The ability of the Sars-CoV-2 Covid coronavirus to mutate into more dangerous forms has undone plans for the UK to lift its remaining pandemic restrictions on June 21. On June 14, Prime Minister Boris Johnson announced that the full opening would be delayed by a month as infections escalate rapidly and hospital admissions are likely to follow. This is despite the fact that almost half of the UK population has been fully vaccinated and many others have received a dose. The new variant now predominant in Great Britain, called the Delta variant – formerly B.1.617.2 or Indian variant – and which accounts for more than 90% of new infections, not only transmits about 60% more effectively than the previously dominant form (B.1.1. 7 or Kent variant, now called Alpha) but is also better at bypassing vaccines. Two shots of the AstraZeneca vaccine provide only 60% protection compared to 74% against the alpha variant, and one dose only offers about 33% protection.

The variant that bypasses vaccinations will be the one that replicates best

Greg Towers, University College London

Meanwhile, other variants such as the Beta – B.1.351 or the South African variant – and Gamma – P.1 or the Brazilian variant – are widespread in large parts of the world. It seems inevitable that others will show up – and the nightmare is that one could almost completely avoid the immune response caused either by a previous natural infection or by vaccines. There is, therefore, an urgent need to understand the molecular mechanisms that make these variants more transmissible, potentially more susceptible to serious diseases, and more resistant to vaccines.

Mutations leave virologists guessing

A picture showing the coronavirus variant B.1.1.7

Virus mutations that increase the rate of transmission have always been likely. There was little evidence of problematic mutations during the first wave of the pandemic in spring and summer 2020, as there was no strong selection pressure due to a lack of population immunity. But now, says University College London virologist Greg Towers, natural and vaccine-induced immunity creates a driving force for the development of increased virus transmission. In some ways, the coexistence of widespread infection with relatively high population immunity poses the greatest threat as it creates strong selective pressures within a large pool of circulating viruses.

Although some virologists have expressed surprise at how quickly the problematic variants emerged because Sars-CoV-2 has a lower mutation rate than flu viruses, systems biologist Nevan Krogan from the University of California, San Francisco in the USA explains that the problem is that the coronavirus is so much more transmissible than the flu and thus creates more mutation opportunities.

There is now the realization that we need to start looking at mutations outside of the spike protein

Nevan Krogan, University of California, San Francisco

What all of this means for virulence is an open question until we have more data. Certainly, Towers says, there is no real basis for the general claim that viruses spread faster but are less harmful as they evolve. In fact, he says, there is some evidence that the alpha variant causes worse illnesses or symptoms that last longer.

Did successful mutations arise independently – that is, through convergent evolution to the same “good” strategy – or because variants share a lineage? It’s hard to say, says Towers, because there are relatively few mutations, making it difficult to construct a reliable phylogenetic tree. For example, a mutation called E484K in the spike protein, which protrudes from the lipid envelope of the virus and attaches to human cell membranes by binding to a cell surface receptor protein called ACE2, has been identified in the alpha, beta, and gamma forms, each in places first seen on different continents. It looks like convergence, says Towers – but “you cannot rule out that someone was on a plane between Brazil and Great Britain at the time”. E484K denotes a substitution of a negatively charged glutamic acid for a positive lysine residue at position 484 in the amino acid sequence of the spike.

Uncover the secrets of the virulence of variants

Much of the previous work on mutations has focused on the spike protein, according to Towers. Mutations that increase its binding affinity for ACE2 can increase the rate of transmission and infection – and in fact, spike mutations are involved in all four major worrying variants. In the Delta variant now prevalent in the UK, a spike mutation called L452R could allow the virus to enter cells more efficiently.1

But Towers and his staff, in collaboration with Krogan’s lab, have just published a preprint2 the alpha variant, which shows that the key to its increased infectivity – about 50% larger than previous forms – seems to lie elsewhere. The researchers infected human cell cultures with the virus, and Krogan’s team used mass spectrometry to identify which proteins were present. The researchers found large amounts of a viral protein called Orf9b.

Krogan says his team recognized this as an “old friend”. Late last year, they identified it as a protein encoded by Sars-CoV-2 that interacts and interferes with a protein called Tom70, which plays an important role in our cells’ innate immune systems3 – the universal immune response, which is immediately triggered by foreign particles. Tom70 is involved in transporting proteins to the cell’s mitochondria before they reach their active form, and also interacts with a protein in the mitochondrial membrane that triggers an antiviral response. So if Tom70 is hindered by Orf9b, our immune defense is weakened and the virus can multiply better in infected cells.

An image showing a cryo-EM structure

But while this happens with all forms of the coronavirus, with the alpha variant the expression of Orf9b is turned way up, “like with steroids,” says Krogan. The researchers also saw elevated levels of two other proteins known to antagonize host immunity, Orf6 and N.

It’s no surprise that Sars-CoV-2 manipulates our immunity. All viruses, says Towers, have to find a way to deal with the host organism’s immune system. Small ones like HIV tend to do this secretly, simply by going unnoticed long enough to multiply, while big ones like herpes viruses actively disrupt the immune response.

But such interventions can be the key to the success of the Alpha variant. “We have now realized that we need to start looking at mutations outside of the spike protein,” says Krogan. “We really need to understand how the virus can mutate in order to break down our defense mechanisms.” It seems that this doesn’t have to involve changes in the viral protein sequences themselves, but simply more by those doing the dirty work – apparently through a change in the regulation of expression levels. As with cells themselves, the genome of viruses contains nucleic acid sequences that do not encode proteins but are involved in gene regulation. These complex regulatory sequences are often poorly understood, says Towers.

Can vaccines beat new Sars-CoV-2 variants?

Could the latest threat – the Delta variant – also use this strategy? The latest evidence certainly confirms that it is even better than the alpha variant to bypass both the antibodies produced by the natural infection by the original form of the virus and the vaccines. Even double-vaccinated people can become infected and transmit the virus, although they are very unlikely to develop severe Covid-19 symptoms.

Towers, Krogan and colleagues are also investigating the Delta variant, but have not yet completed their analysis. The Delta variant has 18 mutations in eight proteins, seven of which are in the spike protein. But the one mutation in alpha that researchers believe will boost Orf9b doesn’t appear in delta. So it can achieve the same goal of suppressing the immune response, but in a different way. “There is still so much to do with these variants,” says Krogan.

What does this mean for vaccine resistance? All vaccines currently in use arm our immune system against viral infections by making antibodies against the spike protein of the original first wave virus. A revised vaccine could include spike sequences from several newer variants, Towers says, as well as other viral proteins: a cocktail tailored to the variants that are expected to be most important in the next wave, like it is now is the case with flu vaccines.

But that won’t be enough if the virus actually inhibits the antibodies’ ability to trigger an immune response. “We’ll need a lot of strategies to fight it,” says Krogan. “We don’t just vaccinate and we’re done.” In order to combat the strategy of the alpha variant, we have to make the immune system itself safer, i.e. not intervene with the virus, but with the host. He thinks that in the face of such bypass mechanisms, future vaccines may have to be a mixture of viral antigens and drugs that target the host and strengthen or protect our immunity. “If we could target one of our proteins that the virus needs, you wouldn’t have to worry about resistance,” he says. Meeting our own proteins can cause toxicity problems, but the use of such drugs in low concentrations for a short time could be justified for such a dire disease.

In any case, says Towers, it’s important to understand why there is increased transmission – because “the variant that bypasses vaccines will be the one that replicates best”.

“Right now we’re chasing the virus,” he says – thinking about what it did instead of what it will do. “But the more we understand what it did, the more likely we are to understand what will happen next.”

This article was updated on June 24, 2021 with the latest research on Delta Variants

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