AUSTIN (KXAN) — Biologist Jason McLellan walked down Speedway’s brick lane to Gregory Gym and waited less than 10 minutes to receive the Pfizer vaccine after successfully dodging COVID-19 for over a year while working tirelessly in his lab.
After people get their vaccination, some buy Tylenol, some return to work and some announce it to their friends on Twitter. Some do all three. But, after McLellan got his shot, he was filmed by the media and asked to take selfies with strangers.
This is because McLellan helped guide global vaccine research by creating a key protein found in the Pfizer, Moderna and Johnson & Johnson vaccines — an achievement earning him praise from Dr. Anthony Fauci. His colleagues describe him as a world-class protein engineer with a knack for teaching.
He's only getting started on making a difference with vaccines.
Most pressing problem: getting vaccines to everyone
The "shocking global disparity" in vaccine access is one of the biggest obstacles to ending the pandemic, The World Health Organization chief said May 10.
In the global rollout of coronavirus vaccinations, resources are surging to high-income nations. The Duke University’s Global Health Innovation Center found high-income nations with less than half of the world’s population have locked up 60% of the COVID-19 vaccine doses — and the world’s poorest countries will not be able to vaccinate a majority of their populations until 2023 or later.
“Most of the world's population lives in low and middle-income countries. No one will be safe from COVID until everyone has equitable access to vaccines,” said Dr. Bruce Innis, Leader of the Center for Vaccine Innovation at PATH.
The path to solving vaccine inequality involves prolonging shelf life of the doses and improving the vaccine’s genetic structure, according to UT researchers.
The cutting-edge mRNA vaccines such as those made by Moderna or Pfizer, while 90–94.5% effective, come with a catch. These vaccines must be kept at temperatures as cold as 80°C, or -112° F, use specialized costly ingredients and are created in factories that require 600-pound steel reactors that grow and convert DNA into mRNA. The technology and supplies make the vaccines an investment for the countries buying them, costing about $60 per patient.
When UT researchers like McLellan realized their work could make a difference in real-world health situations, they felt obligated to translate their findings into something that might help people. They teamed up with the Icahn School of Medicine at Mount Sinai.
One solution came from prior research on the influenza vaccine. Researchers found forming the vaccine in an egg was the most affordable and stable method. Scientists from the UT and Mount Sinai research teams developed a new vaccine, NDV-HXP-S, in a chicken egg. The vaccine began human trials in Brazil, Thailand, Vietnam and Mexico — and, if successful, could be the most affordable, scalable and practical vaccine on the market.
The McLellan Lab at The University of Texas
In 2013, McLellan began researching SARS and MERS coronaviruses. His breakthrough research of methods that make the molecular biology of the coronavirus easier to analyze helped advance the timeline of vaccine development.
Daniel Wrapp first talked to McLellan while interviewing for graduate school at Dartmouth University. Wrapp chose the school with specific hopes of joining McLellan’s lab, and when McLellan was recruited to UT, Wrapp followed.
“When I joined his lab, I didn't have any sort of expertise or background in what I do now,” Wrapp said. “He is willing to spend so much time investing in his students and keeping them at the forefront of the field.”
It starts with the spike protein
In the McLellan lab at the University of Texas, Wrapp was able to determine the 3D structure of the SARS-CoV-2 spike protein. The discovery gave researchers a visual tool to devise a plan to fight the virus.
“Vaccines are the best way to prevent disease,” Wrapp said. “They're much cheaper than trying to develop treatments once somebody is already sick, and they're really effective at eliciting herd immunity, which will stop future pandemics.”
Coronaviruses are named for their crown of “spike proteins'' that surround their surfaces. When the spike proteins latch onto human cells, the hijack results in sickness.
Messenger RNA or adenovirus-based SARS-CoV-2 vaccines target the virus like a trojan horse, supplying the body with specific instructions on how to recreate the spike protein. That triggers an immune response that creates antibodies trained to fight against the virus if the human body ever comes in contact with it.
McLellan’s lab determines 2P changes lock protein in place
Viral fusion proteins, by design, are unstable shape-shifters. This complicates using them to make a vaccine. If the proteins assume the wrong shape, they will not be able to make the correct antibody. To combat this, McLellan’s lab applied a trick they learned in 2017: adding two prolines.
Prolines, the most rigid of the amino acids, make a rusty-hinge that locks a protein into the desired curled-up, mushroom shape known as “prefusion.” The two tweaks gave the discovery the name 2P.
There are different ways that the coronavirus vaccines are being delivered: through messenger mRNA, like Pfizer-BioNTech and Moderna, viral vectors, like Johnson and Johnson, and protein subunits, such as Novavax. Each of these delivery methods use 2P research published by the McLellan lab in 2017.
2P version had its downsides
After 2P was published, labs from around the world asked McLellan to share his lab’s plasmid, or molecules that allow the labs to recreate the protein.
Then, labs started asking McLellan for clarification and guidance for the 2P changes because they were struggling to recreate the spike. McLellan’s lab was having trouble with the protein, too. After they went through their procedures, they were left with little usable product.
“It is a tricky protein to work with, and a lot of labs just don't even have the set up,” McLellan said.
It became apparent to McLellan that there was a need for a second generation version of the protein that other labs could also use.
“We thought we could do it,” McLellan said. “We thought that because my lab had very rapidly determined the structure of the SARS-CoV-2 spike protein early last year, we now had the blueprint to go back in and make additional stabilizing mutations.”
Learning of McLellan’s newest challenge, Jennifer Maynard's and Ilya J. Finkelstein's labs on campus joined the pack and it was “all hands on deck,” Maynard said.
“They were able to help us out quite a bit by stopping their research and transitioning to a completely new topic. They really came into their own pretty quickly,” Wrapp said.
Also stepping in to assist in research of the protein was the Bill and Melinda Gates Foundation. The foundation funded Maynard’s other projects in the past, so Maynard set up a meeting for McLellan to explain the need for a second-generation stabilized mutation. The foundation gave UT $100,000 in emergency funding for its research.
“When I was first talking to Jason, I mean, it's like being on the front lines of a battlefield,” Maynard said. “We said ‘We know it will be a lot of work, but this is our opportunity to contribute.’”
Long days in the lab testing mutations
McLellan and postdoctoral candidate Ching-Lin Hsieh, the lead scientist on the second version project, carefully looked at the structure of the protein and designed 100 different mutations for the team to test based on their knowledge of biochemistry.
“The kind of work we do, it's kind of like doing a really complicated cooking recipe. But we didn't really have a good recipe yet.” Maynard said.
Throughout the summer, timelines condensed and labs were not allowed to work at full capacity. Members of McLellan’s lab described the process as intense but highly collaborative.
“It's easy to make those designs just on a computer, but then you actually have to express the protein in the lab, test it to make sure that you're having the intended effect. And, most of the time that doesn't work,” McLellan lab member Jory Goldsmith said. “But you still have to go through the work to see if you're actually achieving the goal.”
At first, they weren’t having luck, Hsieh said.
“Jason was very encouraging and coming to tell us we should just keep trying different strategies. And, at the end, we actually got it to work,” Hsieh said.
They were able to identify 25 mutations that had beneficial properties and tested combinations of those. One Saturday morning, Hsieh was in the lab when he learned the combination of the original two prolines and four additional prolines had the most beneficial properties. They called it HexaPro.
The results of HexaPro
McLellan said that HexaPro is easier to work with and stays in the desired prefusion shape for longer, resulting in a better immune response and more antibodies. It also expresses, or makes, more protein in the lab than the previous 2P version. If HexaPro is used as a protein subunit vaccine, production increases tenfold.
HexaPro can survive being frozen, thawed and left out at room temperature. It eliminates the need for expensive cold-chain freezers, the price of which has limited vaccine access across the world. McLellan’s lab wanted to make sure HexaPro was available to everyone and published their discovery as soon as they could in September 2020. It did not take long for their paper to grab the attention of the research world.
Collaboration with Icahn School of Medicine at Mount Sinai
McLellan shipped the plasmid DNA, which labs can use to recreate HexaPro, to over 117 labs. For the high number of requests, he received the Blue Flame Award in April 2021. The Blue Flame Award congratulates researchers who have distributed plasmid over 100 times through the nonprofit Addgene.
HexaPro caught the eye of a lab in New York a day after being published. Peter Palese, Chair of Microbiology at the Icahn School of Medicine at Mount Sinai, is a veteran of working with viruses with RNA makeups, such as the coronavirus. He’s done extensive research for the respiratory virus influenza and helped get the flu mist FDA approved.
With his background, he knew COVID-19 was not an entirely different beast. His lab decided to develop their vaccines using a vector virus, an approach that introduces a non-infectious virus to the body.
With help from chicken eggs, researchers create NDV-HXP-S
Palese’s lab worked with NewCastle Disease Virus (NDV), a chicken virus. Palese said they picked NDV because of his past experience using it for the creation of veterinary vaccines.
“It does not do any harm to humans. Every chicken in the world has been vaccinated with NDV. So a lot of people have been infected and nothing has happened,” Palese said.
Palese said he introduced HexaPro’s six mutations to their vaccine as soon as he read the paper from the McLellan lab.
To create the vaccine, eggs are injected with the spike protein gene information from SARS-CoV-2 with the HexaPro variant included. The virus grows and then scientists kill it with a chemical that makes it safe to inject into humans.
“It turned out to be a better and more stable product. This is important, because one of the difficulties of the Pfizer-Biotech and Moderna vaccine is that the cold chain is very difficult. This is logistically very expensive, and if you can have refrigeration temperature it's an easier task.” Palese said.
In a nod to both the Newcastle Disease Virus and the HexaPro spike, they called the vaccine NDV-HXP-S. Palese said another advantage is the production of NDV-HXP-S mimics that of the influenza vaccine, so factories could use the same set up.
“If the countries can make their own vaccine in-house, that gives them a lot of independence. They're not relying on manufacturers; they don't have to get in the queue and wait their turn,” McLellan said. “We have people in our lab from places all over the world and so they were really passionate about making it available.”
Palese said he does not believe NDV-HXP-S will have side effects, especially among younger people who seem to be more prone to feeling sick after mRNA vaccines. They are also working to make the vaccine available through the nose.
“It might be a booster, for example, (so) that we don't have to inject the vaccine, but we can give you another dose a year later or two years later for a different variant through the nose,” Palese said.
Human trials are now underway for the NDV-HXP-S vaccine.
“I can tell you that we can protect against any kind of coronavirus in every mouse, every hamster in the world,” Palese said. “But as you know, mice are not men. So we really have to go to the people.”
Clinical trials begin with the help of PATH
PATH is an international organization with roots in 70 different countries aiming to accelerate the development of affordable and life-saving vaccines that fight illnesses disproportionately burdening people living in low resource settings.
Human trials for NDV-HXP-S began in April 2020 in Vietnam at the Institute of Vaccines and Medical Biologicals, in Thailand at the Government Pharmaceutical Organization and are expected to start soon in Brazil at Butantan Institute. Mexico-based pharmaceutical company Avi-mex plans to test the intranasal spray version of the vaccine.
The development of vaccines is being driven by the countries’ manufacturers. PATH participates as a facilitator and technical advisor, hosting weekly meetings with their partners at Mount Sinai, Vietnam and Brazil.
PATH said each country runs their trial slightly differently, but Innis leverages working with multiple organizations.
“In a very unusual move, they've agreed to be completely transparent with each other and they share their process,” Innis said. “We're a resource for them, but it's their program and it's their vaccine. And that's what makes this very special.”
The Government Pharmaceutical Organization in Thailand is on track to report initial data in August.
“It is a hope and a new capability for Thailand to produce vaccines on their own,” said Anutin Charnvirakul, Deputy Prime Minister and Minister of Public Health, in the Phase 1 press release.
Innis said PATH’s goal is to measure NDV-HXP-S vaccine efficacy in the last quarter of the year and get the vaccines approved by the FDA equivalents in their countries. PATH's second goal is to feed the production into a WHO-backed effort, COVAX, that aims to give every country fair vaccine access.
“It's really up to the countries now to carry it out and see. But I think it's off to a good start.” McLellan said.
For the McLellan lab, the work is not over.
“We're working on pathogens right now people have probably never heard of. Maybe it's not helpful, or maybe that's the next outbreak,” McLellan said. “We just have to increase our general knowledge and be prepared.”
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