective, and then scaling up production can take years, or even decades.
Researchers are now trying to compress that timeline in ways they never have before, against a type of virus they have never successfully quelled. In some cases, they are also harnessing technologies that have never been used in approved vaccines.
In contrast, scientists develop a new flu vaccine each year, an effort that is more of a ‘‘plug and play’’ situation, where a time-tested basic platform can be redirected to fight new flu strains. ‘‘It’s another reason for better preparedness,’’ says Barney Graham, deputy director of the Vaccine Research Center at the NIH, pointing out that his lab had developed a vaccine for Mers, a related coronavirus, but only got it through mouse studies.
‘‘If we’d taken at least two to three vaccine concepts through early phase clinical trials on Mers, we might have a better idea on what to focus on for this Sars coronavirus – so instead of working with 115 different vaccine ideas, we might be working on five.’’
Aggressive timeline
Scientists at Oxford University have announced the most aggressive timeline, with plans to make their vaccine – which depends on a weakened cold virus that typically infects chimpanzees – available in the southern hemisphere spring.
Moderna and Inovio are developing vaccines that ferry two different types of genetic material into cells to train the immune system to recognise the distinctive ‘‘spike’’ protein on the surface of the coronavirus. A Beijing company is trying an inactivated virus.
Giant pharmaceutical companies, flush with govern
‘‘If it’s 12 to 18 months [to develop a vaccine], you’re skipping steps. Is that a little risky? Yes it is, but so is getting infected with the virus.’’
Paul Offit, co-inventor of the rotavirus vaccine
ment funding, are turning their vaccine platforms toward coronavirus. Researchers at Texas A&M University are repurposing an existing tuberculosis vaccine to see if it can prevent deaths or severe illness.
To make things more difficult, as the infection spread across the world, scientific teams have had to change how they work, practising social distancing in their labs so the virus doesn’t take out the effort to combat it. That happened at NIH, when one scientist became infected with Covid-19 and two close colleagues on the effort had to quarantine for 14 days.
Graham’s Vaccine Research Center is working with only about 10 per cent of staff coming in, and his laboratory – which usually houses 20 people – can have only two at any one time.
Many researchers can describe how vaccines are typically developed. But they can’t say precisely how the coronavirus vaccines will come about. So much will depend not just on the science, but on how the outbreak evolves, how flexible regulators decide to be and what we continue to learn about the virus in real time.
Philanthropist Bill Gates argues things can’t really return to normal until the world’s seven billion people are vaccinated – a daunting scenario that could take years and create a new kind of public strife, as governments and individual people scramble for limited doses. More than one vaccine will likely be needed, because the first may not be as effective as the follow-ons.
The front-runner vaccines in the US have never been made at an industrial scale, and some vaccines require two doses to be given, further complicating scale-up.
‘‘We really have never made those kinds of vaccines in large, large quantities. How quickly can that be done?’’ says Kathryn Edwards, a professor of paediatrics at Vanderbilt University School of Medicine. ‘‘We’re not going to be able to say in 18 months that we have enough for all the world’s people to be immunised with two doses.’’
Typically, human clinical trials occur after extensive animal testing. Then, a small number of human subjects receive the vaccine in a phase 1 trial intended to determine the safety and the right dosage. People are monitored for any side-effects, as well as early hints that the vaccine works.
After carefully analysing that data, companies decide to proceed to a larger phase 2 trial in several hundred patients, which looks for signs the vaccine is working. Then, they could proceed to a large phase 3 trial in which people are randomly assigned to receive either the vaccine or a dummy shot – a definitive test of safety and effectiveness, which often takes thousands of patients and several years.
Offit, who is helping advise the US vaccine effort, says the ‘‘large’’ trials being considered that he is aware of range from 1000 to 6000 people that would likely take place over months. In contrast, when he developed a vaccine against rotavirus, the pivotal trial included 70,000 healthy infants over four years. The human papilloma virus vaccine was tested in 30,000 people.
‘We cannot wait’
No-one is talking about that for the coronavirus.
Moderna, the company that manufactures the vaccine Haydon received, plans to start its next larger trial in 500 to 600 people soon, according to Stephane Bancel, its chief executive.
He said the company began planning the trial nearly a month ago, even though it was still giving shots to the first human subjects. ‘‘We said, ‘We cannot wait,’ ’’ he says.
Instead of holding off until the subjects have signs in their blood that the vaccine works, the company will proceed to the next trial as soon as it shows safety. Bancel says Moderna hopes to sign a contract soon with a government agency so it can start manufacturing and stockpiling the vaccine before approval. It could have 100 million doses ready to go on day one, if it is approved in a year.
But vaccine experts point out that many rare safety problems can be picked up only in very large studies, or even through monitoring after a vaccine has deployed. They are most concerned about the risk that the vaccines could actually make the disease worse in some people, as happened in some animal studies of vaccines for Sars, through a mechanism called antibody dependent enhancement.
In 1966, for instance, an experimental vaccine for RSV, a common respiratory virus in children, backfired when some children developed more severe disease. Scientific debate is still raging about a recent dengue vaccine used in the Philippines that increased the risk of hospitalisation in children who had not previously been infected.
One way to speed up vaccine development is ‘‘human challenge’’ experiments, in which people are intentionally infected with the virus after being vaccinated. While the idea has gained steam among some scientists, people working on vaccine trials say it is an ethically challenging approach they would be uncomfortable with unless an effective treatment is discovered.
‘‘Right now, I think it’s a little premature. However, it’s not off the table,’’ says Wilbur Chen, chief of the adult clinical studies section in the University of Maryland’s Center for Vaccine Development and Global Health. ‘‘I think it could be something that could be done; it could help us to really evaluate the efficacy of a vaccine much more quickly.’’
Haydon, who is due for his second shot of the vaccine next week, says he has never participated in a research study before, but is eager to help.
‘‘I’m incredibly hopeful we’ll arrive at a vaccine,’’ he says. ‘‘But in order to do that, we need clinical trials – and at some point, for each new vaccine and each new drug, that has to go into someone for the first time.’’