December 1, 2020

The long game: the race for a vaccine against all coronaviruses – The Guardian

https://www.theguardian.com/world/2020/nov/13/the-mutation-game-the-race-for-a-vaccine-against-all-coronaviruses

Hopes have been raised worldwide this week that a Covid-19 vaccine is getting closer, after one version was shown to be 90% effective in reducing disease symptoms, but a handful of scientists are working on an ambitious plan for a different sort of vaccine.

Their project, which is fraught with technical and financial challenges, is to find a vaccine that could protect against not just Covid, but other viruses in the same family that cause Sars, Mers and the common cold.

There is no precedent for such a plan. No existing licensed vaccine protects against an entire family of viruses, although scientists are working on a “universal flu” vaccine as well as a pan-HIV vaccine.

The global impact of Covid-19 has illlustrated the advantages of a pan-coronavirus vaccine. Such a vaccine could protect against not just diseases we know about, but prevent another grim outbreak caused by a new coronavirus spilling over from animals, experts say.

Dr Laura Walker, the chief scientific officer of Adagio, a company focused on developing antibody therapies that can broadly neutralise the two Sars viruses and other potentially emergent coronaviruses, said: “All of society is shutting down and thousands of people are dying … so you need something on day one for next time. And the only obvious, the most practical way to do that would be to have something in advance.”

She says similar Sars-like viruses are out there in the bat populations, and some of them have been shown to be capable of infecting human cells so what is needed are antibody therapies and vaccines that protect against past, present and future coronaviruses.

Once we have a vaccine, it could force Sars-CoV-2 – the virus that causes Covid-19 – to adapt, said Jeff Baxter, the chief executive of VBI Vaccines, one of the companies working on a pan-coronavirus vaccine. “Viruses are incredibly good at adapting,” he said, “and that’s when we may see significant mutations.”

In order to develop a vaccine that protects against significant mutations of Sars-CoV-2, or a family of coronaviruses, scientists need to find regions that are similar or “conserved” across the individual viruses for the immune system to destroy. The immune system can launch its attack by employing broadly neutralising antibodies – molecules that bind to proteins on the virus’s surface that allow it to enter human cells.

“In the last few years, it’s been shown that there are broadly neutralising antibodies to HIV and to influenza – so this gives you the idea that you can target the viruses that are somewhat different,” said Prof Dennis Burton, chair of the department of immunology and microbiology at Scripps Research.

“For example, Sars-CoV-2 and Sars-CoV – they are quite a lot different, but they’re no more different than different strains of HIV. So, if you can generate or isolate broadly neutralising antibodies to both Sars viruses, then you could use those antibodies against both viruses – and even maybe Sars-CoV-3, which we haven’t seen yet.”

“But there’s a lot of science to be done,” he said.


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After you identify the neutralising antibodies for different coronaviruses, then you’ve got to work out how to induce them through a vaccine, which could take years, he said.

Altogether, at least five companies are taking on the gargantuan task of developing vaccines that can broadly protect against beta-coronaviruses.

All these efforts are in the very early stages, buoyed by the financial stamina of the enduring Covid-19 pandemic. So far, none have even entered human trials – which takes time, effort and millions in funding – so their safety and effectiveness is yet to be determined.

“Every time that there’s an outbreak, everybody cares – the media cares, scientists care, and every lab in the world is working on it. Then as soon as that virus is gone, either because of lockdowns or herd immunity, the funding dries up and people just don’t care any more,” said Walker.

“But … this one has disrupted everybody’s lives so seamlessly that I think it might change things.”

Although there are conserved surfaces across the beta-coronavirus family, which includes Mers-CoV (the virus that causes Mers) Sars-CoV (the virus that causes Sars) and Sars-CoV-2 – antibodies directed to those protein sites were rare, said Walker.

Partly, the problem lay in the fact that these conserved proteins were covered by a shield of sugars that made it difficult for antibodies to access, she explained.

DIOSynVax, another company working on a pan-coronavirus vaccine, is developing technology designed to modify the sugars in order to guide antibodies to the conserved regions.

Meanwhile, Entos Therapeutics has largely sidestepped the sugar issue by working on technology that primarily targets another weapon in the immune system’s arsenal: T-cells.

Two sets of specialised white blood cells – B-cells and T-cells – work like brothers-in-arms for the immune system. Some T-cells are slayers, annihilating respiratory cells the virus has colonised. Other “helper” T-cells take on a supportive role, including some that are tasked with stimulating B-cells to produce antibodies.

Usually, vaccine developers look for antibody levels to determine whether their product is effective – because T-cells are much harder to measure.

Osivax, which has a universal flu vaccine in mid-stage clinical trials, is hoping to replicate its technology, which also primarily targets T-cells, for its pan-coronavirus vaccine candidate.

While developing its universal influenza vaccine, Osivax co-founder Alexandre Le Vert found that because the flu virus mutates rapidly, the mutations on the surface of the virus enable escape from antibodies. But it was much more difficult for the virus to escape a T-cell attack, he said.

Another company, Valo Therapeutics, is focused on generating T-cells by using an alternative method – a vector-based vaccine.

After identifying parts of coronavirus proteins that can generate T-cells, the company plans to use its patented technology to coat them on to a vector – such as a weakened or inactivated virus – and deliver this as a vaccine, according to the company’s CEO, Paul Higham.

Given B-cells and T-cells work in parallel, stimulating T-cell production might or might not have some beneficial effects to the antibody response, said Danny Altmann, professor of immunology at Imperial College London.

But if the approach generates only T-cells, will that ensure protection? “I would say the jury’s completely out on that question,” he said.