Of all of the frustrating aspects of battling Covid-19, the one that has caused scientists most grief is the virus’s tendency to spit out a new variant every few months, each slightly less vulnerable to vaccines than the last. It was the Alpha variant that ruined Christmas for millions last year. Then, in March, came the delta variant, a mutation which gave the virus a degree of immune escape against existing vaccines.
Even as policymakers are kept awake at night by the fear that a new one will emerge, which could yet compromise the route out of the pandemic, a team at Manchester University is trying to vanquish this looming threat by creating a universal, ‘variant-proof’ vaccine that will beat whatever mutation comes our way. If successful, the trial could not only re-mould our approach to Covid, but have ramifications for how we deal with other viruses, perhaps even propelling us towards the prize that has evaded scientists for years: a universal flu jab.
"It’s going very well," says Professor Ian Bruce, senior investigator at Manchester University’s Centre for Epidemiology, whose department is overseeing the trial in collaboration with US pharmaceutical company Gritstone. "You’ll probably get a broader and stronger protection against the virus [than you do from existing vaccines], and it will likely be less subject to variation."
The existing coronavirus vaccines used in the UK all target the spike protein, the virus particle’s jagged outer edge. Like a key in a door, it is the spike protein that allows the virus to latch onto our cells; defeat that, and we effectively lock the virus out, the thinking goes. It’s the ‘Achilles heel’ of viral entry, says Danny Altmann, professor of medicine and immunology at Imperial College London.
But, frustratingly, the spike protein is also the part of the virus most likely to change with each mutation. The alpha and delta variant both came about primarily due to genetic changes in this spike protein.
To circumvent any future variants, the Manchester vaccine will instead target the nucleocapsid, known as the ‘N protein’, a bubble-like particle that sits within the virus’s inner shell. This part of the virus doesn’t change as much from mutation to mutation, potentially giving the Manchester vaccine a much longer shelf life.
The Manchester team is recruiting 20 adults for a Phase One trial, designed simply to assess whether the vaccine is safe. Researchers expect to move through this leg quickly, because the underlying technology has already proved safe in previous trials against other diseases. They will move onto a Phase Two trial later this year, assessing whether the jab actually works against Covid in large numbers of people.
All volunteers must be aged over 60, and all must already have been vaccinated with AstraZeneca (the Manchester vaccine is billed as a booster). Retired couple Andrew and Helen Clarke, 63 and 64, from Bolton, became the first to receive the potentially transformative jab.
"Somebody has to be the first and we’re confident in the science and technology behind this vaccine and convinced of the need for it," Mr Clarke later said.
But it will not be easy. While the spike protein binds to cells, the N-protein is sheltered inside the virus and largely invisible to our immune systems. In its attempt to cater for different variants, the vaccine could end up taking longer to alleviate Covid symptoms, explains Dr Julian Tang, professor of respiratory sciences at the University of Leicester, who is not involved in the trial. "If you target the vaccine against the N-protein, it doesn’t stop the virus from entering the cell," he says. "Also, the N-protein is inside the virus – the antibodies in the blood can’t see it. There’s not going to be as direct a neutralising antibody approach."
Indeed, for evidence of the tough path ahead scientists need only look back 10 or 20 years, to the fraught and often frustrating campaign to create a universal, ‘variant-proof’ jab for influenza. Under the traditional system for dealing with flu, each year virologists pinpoint the flu virus likely to prove most virulent in the coming winter. Then they produce two flu vaccines – one for the northern hemisphere, rolled out around September, and one for the southern hemisphere, rolled out around June. Hundreds of millions of doses are manufactured at speed; in doctor’s surgeries across the world, elderly patients queue up to receive their jab.
It’s costly, time-consuming, and sometimes frustratingly imprecise. "In a good season, we’re up to 60 per cent effectiveness, but in bad, mismatched years it can be as low as 10 per cent or 20 per cent," Barney Graham, deputy director of the Vaccine Research Center, in the US, told the Nature journal in 2019.
Last year, due to Covid prevention measures, influenza cases across the world fell to minute levels – a welcome side effect, but with the less welcome result that predicting the next dominant flu variant will be even more of a guessing game than usual.
In the late 2000s, a group of scientists in the UK, US and elsewhere began working on a universal flu vaccine, using ‘anti-stalk’ technology designed to attack the haemagglutinin stalk domain, rather than the ‘head’ of the virus (the part usually targeted by seasonal flu vaccines). The task occupied the minds of some of the most talented virologists in the world, including none other than Oxford’s Dame Sarah Gilbert, who before devoting her attention to Covid spent many hours in a lab near Woking, infecting pigs with influenza.
Animal trials have shown promising results; but generally, progress is sluggish. It took Dr Graham’s team seven years just to isolate a stable sample of the virus’s stalk. Human trials have been difficult to organise, requiring thousands of vaccinated volunteers to be naturally exposed to multiple strains of influenza over several years – a difficult task when flu strains tend to come and go each winter.
Indeed, some immunologists fear we’re not any closer to a universal vaccine for influenza than when we started over a decade ago – a pattern we could see again with Covid. "The problem with this approach in influenza is that it’s not very immunogenic – it doesn’t produce a strong immune response to actually suppress viral replication," says Prof Tang.
For Prof Altmann, the failure to find a universal influenza vaccine is more a story of bureaucratic inertia than anything else. "I’ve always thought of the vaccine industry as being very conservative, traditional, risk-averse. There’s big money at stake, big regulatory hurdles. They like the old stuff that they know. Immunologists were very frustrated that we had all this knowledge, discoveries that never got put to use."
But he thinks Covid could change all that. Vast amounts of time and money have been poured into vaccines over the last 18 months, unprecedented attention that could "light a rocket under the industry", says Prof Altmann, perhaps even leading to the creation of a universal flu jab.
Trials into vaccines for malaria and HIV have already been dramatically illuminated and accelerated.
The Manchester vaccine uses largely the same scientific approach as the universal flu jab: if the Manchester team can prove it works, it takes virologists a major step towards delivering a universal flu jab.
Prof Altmann compares it with technology "making a quantum leap in a world war. Now in the blink of an eye, all this stuff that was there ready to go waiting in the wings, is suddenly happening."
The Daily Telegraph