The stakes could hardly be higher; the prize still tantalisingly out of reach. It is no exaggeration to say that the fate of many millions of people rests on the discovery of a vaccine for Covid-19 – the only sure escape route from the pandemic.
Yet the optimism that accompanied the launch of Oxford University’s human trials this week has to be put in context, and the hurdles facing the scientists need to be understood.
The vaccine hunters are trying to outwit an invisible enemy so small that a million viral particles could fit inside a human cell, but whose biological ingenuity has brought everyday life to a standstill.
So what is the path to success?
How vaccines train our immune system
Traditional vaccines work by creating a weakened version of a virus, similar enough to the original that the immune system will be forearmed if the person is exposed to a full infection in future, helping prevent actual illness.
The approach has led to some of our best vaccines, but is also fundamentally risky because there is always a chance that a newly developed attenuated virus won’t be as innocuous as hoped. Clinical trials have to be approached cautiously and slowly – especially when there are no effective treatments for a disease.
A slow approach is not ideal in a pandemic.
So it’s perhaps unsurprising that only two of the 76 vaccine candidates that the World Health Organization has on its radar have opted for this traditional approach.
The rest rely on the fast-track idea that the immune system doesn’t need to see the entire virus to generate the ammunition to fight it off in the future. If the virus is the warship, the theory is that the immune system needs only to see the enemy flag to form an indelible immune memory. In the case of Covid-19, this flag takes the form of prominent protrusions, known as spike proteins, that form a halo or “corona” around the virus.
Advances in genetic engineering have given full flight to scientists’ creativity in developing this defence.
Teams around the world have moved at unprecedented pace, going from having the genetic sequence for the spike protein in January to vaccine candidates a matter of weeks later.
But many of these technologies are unproven and the success of any trial is far from guaranteed, as this week’s disappointing results for the drug remdesivir show. Ethical questions need to be navigated to ensure the safety of volunteers.
And then, potentially the most contentious question of all: if a vaccine is found, who gets it first?
First into clinical trials, just eight weeks after the genetic sequence for Covid-19 was published in January, was the US biotech company Moderna, with its RNA vaccine.
RNA is a single-stranded messenger molecule that normally delivers genetic instructions from DNA, coiled up inside cells, to protein-making factories that sit outside cells.
In this case, the RNA instructs the muscle cells to start churning out the harmless spike protein as a warning to the immune system. Imperial College London’s team, this week backed by £22.5m government funding, is also developing an RNA vaccine, but in a form that hasn’t been tested before in people.
“Some groups have skipped animal studies because their technology has been used in human studies,” said Prof Robin Shattock, who is leading the Imperial team. “We don’t have that luxury. It’s probably cost us one or two months, but it’s much better to be cautious and be sure you’ve got something that’s really safe.”
Also testing their candidates in human trials are the Chinese vaccine company CanSino Biologics, and a team at Oxford University led by Prof Sarah Gilbert.
Both are using harmless viruses that have been disabled so that they don’t replicate once they get inside cells. These delivery vehicles are known as “non-replicating viral vectors”.
These teams had already tried and tested the approach for other diseases, such as Ebola, and had flasks of their vectors sitting in freezers, ready to go.
A third approach is that of the US biotech company Inovio, a firm that has existed for four decades without developing an approved product, but whose stock soared after it started its trial earlier this month.
Its vaccine uses DNA to carry instructions for making the spike protein into cells, which gets transcribed into messenger RNA, which then orders the protein factories to start pumping out the enemy spike protein.
This might seem an unnecessarily elaborate cascade, but some think that getting the enemy flag inside cells and not just into the bloodstream could be important .
“Clearly it is true that there are no approved RNA or DNA vaccines on the market today,” said Joseph Kim, Inovio’s CEO. “But I think it’s just a matter of time.”
Finally, a fourth strategy simply manufactures massive supplies of the spike protein itself, and injects a dose directly into people.
This is what the big pharma team-up of Sanofi and GSK are betting on. Sanofi is repurposing a vaccine candidate that was developed for Sars in the early 2000s, while GSK is providing an ingredient, known as an adjuvant, that boosts the immune response, which has also been tried and tested.
It’s too early to say which option looks the most promising, according to Richard Hatchett, chief executive officer of the Coalition for Epidemic Preparedness Innovations (Cepi), which is funding the development and testing of eight candidates.
“Some vaccines are going to be very fast to clinic, others have tremendous potential to scale up,” he said. “And the challenge that we face is that there’s going to be a great deal of urgency and pressure to roll out vaccines quickly for obvious reasons. You’re talking about giving a medical product to someone who is well.”
What are the odds they’ll work?
A few candidates will be filtered out in toxicology testing in animals. Others might fail because phase one trials in people produce unexpected side effects.
There is a chance none of them will work.
For some illnesses, including other circulating coronaviruses, the immune system wages its battle, then a few months later forgets it ever happened. Others, like chicken pox or mumps, trigger lifelong immunity.
The truth is we’re not yet sure where on this spectrum Covid-19 lies.
“Reasonable guesses are that there might be partial protection for close to a year,” according to Marcus Lipsitch, a professor of epidemiology at Harvard, whose team recently predicted that, in the absence of a vaccine, social distancing may need to continue until 2022. “On the long end, it might be several years of good protection. It’s really speculative at this point.”
On the positive side, Covid-19 appears quite stable genetically, meaning that the spike protein that vaccines are built around should still look the same next winter.
This isn’t the case for flu, which shuffles its genes around so rapidly that new vaccines are needed each year.
There are also questions around the type of immunity required.
The body overcomes illness through antibodies, which see off the virus itself, and killer T-cells, which eliminate cells already infected by the foreign invader. For some illnesses, antibodies do the heavy lifting, but the balance varies depending on pathogen and even across people.
“An ideal vaccine should generate a response in both arms of the immune system – antibodies and T cells,” said Kim. He predicts this could be a weakness of RNA and protein vaccines, which are delivered outside of cells, meaning that killer T-cells are not likely to be recruited.
There is also a chance that some trials could grind to a halt, simply because the pandemic has been so well controlled by lockdowns and other measures. “You need a certain hit rate in the population you’re vaccinating to get the statistics to show your vaccine is having protective ability,” said Miles Carroll, head of research at Public Health England’s National Infection Service at Porton Down.
The possibility of “challenge trials”, in which people are deliberately infected, have been considered, but there are obvious ethical issues with exposing volunteers to a potentially deadly disease.
“There’s a lot of interest in this … because it would really accelerate vaccine development, but there are some major hurdles to ensure the safety of the volunteers in that setting,” said Prof Andrew Pollard, chief investigator on the Oxford study.
Vaccine manufacturers talk in terms of yield: how many doses of vaccine do you get out per litre of culture. And there could be significant differences in the ability of teams to produce the number of doses required to make a difference.
Shattock believes this will be a strength of Imperial’s RNA vaccine candidate, which has the unique feature of replicating itself thousands of times once inside the body.
“We can make the equivalent of a million doses within a litre of material,” said Shattock. “Many other vaccines would need hundreds or thousands of litres for that. It’s the scalability. Towards the end of the year we’ll be hoping to make tens of millions of doses.”
“If our vaccine were shown to be successful, if everything goes well – and that’s still a big if – we could deploy it in the UK this winter,” said Shattock. “All these smaller approaches will hold the fort until a larger global solution comes.”
By September there could be a vaccine – maybe several – that appear broadly safe and effective.
That’s not enough to get a vaccine licensed, but governments are already talking about the potential for rolling out such candidates to high-risk groups, potentially including millions of health workers, under “emergency use” rules in the absence of this ultimate seal of approval.
There are precedents for this – in the 2018 Ebola outbreak, more than 200,000 people in Democratic Republic of Congo received the Merck vaccine before it was licensed in 2019.
“That might be enough if you are an intensive care nurse or living in an old people’s home, to say that for you, because you have the most to gain from being vaccinated, the risk-benefit balance is favourable,” said Sandy Douglas, an Oxford vaccine researcher.
But very rare side-effects cannot be ruled out. And there have been vaccine calamities in the past – recently the GSK vaccine Pandemrix, given to millions during the swine flu pandemic of 2009, which was linked to narcolepsy in one in every 55,000 jabs.
The principle of transparent informed consent will be critical, Douglas added. “In this case, that would include the fact that if you’re being offered a vaccine in October that didn’t exist in April, there will not yet be long-term safety follow-up experience, although we do have longer term experience with several similar vaccines.”
Individuals could be faced with tough choices – take an experimental vaccine or leave themselves at risk of infection.
At the moment, many teams are trying all sorts of ways to develop a vaccine, but there is no coherent solution for the whole planet. Some are banking on big pharma swooping in with a blockbuster product. Sanofi and GSK, as a joint force, are unique in having the ability to manufacture hundreds of millions of doses without relying on external support.
But multinationals are not built for speed and their reputations depend on absolute safety, so there is no prospect of this team making its vaccine widely available before mid to late-2021.
Others urge a unified approach; governments, the UN, the World Bank and the WHO need to agree a way forward before a lead candidate emerges.
National governments are already making advance purchase agreements and looking to secure their own supply chains.
“If vaccine nationalism asserts itself, you could end up having a limitation of a vaccine to one specific population,” said Hatchett. “It’s an understandable response of a leader who is elected by a particular population to protect that population. [But] you can’t protect your people and your economy until the global pandemic is brought under control. We really can’t deal with this one country at a time.”
Hatchett and others are arguing for a global commitment of tens of billions of dollars to ensure that any successful vaccine is distributed globally and according to need. “In global health terms that’s a very big number,” he said. “But if your point of reference is the global impact that this pandemic is having on the economy, then that’s a very small number. If you buy into the idea that the vaccine is the escape route from the pandemic then that’s a really good investment.”