A new vaccine against Covid-19 entering clinical trials in Brazil, Mexico, Thailand and Vietnam could change the way the world is fighting the pandemic. Named NVD-HXP-S, the vaccine is the first in clinical trials to use a new molecular design that is widely expected to produce more potent antibodies than the current generation of vaccines. And the new vaccine could be a lot easier to make.
Existing vaccines from companies like Pfizer and Johnson & Johnson must be manufactured in specialized factories using ingredients that are difficult to source. In contrast, the new vaccine can be mass-produced in chicken eggs – the same eggs that produce billions of influenza vaccines each year in factories around the world.
If NVD-HXP-S is shown to be safe and effective, influenza vaccine manufacturers could potentially produce well over a billion doses of it per year. Low- and middle-income countries that are currently struggling to obtain vaccines from wealthier countries may be able to manufacture NVD-HXP-S for themselves or purchase it from neighbors at a low cost.
“This is breathtaking – it would change the game,” said Andrea Taylor, associate director of the Duke Global Health Innovation Center.
However, clinical studies must first prove that NVD-HXP-S actually works in humans. The first phase of clinical trials will be completed in July and the final phase will take a few more months. However, experiments with vaccinated animals have raised hopes for the vaccine’s prospects.
“It’s a home race for protection,” said Dr. Bruce Innes of the PATH Center for Vaccine Innovation and Access, who coordinated the development of the NVD-HXP-S. “I think it’s a world-class vaccine.”
2P to the rescue
Vaccines work by introducing the immune system to a virus enough to make it fight it. Some vaccines contain whole viruses that have been killed. others contain only a single protein from the virus. Still others contain genetic instructions that our cells can use to make the viral protein.
Once the immune system is exposed to a virus or part of it, it can learn to make antibodies to attack it. Immune cells can also learn to recognize and destroy infected cells.
In the case of the coronavirus, the best target for the immune system is the protein that covers its surface like a crown. The protein known as spike attaches to the cells and then allows the virus to fuse with them.
However, simply injecting coronavirus spike proteins into people is not the best way to get them vaccinated. This is because spike proteins sometimes take the wrong shape and cause the immune system to make the wrong antibodies.
This realization came long before the Covid-19 pandemic. Another coronavirus emerged in 2015, causing a deadly form of pneumonia called MERS. Jason McLellan, then a structural biologist at the Geisel School of Medicine in Dartmouth, and his colleagues set about making a vaccine against it.
They wanted to target the spike protein. But they had to expect that the spike protein is a shape shifter. As the protein prepares to fuse with a cell, it warps from a tulip-like shape to something more like a spear.
Scientists call these two shapes the prefusion and postfusion shapes of the tip. Antibodies to the prefusion form are strong against the coronavirus, but postfusion antibodies don’t stop it.
Dr. McLellan and his colleagues used standard techniques to make a MERS vaccine, but ended up with many post-fusion spikes that were useless for their purposes. Then they discovered a way to keep the protein in a tulip-like prefusion shape. All they had to do was convert two out of 1,000 or more building blocks in the protein into a compound called proline.
The resulting tip – called 2P – for the two new proline molecules it contained was far more likely to take on the desired tulip shape. The researchers injected the 2P spikes into mice and found that the animals were able to fight off MERS coronavirus infections easily.
The team filed a patent for its modified spike, but the world took little notice of the invention. While MERS is deadly, it is not very contagious and has been shown to be a relatively minor threat. less than 1,000 people have died from MERS since it first appeared in humans.
However, in late 2019, a new coronavirus, SARS-CoV-2, emerged and began to devastate the world. Dr. McLellan and his colleagues took action and designed a 2P spike that only applies to SARS-CoV-2. Within a few days, Moderna used this information to develop a vaccine against 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 vaccines approved to date in the US – from Johnson & Johnson, Moderna and Pfizer-BioNTech – use the 2P spike.
Other vaccine manufacturers use it as well. Novavax has had strong results with the 2P surge in clinical trials and is expected to apply to the Food and Drug Administration for emergency approval in the next few weeks. Sanofi is also testing a 2P spike vaccine and expects clinical trials to be completed later this year.
Two prolines are good; Six are better
Dr. McLellan’s ability to find lifesaving clues in the structure of proteins has earned him deep admiration in the vaccine world. “This guy’s a genius,” said Harry Kleanthous, senior program officer at the Bill & Melinda Gates Foundation. “He should be proud of this great thing that he has done for humanity.”
But when Dr. McLellan and his colleagues passed the 2P spike on to vaccine manufacturers, he turned back to protein for a closer look. If exchanging just two prolins would improve a vaccine, additional tweaks could certainly make it even better.
“It made sense to try a better vaccine,” said Dr. McLellan, who is now an Associate Professor at the University of Texas at Austin.
In March, he teamed up with two other University of Texas biologists, Ilya Finkelstein and Jennifer Maynard. In their three laboratories, 100 new spikes, each with a different component, were created. With funds from the Gates Foundation, they tested each one and then combined the promising changes to new spikes. Eventually, they created a single protein that suited their needs.
The winner contained the two prolins in the 2P spike plus four additional prolins found elsewhere in the protein. Dr. McLellan named the new Spike HexaPro in honor of its six Prolines.
HexaPro’s structure was even more stable than that of 2P, the team found. It was also tough, better able to withstand heat and harmful chemicals. Dr. McLellan hoped its rugged design would make it effective in a vaccine.
Dr. McLellan also hoped that HexaPro-based vaccines would reach more of the world – especially low- and middle-income countries that have so far received only a fraction of the total distribution of first-wave vaccines.
“The proportion of vaccines they have received so far is terrible,” said Dr. McLellan.
To that end, the University of Texas has signed a license agreement for HexaPro that allows companies and laboratories in 80 low- and middle-income countries to use the protein in their vaccines without paying royalties.
In the meantime, Dr. Innes and his colleagues at PATH looking for a way to increase production of Covid-19 vaccines. They wanted a vaccine that less affluent nations could make themselves.
With a little help from eggs
The first wave of approved Covid-19 vaccines requires special, costly ingredients. For example, Moderna’s RNA-based vaccine requires genetic building blocks called nucleotides and a tailor-made fatty acid to build a bubble around them. These ingredients have to be processed into vaccines in specially built factories.
By contrast, the way influenza vaccines are made is a study. Many countries have huge cheap flu vaccine factories that inject chicken eggs with influenza viruses. The eggs produce an abundance of new copies of the virus. Factory workers then extract, weaken, or kill the viruses and then use them in vaccines.
The PATH team wondered if scientists could create a Covid-19 vaccine that could be cheaply grown in chicken eggs. That way, the same factories that do flu vaccinations could also do Covid-19 vaccinations.
In New York, a team of scientists from the Mount Sinai Icahn School of Medicine knew how to make such a vaccine using an avian virus called Newcastle Disease Virus, which is harmless to humans.
For years, scientists have been experimenting with the Newcastle virus to develop vaccines for a range of diseases. For example, to develop an Ebola vaccine, the researchers added an Ebola gene to Newcastle disease virus’ own set of genes.
The scientists then put the engineered virus into chicken eggs. Since it is an avian virus, it multiplied quickly in the eggs. The researchers had Newcastle disease viruses coated with Ebola proteins.
At Mount Sinai, researchers set out to do the same, using coronavirus spike proteins instead of Ebola proteins. When she was told by Dr. When McLellan’s new version of HexaPro learned, they added it to the Newcastle disease viruses. The viruses were full of spike proteins, many of which were in the desired prefusion form. In reference to the Newcastle virus and the HexaPro spike, they named it NDV-HXP-S.
PATH arranged for thousands of cans of NDV-HXP-S to be made in a Vietnamese factory that normally produces influenza vaccines in chicken eggs. In October, the factory sent the vaccines to New York for testing. The Mount Sinai researchers found that NDV-HXP-S gave mice and hamsters strong protection.
“I can honestly say that I can protect every hamster, every mouse in the world from SARS-CoV-2,” said Dr. Peter Palese, the head of research. “But the jury is still not sure what it is doing with humans.”
The effectiveness of the vaccine brought an additional benefit: the researchers needed fewer viruses for an effective dose. A single egg can make five to 10 doses of NDV-HXP-S compared to one or two doses of influenza vaccines.
“We are very excited about this because we believe this is a way to make a cheap vaccine,” said Dr. Palese.
PATH then linked the Mount Sinai team with influenza vaccine makers. On March 15, the Vietnamese Institute for Vaccines and Medical Biologics announced the start of a clinical study with NDV-HXP-S. A week later, Thailand’s Government Pharmaceutical Organization followed suit. On March 26, the Brazilian Butantane Institute announced approval to begin its own clinical studies with NDV-HXP-S.
The Mount Sinai team has now also licensed the vaccine as an intranasal spray to the Mexican vaccine manufacturer Avi-Mex. The company will start clinical trials to see if the vaccine is even more effective in this form.
For the nations involved, the prospect of producing the vaccines entirely in-house was attractive. “This vaccine production is made by Thai people for Thai people,” said Thailand’s Minister of Health Anutin Charnvirakul at the announcement in Bangkok.
In Brazil, the Butantane Institute has named its version of NDV-HXP-S a “Brazilian Vaccine” which is “entirely made in Brazil without being dependent on imports”.
Ms. Taylor at the Duke Global Health Innovation Center was compassionate. “I could understand why this would be such an attractive prospect,” she said. “They were at the mercy of the global supply chains.”
Madhavi Sunder, an intellectual property expert at Georgetown Law School, warned that NDV-HXP-S would not help countries like Brazil right away as they grapple with the current wave of Covid-19 infections. “We’re not talking about 16 billion doses in 2020,” she said.
Instead, the strategy for long-term vaccine production will be important – not just for Covid-19, but for other pandemics that may arise in the future. “It sounds super promising,” she said.
In the meantime, Dr. McLellan returned to the molecular drawing board to try and make a third version of their spike that is even better than HexaPro.
“There really is no end to this process,” he said. “The number of permutations is almost infinite. At some point you would have to say: “This is the next generation.”