In October last year, shortly before the Omicron variant shattered hopes that the pandemic was burning out, zoonotic disease specialist Linfa Wang published a study that he considers one of his most significant in decades of coronavirus research.
For almost two years pharmaceutical companies and governments had ploughed billions of dollars into the creation, production and distribution of vaccines that would safeguard populations from Sars-Cov-2, the virus that causes Covid-19. But Omicron’s sudden emergence and rapid spread underlined how vulnerable the world remained. The vaccines that had been sunk into millions of arms had been designed to neutralise the original viral strain, first identified in Wuhan. While booster jabs offered good protection against severe disease, they did not stop Omicron — which has about 50 genetic mutations compared with the original strain — ripping through nations.
Pharmaceutical companies scrambled to update their existing jabs. A clinical trial of BioNTech/Pfizer’s vaccine that specifically targets Omicron has begun and the company estimates it will be ready by March — arguably several months too late for regions where Omicron has peaked.
Wang, who is based at Singapore’s Duke-NUS Medical School and led the team that revealed the 2003 Sars-Cov-1 outbreak had probably originated in bats, had a more ambitious goal. He thought it might be possible to protect people against all Sars-related coronaviruses. In early 2020 he started tracking down survivors of the first Sars outbreak, acting on a theory that the antibodies still present in their blood would shield them from Sars-Cov-2, but was disappointed to see that they only had immunity to the original Sars virus.
As new variants emerged in early 2021, Wang tried again. By then, eight of the Sars survivors had been injected with the BioNTech/Pfizer vaccine and this time their blood generated neutralising antibodies not only against Sars-Cov-1 and three Sars-Cov-2 variants of concern (Alpha, Beta and Delta), but five other coronaviruses living in bats and pangolins. “I’m a professional scientist, I’ve been in the game for 30 years, and as soon as I saw the results I was telling my students ‘that’s really groundbreaking’,” Wang says.
Published in October, Wang’s research provides the first human data to suggest a broadly protective “super shot” is possible. His work “gives us hope”, says Melanie Saville, director of vaccine research and development at the Coalition for Epidemic Preparedness Innovations (Cepi), a non-profit foundation which funds vaccine development for emerging diseases.
Even before the emergence of Omicron, there was considerable interest in the idea of a “universal” vaccine. But the subject has become a pressing priority for public health officials over the past three months as Omicron has exposed the limits of current vaccines and therapeutics.
There are already some indications that more boosters of the existing vaccines might not be a long-term solution. One study involving health workers in Israel underlined the limitations, showing that a fourth dose of the BioNTech/Pfizer vaccine was largely ineffective in stopping Omicron infections despite increasing antibodies. Last month, the US drugs regulator withdrew its authorisation for the monoclonal antibody treatments made by Eli Lilly and Regeneron, which had proved effective against earlier strains but do not work well against Omicron.
Since the arrival of new variants there has been a flurry of new funding into research on a universal coronavirus vaccine. In theory, such a jab would not only protect people against known strains, but coronaviruses yet to emerge. After three major outbreaks — Sars, Mers and Covid-19 — in less than two decades, it would be “naive” to assume there will not be others, says Anthony Fauci, US president Joe Biden’s chief medical adviser.
“So rather than being responsive to it, we should be prepared for it. And that’s the entire rationale of trying to get a [vaccine] that covers all the iterations of, certainly, beta coronaviruses” — the family that includes Sars-Cov-2 — “but possibly and hopefully and aspirationally all coronaviruses.”
Health leaders are in no doubt that this broad-based protection is needed if the world is not to live permanently in fear of another devastating pandemic. The pursuit of a universal vaccine goes beyond public health considerations, says Saville, citing the massive shocks the global economy has suffered since early 2020. The IMF recently warned that global gross domestic product losses could be as high as $5.3tn over the next five years if the “great vaccination divide” between rich and poor nations is not closed.
A vaccine that offers global protection would also be cheaper, and less demanding of overburdened health systems, Saville adds, pointing to the huge R&D costs of updating and rolling out a vaccine against each new variant.
But while the pandemic spurred researchers to develop highly effective vaccines in record time, it does not follow that they will have the same success with a universal vaccine, which is still at the level of basic clinical research. Generations of scientists have struggled in vain to create such a broadly protective vaccine against another fast-mutating virus: influenza.
Fauci explains that the task is considerably more complex than developing the first crop of Covid-19 vaccines where scientists knew the virus’s genetic sequence. “We knew what the target was: it was there, it was right in front of us,” he says. In contrast, a universal jab would need to work on viral genetic sequences that are as yet unknown.
If scientists knew how to induce broad immunity, “we would be cranking [a vaccine] out like Operation Warp Speed tomorrow”, says Fauci, referring to the US government-backed programme. “But when you don’t know what the right product is, then you’re still in the realm of discovery. And discovery is a heck of a lot more unpredictable than implementation.”
A change of tack
A vaccine’s basic function is to train the body’s immune system to identify and attack a virus. It mimics the natural infection and recovery process, where antibodies produced to neutralise a specific pathogen linger in the blood for years or decades.
The first generation of Sars-Cov-2 vaccines worked by generating antibodies that neutralise the “spike” protein that the virus uses to enter cells. But this key part of the virus has changed as Sars-Cov-2 has mutated, making it harder for the immune system to recognise the virus and diminishing the effectiveness of vaccines devised for the spike on the initial strain.
For the universal vaccine, researchers are trying a different approach. Most are working on identifying so-called “conserved” parts of the virus — pieces of protein known as epitopes that are present in all coronaviruses and resist change however much they mutate. The idea is to have a vaccine that trains the body to recognise this conserved region, prompting an immune response to a broader array of coronaviruses.
The US’s National Institute of Allergy and Infectious Diseases (NIAID), which Fauci directs, has given three academic institutions $36.3mn to conduct research into vaccines against multiple coronaviruses. Cepi has earmarked $200mn for similar research, about $80mn of which has so far been dispersed, with more awards expected in the next few weeks.
While most research teams are still at the proof-of-concept stage in the lab, a small number have progressed to human trials. One of the most advanced candidates has been developed by scientists at the US military’s Walter Reed Army Institute of Research. A phase 1 trial of its vaccine began last April, with the first results expected soon. An earlier pre-clinical study suggested it may provide “broad protection against Sars-Cov-2 variants of concern as well as other coronaviruses”, according to a statement issued by Walter Reed in December.
Also in the vanguard is a vaccine against the group of viruses that includes Sars-Cov-1 and Sars-Cov-2, developed by DIOSynVax, a biotech spinout of the University of Cambridge led by Professor Jonathan Heeney. The team has identified several unique structures on the Sars group that do not mutate, “presenting promising targets for broad vaccine protection against this group of coronaviruses and their variants”, he says.
In the US, Barton Haynes, director of the Human Vaccine Institute at Duke University School of Medicine, and his team have also identified an epitope resistant to mutation on the spike protein. Their vaccine would combine a synthetic nanoparticle derived from that spike protein with an “adjuvant”, a chemical substance that enhances the immune system’s response to a virus. Preliminary studies in animals suggest that the vaccine triggers neutralising antibodies and other immune responses to all the Sars-Cov-2 variants that have arisen so far, and Haynes hopes it will also work against variants that appear in the near future.
While many researchers are focused on trying to find specific regions of the virus that do not mutate, researchers at Massachusetts-based VBI Vaccines are attempting something new. They have placed the spike proteins for three human coronaviruses — Sars-Cov-1, Mers and Sars-Cov-2 — on the surface of virus-like particles which “resemble the virus so well they are a very, very potent way to activate the immune system”, according to David Anderson, the company’s chief scientific officer. When injected into animals, the particles, which are non-infectious but mimic the natural viruses, generated antibody levels that were between two and seven times higher against a variety of variants than vaccines aimed at single strains.
There has never been a vaccine developed using this method before. Anderson says he is often asked: “what’s the precedent for this? And I have to candidly say there isn’t any. But by the same token, there was no precedent for an mRNA vaccine until a couple years ago.”
As scientists such as Anderson and Heeney focus on coronaviruses, the protracted search for a universal flu shot offers caution and inspiration in equal measure.
The “tweak-and-boost” vaccine model currently used against Sars-Cov-2 broadly resembles the World Health Organization’s approach to influenza. Each year scientists have to devise a different version of the flu shot, meeting in February and September to estimate which flu viruses will circulate and gain dominance in the coming six to 12 months. It is a less than exact science. Effectiveness against infection varies from year to year but rarely exceeds 60 per cent.
In designing each flu vaccine, scientists must contend with a complicating factor: immunity to earlier strains. “When we try to design a universal influenza vaccine, we have to come up with something that’s better than the current vaccine and that works in a population of people who have already seen influenza before. Those two things are similar for Covid,” says John Mascola, director of vaccine research at the US’s NIAID.
He adds that in terms of identifying a common part of coronavirus that will not mutate, many of the same principles apply to flu. “[A lot of those] ideas have been in the influenza field and are now being used also in the coronavirus field,” he says.
Jeffery Taubenberger, a senior investigator at NIAID who first sequenced the genome of the virus which caused the 1918 Spanish flu pandemic, notes that influenza and coronavirus share a capacity to develop strains that escape pre-existing immunity.
“So making just a ‘matched’ vaccine to try to chase the evolution of the virus is always going to have you behind the game . . . by the time you’ve given that vaccine the virus is on to someplace else, so that strategy is not a winning strategy,” he says.
Taubenberger believes that scientists need a better understanding of how long-term immunity in the respiratory system can be achieved. He warns that a universal vaccine that provides life-long immunity from a single jab is probably “too high a bar”. A more realistic proposition may be a vaccine to protect against multiple variants for which you would only need to boost every five or 10 years.
But even that would be a considerable leap. “I’ve spent the last 25 years of my life thinking intensively about influenza virus every day, and I’ve spent two years thinking about coronavirus, and I’ve learnt enough to now realise that I don’t understand anything,” Taubenberger says. A virus is “this little tiny packet of genetic material wrapped in protein”. Influenza viruses, for example, encode about 10 to 11 proteins, as opposed to the 40,000-50,000 proteins that humans make. “And we don’t even know what they all do yet — and that’s crazy.”
Chinks in the armour
As they grapple with these fundamentals, researchers have a new weapon at their disposal: computational predictive modelling.
Heeney and his team in Cambridge have used computer models to explore Sars-Cov-2’s structure, using information about Mers and other coronaviruses that can spill over from animals. These virtual models have allowed them to identify what he calls “chinks in its armour” as they have sought to find ways to disable the virus.
In a programme in the US, Haynes of Duke University is collaborating with the Los Alamos National Laboratory to predict what the next variants of Sars-Cov-2 might be as he continues efforts to develop a universal vaccine.
But even with advanced technology, it is not easy to predict how quickly a universal vaccine might emerge. The speed at which Covid-19 vaccines were developed was unprecedented — just 326 days from the sequencing of the virus to the first vaccine being approved. Cepi would like to squeeze that timescale still further, so a vaccine would be available within just 100 days of the emergence of a new pathogen. But this is no guide to the time needed for the more complex universal vaccine project, says Saville.
Cepi’s aim is to have proof of concept for a broadly-protective, variant-proof vaccine against Sars-1 and Sars-2 “in the 2023 timeframe”, she says. It would then take another year or two to be licensed for use. As to a truly protective vaccine against all coronaviruses of concern to humans, “we’re really looking in the timeframe of 2024 to 2025 . . . so it is a long haul,” she adds.
Fauci is equally cautious. “You’re not going to hit a home run the first time up, that’s for sure,” he says.
Yet researchers will continue operating on parallel tracks, both working towards the creation of a pan-coronavirus vaccine and finding smarter ways to respond to variants as they emerge. One thing the pandemic has proved is that humanity is capable of feats of vaccine production and distribution that were previously unimaginable. “When you’ve cracked the scientific problem [of a universal vaccine], then you could do a Manhattan Project to get it out,” Fauci adds.