Researchers are hatching low-cost vaccine
Product using eggs appears potent, cheap
A new vaccine for COVID-19 that is entering clinical trials in Brazil, Mexico, Thailand and Vietnam could change how the world fights the pandemic.
The vaccine, called NDVHXP-S, is the first in clinical trials to use a new molecular design that is widely expected to create more potent antibodies than the current generation of vaccines.
And the new vaccine could be far easier to make.
Existing vaccines from companies like Pfizer and Johnson & Johnson must be produced in specialized factories using hard-to-acquire ingredients.
In contrast, the new vaccine can be mass-produced in chicken eggs — the same eggs that produce billions of influenza vaccines every year in factories around the world.
If NDV-HXP-S proves safe and effective, flu vaccine manufacturers could potentially produce well over a billion doses of it a year. Lowand middle-income countries currently struggling to obtain vaccines from wealthier countries may be able to make NDV-HXP-S for themselves or acquire it at low cost from neighbors.
“That’s staggering — it would be a game-changer,” said Andrea Taylor, assistant director of the Duke Global Health Innovation Center.
First, however, clinical trials must establish that NDV-HXP-S actually works in people.
The first phase of clinical trials will conclude in July, and the final phase will take several months more. But experiments with vaccinated animals have raised hopes for the vaccine’s prospects.
“It’s a home run for protection,” said Dr. Bruce Innis of the PATH Center for Vaccine Innovation and Access, which has coordinated the development of NDV-HXP-S.
“I think it’s a world-class vaccine.”
2P to the rescue
Vaccines work by acquainting the immune system with a virus well enough to prompt a defense against it. Some vaccines contain entire viruses that have been killed; others contain just a single protein from the virus. Still others contain genetic instructions that our cells can use to make the viral protein.
Once exposed to a virus, or part of it, the immune system can learn to make antibodies that attack it. Immune cells can also learn to recognize infected cells and destroy them.
In the case of the coronavirus, the best target for the immune system is the protein, known as a spike, that covers its surface like a crown.
But simply injecting coronavirus spike proteins into people is not the best way to vaccinate them. That is because spike proteins sometimes assume the wrong shape, and prompt the immune system to make the wrong antibodies.
This insight emerged long before the COVID-19 pandemic. In 2015, another coronavirus appeared, causing a deadly form of pneumonia called Middle East respiratory syndrome. Jason Mclellan, a structural biologist then at the Geisel School of Medicine at Dartmouth, and his colleagues set out to make a vaccine against it.
They wanted to use the spike protein as a target. But they had to reckon with the fact that the spike protein is a shape-shifter. As the protein prepares to fuse to a cell, it contorts from a tuliplike shape into something more akin to a javelin.
Scientists call these two shapes the prefusion and postfusion forms of the spike. Antibodies against the prefusion shape work powerfully against the coronavirus, but postfusion antibodies don’t stop it.
Mclellan and his colleagues
used standard techniques to make a MERS vaccine but ended up with a lot of postfusion spikes, useless for their purposes. Then they discovered a way to keep the protein locked in a tulip-like prefusion shape. All they had to do was change two of more than 1,000 building blocks in the protein into a compound called proline.
The resulting spike — called 2P, for the two new proline molecules it contained — was far more likely to assume the desired tulip shape. The researchers injected the 2P spikes into mice and found that the animals could easily fight off infections of the MERS coronavirus.
The team filed a patent for its modified spike, but the world took little notice of the invention.
But in late 2019 a new coronavirus, SARS-COV-2, emerged and began ravaging the world. Mclellan and his colleagues swung into action, designing a 2P spike unique to SARS-COV-2. In a
matter of days, Moderna used that information to design a vaccine for COVID-19; it contained a genetic molecule called RNA with the instructions for making the 2P spike.
Other companies soon followed suit, adopting 2P spikes for their own vaccine designs and starting clinical trials. All three of the vaccines that have been authorized so far in the United States — from Johnson & Johnson, Moderna and Pfizer-biontech — use the 2P spike.
Work of a genius
Mclellan’s ability to find lifesaving clues in the structure of proteins has earned him deep admiration in the vaccine world.
“This guy is a genius,” said Harry Kleanthous, a senior program officer at the Bill & Melinda Gates Foundation. “He should be proud of this huge thing he’s done for humanity.”
But once Mclellan and his colleagues handed off the 2P spike to vaccine-makers, he turned back to the protein for a closer look. If swapping just two prolines improved a vaccine, surely additional tweaks could improve it even more.
“It made sense to try to have a better vaccine,” said Mclellan, who is now an associate professor at the University of Texas at Austin.
In March, he joined forces with two fellow University of Texas biologists, Ilya Finkelstein and Jennifer Maynard. Their three labs created 100 new spikes, each with an altered building block. With funding from the Gates Foundation, they tested each one and then combined the promising changes in new spikes. Eventually, they created a single protein that met their aspirations.
The winner contained the two prolines in the 2P spike, plus four additional prolines found elsewhere in the protein. Mclellan called the new spike Hexapro, in honor of its total of six prolines.
The structure of Hexapro was even more stable than 2P, the team found. It was also resilient, better able to withstand heat and damaging chemicals. Mclellan hoped that its rugged design would make it potent in a vaccine.
Meanwhile, Innis and his colleagues at PATH were looking for a way to increase the production of COVID-19 vaccines. They wanted a vaccine that less wealthy nations could make on their own.
Help from chickens
Many countries have huge factories for making cheap flu shots, with influenza viruses injected into chicken eggs. The eggs produce an abundance of new copies of the viruses. Factory workers then extract the viruses, weaken or kill them and then put them into vaccines.
The PATH team wondered if scientists could make a COVID-19 vaccine that could be grown cheaply in chicken eggs. That way, the same factories that make flu shots could make COVID-19 shots as well.
In New York, a team of scientists at the Icahn School of Medicine at Mount Sinai knew how to make just such a vaccine, using a bird virus called Newcastle disease virus that is harmless in humans.
The researchers set out to do the same thing. When they learned about Mclellan’s new Hexapro version, they added that to the Newcastle disease viruses. The viruses bristled with spike proteins, many of which had the desired prefusion shape. In a nod to both the Newcastle disease virus and the Hexapro spike, they called it NDV-HXP-S.
PATH then connected the Mount Sinai team with influenza vaccine-makers. On March 15, Vietnam’s Institute of Vaccines and Medical Biologicals announced the start of a clinical trial of NDVHXP-S. A week later, Thailand’s Government Pharmaceutical Organization followed suit. On March 26, Brazil’s Butantan Institute said it would ask for authorization to begin its own clinical trials of NDV-HXP-S.
In the meantime, Mclellan has returned to the molecular drawing board to try to make a third version of their spike that is even better than Hexapro.
“There’s really no end to this process,” he said. “The number of permutations is almost infinite. At some point, you’d have to say, ‘This is the next generation.’”