A new vaccine against Covid-19 is undergoing clinical trials in Brazil, Mexico, Thailand and Vietnam, which may change the way the world fights the pandemic. The vaccine, called NVD-HXP-S, is the first vaccine in clinical trials to use a new molecular design that can produce stronger antibodies than current vaccines. And new vaccines may be easier to manufacture.
Existing vaccines from companies such as Pfizer and Johnson & Johnson must be produced in specialized factories using hard-to-obtain ingredients. In contrast, this new vaccine can be produced in large quantities from eggs, and this kind of eggs produces billions of flu vaccines in factories around the world every year.
Andrea Taylor, assistant director of Duke University’s Center for Global Health Innovation, said: “This is really amazing and it will change the rules of the game.”
However, first, clinical trials must confirm that NVD-HXP-S is indeed effective in humans. The first phase of the clinical trial will end in July, and the final phase will take several months. But experiments with vaccinated animals have brought hope to the prospects of vaccines.
“This is a home run for protection,” said Dr. Bruce Innes of the PATH Vaccine Innovation and Acquisition Center, which coordinated the development of NVD-HXP-S. “I think this is a world-class vaccine.”
The working principle of the vaccine is to enable the immune system to fully understand the virus, so as to defend against the virus. Some vaccines contain the entire virus that has been killed; others contain only one protein in the virus. Others contain genetic instructions that our cells can use to make viral proteins.
Once exposed to the virus or part of it, the immune system can learn to make antibodies that attack the virus. Immune cells can also learn to recognize infected cells and destroy them.
As far as coronavirus is concerned, the best target of the immune system is the protein that covers its surface like a crown. This protein, called a spike, latches onto the cell and then causes the virus to fuse to the cell.
However, simply injecting coronavirus spike proteins into the human body is not the best way to vaccinate them. This is because the spike protein sometimes assumes the wrong shape and prompts the immune system to produce the wrong antibodies.
This kind of insight appeared before the Covid-19 pandemic. In 2015, another coronavirus appeared, which caused a fatal pneumonia called MERS. Jason McLellan, a structural biologist at the Gessel Medical School in Dartmouth at the time, and his colleagues set out to develop a vaccine against the vaccine.
They want to use the spike protein as a target. But they had to take into account the fact that the spike protein is a deformer. When the protein is ready to fuse to the cell, it will twist from a tulip-like shape to a javelin-like shape.
Scientists call these two shapes the pre-fusion and post-fusion forms of spikes. Antibodies targeting the shape before the fusion can effectively resist the coronavirus, but the antibodies after the fusion cannot stop it.
Dr. McLellan and his colleagues used standard techniques to produce the MERS vaccine, but eventually there were many post-fusion peaks that were useless for their purposes. Then, they discovered a way to lock the protein in a tulip-like pre-fusion shape. All they had to do was to change two of the more than 1,000 structural units in the protein into compounds called prolines.
The resulting spikes-the two new proline molecules contained in them called 2P-are more likely to take on the desired tulip shape. Researchers injected 2P spikes into mice and found that these animals can easily resist MERS coronavirus infection.
The team applied for a patent for its improved spike, but the world paid little attention to this invention. Although the Middle East Respiratory Syndrome is fatal, it is not very contagious and proved to be a relatively small threat. Since MERS first appeared in humans, less than 1,000 people have died of MERS.
But at the end of 2019, a new coronavirus SARS-CoV-2 appeared and began to ravage the world. Dr. McLellan and his colleagues took immediate action and designed the 2P spike unique to SARS-CoV-2. In just a few days, Moderna used this information to design a vaccine for Covid-19. It contains a genetic molecule called RNA with instructions for making 2P spikes.
Other companies soon followed suit and adopted peak 2P doses for their vaccine designs and started clinical trials. To date, all three vaccines approved in the United States (Johnson & Johnson, Moderna, and Pfizer BioNTech) use 2P spikes.
Other vaccine manufacturers are also using it. Novavax has achieved excellent results in a clinical trial with soaring 2P doses, and is expected to apply for an emergency use authorization from the Food and Drug Administration in the next few weeks. Sanofi is also testing the 2P spike vaccine and is expected to complete clinical trials later this year.
Two prolines are good; six are better
Dr. McLellan’s ability to find life-saving clues in protein structures has won high praise from the vaccine industry. “This guy is really a genius,” said Harry Klinthos, a senior program officer at the Bill and Melinda Gates Foundation. “He should be proud of what he has done for mankind.”
But once Dr. McLellan and his colleagues handed over the 2P peak to the vaccine manufacturer, he switched to using this protein for careful observation. If only swapping two prolines can improve the vaccine, then there are definitely other adjustments that can further improve it.
Dr. McClellan said: “It makes sense to try a better vaccine.” Dr. McClellan is now an associate professor at the University of Texas at Austin.
In March, he formed an alliance with Ilya Finkelstein and Jennifer Maynard, two biologists at the University of Texas. Their three laboratories created 100 new peaks, each with changing building blocks. With funding from the Gates Foundation, they tested each product and then merged the welcome changes in the new product. In the end, they created a protein that can satisfy their wishes.
The winner contained two prolines in the 2P spike, and four prolines were found elsewhere in the protein. Dr. McLellan called it the new spike protein HexaPro to commemorate its total of six prolines.
The research team found that the structure of HexaPro is even more stable than 2P. It is also resilient and can better withstand heat and destructive chemicals. Dr. McClellan hopes that its robust design will make it useful in vaccines.
Dr. McClellan also hopes that HexaPro-based vaccines can be spread to more parts of the world, especially low- and middle-income countries, which have so far received only a small part of the first wave of vaccine distribution.
Dr. McClellan said: “So far, the proportion of vaccines they have received is very bad.”
To this end, the University of Texas has set up a license agreement for HexaPro, which allows companies and laboratories in 80 low- and middle-income countries to use it for vaccines without paying royalties.
At the same time, Dr. Innes of PATH and his colleagues are looking for ways to increase the production of the Covid-19 vaccine. They want a vaccine that less affluent countries can produce on their own.
With the help of eggs
The first production of the authorized Covid-19 vaccine requires specialized and expensive raw materials. For example, Moderna’s RNA-based vaccine requires genetic building blocks called nucleotides, and customized fatty acids to form bubbles around them. These components must be assembled into vaccines in specially constructed factories.
In contrast, the way the flu vaccine is made is a study. Many countries/regions have large factories that manufacture cheap flu vaccines and have injected flu virus into eggs. The egg produces a large number of new virus replications. Then, factory workers extract the viruses, weaken or kill them, and then put them in a vaccine.
The PATH team wants to know whether scientists can make a Covid-19 vaccine, which can be made from eggs cheaply. In this way, those factories that make flu vaccines can also make Covid-19 vaccines.
In New York, a team of scientists at the Icahn School of Medicine at Mount Sinai knows how to make this vaccine using a bird flu virus called Newcastle disease that is harmless to humans.
For many years, scientists have been experimenting with Newcastle disease virus to produce vaccines against many diseases. For example, in order to develop an Ebola vaccine, researchers added the Ebola gene to a set of genes in the Newcastle disease virus itself.
Then, the scientists inserted the engineered virus into the egg. Because it is an avian virus, it reproduces rapidly in eggs. The researchers finally discovered the Newcastle disease virus with Ebola virus protein.
In Mount Sinai, the researchers set out to do the same thing, using the coronavirus spike protein instead of the Ebola virus protein. When they learned about Dr. McLellan’s new HexaPro version, they added it to the Newcastle disease virus. Viruses carry spike proteins, many of which have the desired pre-fusion shape. To show their recognition of Newcastle disease virus and HexaPro, they named it NDV-HXP-S.
PATH arranged to produce thousands of doses of NDV-HXP-S at a factory in Vietnam, which usually produces influenza vaccine in eggs. In October, the factory sent the vaccine to New York for testing. Researchers at Mount Sinai found that NDV-HXP-S has a powerful protective effect in mice and hamsters.
“I can honestly say that I can protect every hamster and every mouse in the world from SARS-CoV-2,” said research leader Dr. Peter Palese. “But the jury has yet to determine its role in humans.”
The effectiveness of the vaccine brings an additional benefit: researchers at effective doses need less virus. Compared with one or two doses of influenza vaccine, one egg can produce five to ten doses of NDV-HXP-S.
Dr. Pares said: “We are very excited about this because we think this is a cheap way to produce vaccines.”
PATH then connected the Mount Sinai team with flu vaccine manufacturers. On March 15, the Vietnam Institute of Vaccines and Medical Biology announced the start of clinical trials of NDV-HXP-S. A week later, the Thai government pharmaceutical organization followed suit. On March 26, the Butantan Institute in Brazil stated that it would request approval to start its own NDV-HXP-S clinical trial.
At the same time, the Mount Sinai team also licensed the vaccine to Mexican vaccine manufacturer Avi-Mex in the form of an intranasal spray. The company will begin clinical trials to see if this form of vaccine is more effective.
For the countries involved, the prospect of producing vaccines entirely on their own is attractive. Thai Health Minister Anutin Charnvirakul said in a statement in Bangkok: “The production of this vaccine is made by Thais for Thais.”
In Brazil, the Butantan Institute claims that its NDV-HXP-S version is the “Brazilian vaccine”. This vaccine “will be produced entirely in Brazil without relying on imports.”
Ms. Taylor of Duke University’s Center for Global Health Innovation is very sympathetic. She said: “I can understand why this is indeed such an attractive prospect.” “They have always been at the mercy of the global supply chain.”
Madhavi Sunder, an intellectual property expert at Georgetown Law School, warned that NDV-HXP-S will not immediately help countries like Brazil because they are dealing with the current wave of Covid-19 infections. She said: “By 2020, our dose will not reach 16 billion doses.”
On the contrary, this strategy is very important for long-term vaccine production-not only for Covid-19, but also for other pandemics that may occur in the future. She said: “This sounds promising.”
At the same time, Dr. McLellan went back to the molecular drawing board and tried to make a third type of spike better than HexaPro.
He said: “This process really has no end.” “The number of permutations is almost unlimited. At some point, you have to say, “This is the next generation. “”