In the 1950s, Albert Sabin was looking for an improved polio vaccine. To that end, his lab infected the brains of mice, chimpanzees and monkeys with the virus that causes the disease. They want to see if the pathogen will change and if they may form weakened forms.
Finally they isolated versions of the polio virus that could infect people but did not cause paralysis. The so-called attenuated strains of Sabin have become the famous oral polio vaccine given on a sugar cube to billions of children.
Now, researchers say, synthetic biology has led to a way to create a weakened form of the pandemic coronavirus that causes covid-19. Although the idea remains a long-term hit in the vaccine race, an attenuated coronavirus can be formulated into economical nose drops for use around the world.
The startup company behind the new version of SARS-CoV-2, called Codagenix, is working with the Pune-based Serum Institute of India, which is billed as the largest vaccine manufacturer in the world. The plans are for the first volunteers to blow up the synthetic conceived virus starting in November, in the first human safety tests in the UK.
The most advanced covine vaccine candidates, including those from AstraZeneca and Moderna Pharmaceuticals, expose a person to a single part of the virus, the crown-shaped “spike” that gives it its name, to generate antibodies.
The potential advantage of a vaccine using a live attenuated strain is that the body will encounter – and be able to react to – the entire virus. People will “grab” it through their nose, and it will grow into them too. In theory, this could push the formation of not only antibodies but also T cells and specialized forms of immunity in the nasal passage, leading to greater protection.
It may seem scary to imagine yourself infected with the coronavirus on purpose, but attenuated anti-virus vaccines are common. The children’s FluMist vaccine has a weakened influenza virus. And Serum Institute sells 750,000 doses a year of live measles vaccines. The only disease ever successfully eradicated from the globe, chickenpox, has been wiped out with strokes of a live virus.
“If you want to complete the immune response, then you need to mimic the course of the disease,” says Rajeev Dhere, director of Serum Institute. “This can only be done with a live attenuated vaccine.”
In the past, finding an attenuated strain to use as a vaccine was a painstaking process, says Stanley Plotkin, who advises Codagenix and was involved in early polio studies. This is because it has been done by growing a virus in cells of other species and waiting for a weaker strain to appear by chance. That may take 10 years. Sometimes you never find a strain that behaves properly.
A new rational approach was born in 2002. That’s when Eckard Wimmer, a virologist at Stony Brook University, caused a sensation by creating the infectious polio virus based on only genetic instructions. It was the “first creation of life in a test case,” according to newspaper headlines, and a possible bioterror threat, too.
Some have said the Wimmer demonstration was irresponsible. But the technology to generate viruses from data also allows researchers to become creative, since the procedure leaves them rewrite the viral genes in any way they want. “That’s where synthetic biology comes in, genome editing. You can take evolution, which has taken years to be, to days,” says Farren Isaacs, a biologist at Yale University. “Unfortunately, the pandemic creates an opportunity for this technology.”
Instead of creating dangerous germs, by 2008 Wimmer and J. Robert Coleman, then a member of their lab and now the CEO of Codagenix, had begun to show how they could use synthetic biology to conceive weakened versions of polio using a strategy. called “synthetic” attenuated virus engineering “or, more colorfully,” death by a thousand cuts. “
To understand how they are done, it is necessary to know which genes work with a three-letter code. To make proteins, a cell looks at these three-letter “codons” to determine which amino acid to add from next to a building protein. But it turns out that the genetic code has redundancy. There are 64 codons that can be written with the genetic alphabet, but only 20 amino acids to make. For example, four codons encode the same amino acid, serine.
The way evolution has handled that redundancy matters, too. All life uses the same rules, but depending on whether you are a bacterium, a human or a starfish, you will have a preference to use certain codons or pairs of codons.
Viruses, which divert cells to copy their proteins, have, predictably, developed a taste for the same codons that human cells prefer. But evolutionary choices can be reversed in the lab, in a process Codagenix calls “deoptimization”. Coleman says the company has made versions of the coronavirus whose genes are driven by 240 mutations that endow it with some of the codons with the worst performance.
The result: the engineered virus looks exactly the same on the outside but has a “virtual brake pedal” on the inside, making it replicate much less quickly. The coronavirus can usually make 100 million copies of itself in a cell in about a day, but Coleman says the optimized version copies half as many even in the lab. In a person, it might be less efficient by a factor of up to 1,000, giving the immune system time to respond.
Some scientists do not see a role for a live vaccine in the fight covid-19. “It’s a stupid and easy virus to vaccinate,” says Michael Farzan, a specialist at the Scripps Research Institute. He says the virus exposes its most important vulnerability, the protein spike, in a way that makes it a ready target for antibodies, which other vaccines can generate. “You only need live attenuated viruses when you don’t have a safer one. In this case it carries a risk that is not necessary. There is no need to have a live virus that multiplies in you.”
The Serum Institute, which sells vaccines for the most part in the developing world, is working to manufacture four potential coronavirus vaccines, including front-runners from Oxford University and Novavax, an American biotechnology company. These are in advanced stages of testing, but there is no guarantee that they will work, and there may be supply shortages.
Dhere calls the live vaccine something of a safety plan for the Serum Institute. Such vaccines are made with a well-established old technology, and can be delivered without a needle. “Oral polio vaccination is so successful all over the world because it’s a drop in a child’s mouth. You don’t need a big medical paraphernalia, “he says.” So we’ve learned that during a pandemic, the simplest version of a vaccine is one that could reach billions of doses. When it comes to a mass scale, we think intranasal will be the best approach. ”
Risk of reversal
What are the risks? An attenuated virus can still be dangerous for people with compromised immune systems. Another risk is that a weakened virus can “return” to its most dangerous form. “We still have the question of whether he will return,” Coleman says.
What happens with polio. In recent decades, more epidemics have been caused by vaccine strains than by wild-type viruses. According to Plotkin, this is because only “relatively few” mutations distinguish Sabin vaccines from wild polio, and the attenuated virus (which multiplies in people and even spreads among them) can eventually mutate back to its original form.
In contrast, the “deoptimized” coronavirus has several hundred genetic changes. The evolutionary probabilities of finding a way to cancel even a part of them are mathematically minuscule. “I think it’s impossible,” Dhere says.
While the vaccine strain is returning to the dangerous form, Dhere says the biggest risk is that wild coronavirus will mutate in ways that make some vaccines less effective. The coronavirus has not been much modified so far: in fact, it has been very stable. However, if the spike protein changed, the main candidate vaccines could become less effective because they target only that molecule.
A live attenuated vaccine – because it includes all parts of the virus – might not have this problem. “We don’t want to chase the virus if it changes,” he says. But if it does, “we’ll still have a vaccine that’s still 99% similar.”