Scientists search for a universal coronavirus vaccine
The Covid-19 pandemic had barely begun when VBI Vaccines, a biopharmaceutical company based in Cambridge, Massachusetts, initiated their search for a universal coronavirus vaccine.
It was March 2020, and while most pharmaceutical companies were scrambling to initiate vaccine programs which specifically targeted the SARS-CoV-2 virus, VBI’s executives were already keen to look at the broader picture.
Having observed the SARS and MERS coronavirus outbreaks over the last two decades, Jeff Baxter, CEO of VBI Vaccines, was aware that SARS-CoV-2 is unlikely to be the last coronavirus to move from an animal host into humans. “It's absolutely apparent that the future is to create a vaccine which gives more broad protection against not only pre-existing coronaviruses, but those that will potentially make the leap into humans in future,” says Baxter.
It was a prescient decision. Over the last two years, more biotechs and pharma companies have joined the search to find a vaccine which might be able to protect against all coronaviruses, along with dozens of academic research groups. Last September, the US National Institutes of Health dedicated $36 million specifically to pan-coronavirus vaccine research, while the global Coalition for Epidemic Preparedness Innovations (CEPI) has earmarked $200 million towards the effort.
Until October 2021, the very concept of whether it might be
theoretically possible to vaccinate against multiple coronaviruses remained an open question. But then a groundbreaking study renewed optimism.
The emergence of new variants of Covid-19 over the past year, particularly the highly mutated Omicron variant, has added greater impetus to find broader spectrum vaccines. But until October 2021, the very concept of whether it might be theoretically possible to vaccinate against multiple coronaviruses remained an open question. After all, scientists have spent decades trying to develop a similar vaccine for influenza with little success.
But then a groundbreaking study from renowned virologist Linfa Wang, who runs the emerging infectious diseases program at Duke-National University of Singapore Medical School, provided renewed optimism.
Wang found that eight SARS survivors who had been injected with the Pfizer/BioNTech Covid-19 vaccine had neutralising antibodies in their blood against SARS, the Alpha, Beta and Delta variants of SARS-CoV-2, and five other coronaviruses which reside in bats and pangolins. He concluded that the combination of past coronavirus infection, and immunization with a messenger RNA vaccine, had resulted in a wider spectrum of protection than might have been expected.
“This is a significant study because it showed that pre-existing immunity to one coronavirus could help with the elicitation of cross-reactive antibodies when immunizing with a second coronavirus,” says Kevin Saunders, Director of Research at the Duke Human Vaccine Institute in North Carolina, which is developing a universal coronavirus vaccine. “It provides a strategy to perhaps broaden the immune response against coronaviruses.”
In the next few months, some of the first data is set to emerge looking at whether this kind of antibody response could be elicited by a single universal coronavirus vaccine. In April 2021, scientists at the Walter Reed Army Institute of Research in Silver Spring, Maryland, launched a Phase I clinical trial of their vaccine, with a spokesman saying that it was successful, and the full results will be announced soon.
The Walter Reed researchers have already released preclinical data, testing the vaccine in non-human primates where it was found to have immunising capabilities against a range of Covid-19 variants as well as the original SARS virus. If the Phase I trial displays similar efficacy, a larger Phase II trial will begin later this year.
Two different approaches
Broadly speaking, scientists are taking two contrasting approaches to the task of finding a universal coronavirus vaccine. The Walter Reed Army Institute of Research, VBI Vaccines – who plan to launch their own clinical trial in the summer – and the Duke Human Vaccine Institute – who are launching a Phase I trial in early 2023 – are using a soccer-ball shaped ferritin nanoparticle studded with different coronavirus protein fragments.
VBI Vaccines is looking to elicit broader immune responses by combining SARS, SARS-CoV-2 and MERS spike proteins on the same nanoparticle. Dave Anderson, chief scientific officer at VBI Vaccines, explains that the idea is that by showing the immune system these three spike proteins at the same time, it can help train it to identify and respond to subtle differences between coronavirus strains.
The Duke Human Vaccine Institute is utilising the same method, but rather than including the entire spike proteins from different coronaviruses, they are only including the receptor binding domain (RBD) fragment from each spike protein. “We designed our vaccine to focus the immune system on a site of vulnerability for the virus, which is the receptor binding domain,” says Saunders. “Since the RBD is small, arraying multiple RBDs on a nanoparticle is a straight-forward approach. The goal is to generate immunity to many different subgenuses of viruses so that there will be cross-reactivity with new or unknown coronaviruses.”
But the other strategy is to create a vaccine which contains regions of the viral protein structure which are conserved between all coronavirus strains. This is something which scientists have tried to do for a universal influenza vaccine, but it is thought to be more feasible for coronaviruses because they mutate at a slower rate and are more constrained in the ways that they can evolve.
DIOSynVax, a biotech based in Cambridge, United Kingdom, announced in a press release earlier this month that they are partnering with CEPI to use their computational predictive modelling techniques to identify common structures between all of the SARS coronaviruses which do not mutate, and thus present good vaccine targets.
Stephen Zeichner, an infectious disease specialist at the University of Virginia Medical Center, has created an early stage vaccine using the fusion peptide region – another part of the coronavirus spike protein that aids the virus’s entry into host cells – which so far appears to be highly conserved between all coronaviruses.
So far Zeichner has trialled this version of the vaccine in pigs, where it provided protection against a different coronavirus called porcine epidemic diarrhea virus, which he described as very promising as this virus is from a different family called alphacoronaviruses, while SARS-CoV-2 is a betacoronavirus.
“If a betacoronavirus fusion peptide vaccine designed from SARS-CoV-2 can protect pigs against clinical disease from an alphacoronavirus, then that suggests that an analogous vaccine would enable broad protection against many, many different coronaviruses,” he says.
The road ahead
But while some of the early stage results are promising, researchers are fully aware of the scale of the challenge ahead of them. Although CEPI have declared an aim of having a licensed universal coronavirus vaccine available by 2024-2025, Zeichner says that such timelines are ambitious in the extreme.
“I was incredibly impressed at the speed at which the mRNA coronavirus vaccines were developed for SARS-CoV-2,” he says. “That was faster than just about anybody anticipated. On the other hand, I think a universal coronavirus vaccine is more equivalent to the challenge of developing an HIV vaccine and we're 35 years into that effort without success. We know a lot more now than before, and maybe it will be easier than we think. But I think the route to a universal vaccine is harder than an individual vaccine, so I wouldn’t want to put money on a timeline prediction.”
The major challenge for scientists is essentially designing a vaccine for a future threat which is not even here yet. As such, there are no guidelines on what safety data would be required to license such a vaccine, and how researchers can demonstrate that it truly provides efficacy against all coronaviruses, even those which have not yet jumped to humans.
The teams working on this problem have already devised some ingenious ways of approaching the challenge. VBI Vaccines have taken the genetic sequences of different coronaviruses found in bats and pangolins, from publicly available databases, and inserted them into what virologists call a pseudotype virus – one which has been engineered so it does not have enough genetic material to replicate.
This has allowed them to test the neutralising antibodies that their vaccine produces against these coronaviruses in test tubes, under safe lab conditions. “We have literally just been ordering the sequences, and making synthetic viruses that we can use to test the antibody responses,” says Anderson.
However, some scientists feel that going straight to a universal coronavirus vaccine is likely to be too complex. Instead they say that we should aim for vaccines which are a little more specific. Pamela Bjorkman, a structural biologist at the California Institute of Technology, suggests that pan-coronavirus vaccines which protect against SARS-like betacoronaviruses such as SARS or SARS-CoV-2, or MERS-like betacoronaviruses, may be more realistic.
“I think a vaccine to protect against all coronaviruses is likely impossible since there are so many varieties,” she says. “Perhaps trying to narrow down the scope is advisable.”
But if the mission to develop a universal coronavirus vaccine does succeed, it will be one of the most remarkable feats in the annals of medical science. In January, US chief medical advisor Anthony Fauci urged for greater efforts to be devoted towards this goal, one which scientists feel would be the biological equivalent of the race to develop the first atomic bomb
“The development of an effective universal coronavirus vaccine would be equally groundbreaking, as it would have global applicability and utility,” says Saunders. “Coronaviruses have caused multiple deadly outbreaks, and it is likely that another outbreak will occur. Having a vaccine that prevents death from a future outbreak would be a tremendous achievement in global health.”
He agrees that it will require creativity on a remarkable scale: “The universal coronavirus vaccine will also require ingenuity and perseverance comparable to that needed for the Manhattan project.”
After spaceflight record, NASA looks to protect astronauts on even longer trips
At T-minus six seconds, the main engines of the Atlantis Space Shuttle ignited, rattling its capsule “like a skyscraper in an earthquake,” according to astronaut Tom Jones, describing the 1988 launch. As the rocket lifted off and accelerated to three times the force of Earth's gravity, “It felt as if two of my friends were standing on my chest and wouldn’t get off.” But when Atlantis reached orbit, the main engines cut off, and the astronauts were suddenly weightless.
Since 1961, NASA has sent hundreds of astronauts into space while working to making their voyages safer and smoother. Yet, challenges remain. Weightlessness may look amusing when watched from Earth, but it has myriad effects on cognition, movement and other functions. When missions to space stretch to six months or longer, microgravity can impact astronauts’ health and performance, making it more difficult to operate their spacecraft.
Yesterday, NASA astronaut Frank Rubio returned to Earth after over one year, the longest single spaceflight for a U.S. astronaut. But this is just the start; longer and more complex missions into deep space loom ahead, from returning to the moon in 2025 to eventually sending humans to Mars. To ensure that these missions succeed, NASA is increasing efforts to study the biological effects and prevent harm.
The dangers of microgravity are real
A NASA report published in 2016 details a long list of incidents and near-misses caused – at least partly – by space-induced changes in astronauts’ vision and coordination. These issues make it harder to move with precision and to judge distance and velocity.
According to the report, in 1997, a resupply ship collided with the Mir space station, possibly because a crew member bumped into the commander during the final docking maneuver. This mishap caused significant damage to the space station.
Returns to Earth suffered from problems, too. The same report notes that touchdown speeds during the first 100 space shuttle landings were “outside acceptable limits. The fastest landing on record – 224 knots (258 miles) per hour – was linked to the commander’s momentary spatial disorientation.” Earlier, each of the six Apollo crews that landed on the moon had difficulty recognizing moon landmarks and estimating distances. For example, Apollo 15 landed in an unplanned area, ultimately straddling the rim of a five-foot deep crater on the moon, harming one of its engines.
Spaceflight causes unique stresses on astronauts’ brains and central nervous systems. NASA is working to reduce these harmful effects.
NASA
Space messes up your brain
In space, astronauts face the challenges of microgravity, ionizing radiation, social isolation, high workloads, altered circadian rhythms, monotony, confined living quarters and a high-risk environment. Among these issues, microgravity is one of the most consequential in terms of physiological changes. It changes the brain’s structure and its functioning, which can hurt astronauts’ performance.
The brain shifts upwards within the skull, displacing the cerebrospinal fluid, which reduces the brain’s cushioning. Essentially, the brain becomes crowded inside the skull like a pair of too-tight shoes.
That’s partly because of how being in space alters blood flow. On Earth, gravity pulls our blood and other internal fluids toward our feet, but our circulatory valves ensure that the fluids are evenly distributed throughout the body. In space, there’s not enough gravity to pull the fluids down, and they shift up, says Rachael D. Seidler, a physiologist specializing in spaceflight at the University of Florida and principal investigator on many space-related studies. The head swells and legs appear thinner, causing what astronauts call “puffy face chicken legs.”
“The brain changes at the structural and functional level,” says Steven Jillings, equilibrium and aerospace researcher at the University of Antwerp in Belgium. “The brain shifts upwards within the skull,” displacing the cerebrospinal fluid, which reduces the brain’s cushioning. Essentially, the brain becomes crowded inside the skull like a pair of too-tight shoes. Some of the displaced cerebrospinal fluid goes into cavities within the brain, called ventricles, enlarging them. “The remaining fluids pool near the chest and heart,” explains Jillings. After 12 consecutive months in space, one astronaut had a ventricle that was 25 percent larger than before the mission.
Some changes reverse themselves while others persist for a while. An example of a longer-lasting problem is spaceflight-induced neuro-ocular syndrome, which results in near-sightedness and pressure inside the skull. A study of approximately 300 astronauts shows near-sightedness affects about 60 percent of astronauts after long missions on the International Space Station (ISS) and more than 25 percent after spaceflights of only a few weeks.
Another long-term change could be the decreased ability of cerebrospinal fluid to clear waste products from the brain, Seidler says. That’s because compressing the brain also compresses its waste-removing glymphatic pathways, resulting in inflammation, vulnerability to injuries and worsening its overall health.
The effects of long space missions were best demonstrated on astronaut twins Scott and Mark Kelly. This NASA Twins Study showed multiple, perhaps permanent, changes in Scott after his 340-day mission aboard the ISS, compared to Mark, who remained on Earth. The differences included declines in Scott’s speed, accuracy and cognitive abilities that persisted longer than six months after returning to Earth in March 2016.
By the end of 2020, Scott’s cognitive abilities improved, but structural and physiological changes to his eyes still remained, he said in a BBC interview.
“It seems clear that the upward shift of the brain and compression of the surrounding tissues with ventricular expansion might not be a good thing,” Seidler says. “But, at this point, the long-term consequences to brain health and human performance are not really known.”
NASA astronaut Kate Rubins conducts a session for the Neuromapping investigation.
NASA
Staying sharp in space
To investigate how prolonged space travel affects the brain, NASA launched a new initiative called the Complement of Integrated Protocols for Human Exploration Research (CIPHER). “CIPHER investigates how long-duration spaceflight affects both brain structure and function,” says neurobehavioral scientist Mathias Basner at the University of Pennsylvania, a principal investigator for several NASA studies. “Through it, we can find out how the brain adapts to the spaceflight environment and how certain brain regions (behave) differently after – relative to before – the mission.”
To do this, he says, “Astronauts will perform NASA’s cognition test battery before, during and after six- to 12-month missions, and will also perform the same test battery in an MRI scanner before and after the mission. We have to make sure we better understand the functional consequences of spaceflight on the human brain before we can send humans safely to the moon and, especially, to Mars.”
As we go deeper into space, astronauts cognitive and physical functions will be even more important. “A trip to Mars will take about one year…and will introduce long communication delays,” Seidler says. “If you are on that mission and have a problem, it may take eight to 10 minutes for your message to reach mission control, and another eight to 10 minutes for the response to get back to you.” In an emergency situation, that may be too late for the response to matter.
“On a mission to Mars, astronauts will be exposed to stressors for unprecedented amounts of time,” Basner says. To counter them, NASA is considering the continuous use of artificial gravity during the journey, and Seidler is studying whether artificial gravity can reduce the harmful effects of microgravity. Some scientists are looking at precision brain stimulation as a way to improve memory and reduce anxiety due to prolonged exposure to radiation in space.
Other scientists are exploring how to protect neural stem cells (which create brain cells) from radiation damage, developing drugs to repair damaged brain cells and protect cells from radiation.
To boldly go where no astronauts have gone before, they must have optimal reflexes, vision and decision-making. In the era of deep space exploration, the brain—without a doubt—is the final frontier.
Additionally, NASA is scrutinizing each aspect of the mission, including astronaut exercise, nutrition and intellectual engagement. “We need to give astronauts meaningful work. We need to stimulate their sensory, cognitive and other systems appropriately,” Basner says, especially given their extreme confinement and isolation. The scientific experiments performed on the ISS – like studying how microgravity affects the ability of tissue to regenerate is a good example.
“We need to keep them engaged socially, too,” he continues. The ISS crew, for example, regularly broadcasts from space and answers prerecorded questions from students on Earth, and can engage with social media in real time. And, despite tight quarters, NASA is ensuring the crew capsule and living quarters on the moon or Mars include private space, which is critical for good mental health.
Exploring deep space builds on a foundation that began when astronauts first left the planet. With each mission, scientists learn more about spaceflight effects on astronauts’ bodies. NASA will be using these lessons to succeed with its plans to build science stations on the moon and, eventually, Mars.
“Through internally and externally led research, investigations implemented in space and in spaceflight simulations on Earth, we are striving to reduce the likelihood and potential impacts of neurostructural changes in future, extended spaceflight,” summarizes NASA scientist Alexandra Whitmire. To boldly go where no astronauts have gone before, they must have optimal reflexes, vision and decision-making. In the era of deep space exploration, the brain—without a doubt—is the final frontier.
A newly discovered brain cell may lead to better treatments for cognitive disorders
Swiss researchers have discovered a third type of brain cell that appears to be a hybrid of the two other primary types — and it could lead to new treatments for many brain disorders.
The challenge: Most of the cells in the brain are either neurons or glial cells. While neurons use electrical and chemical signals to send messages to one another across small gaps called synapses, glial cells exist to support and protect neurons.
Astrocytes are a type of glial cell found near synapses. This close proximity to the place where brain signals are sent and received has led researchers to suspect that astrocytes might play an active role in the transmission of information inside the brain — a.k.a. “neurotransmission” — but no one has been able to prove the theory.
A new brain cell: Researchers at the Wyss Center for Bio and Neuroengineering and the University of Lausanne believe they’ve definitively proven that some astrocytes do actively participate in neurotransmission, making them a sort of hybrid of neurons and glial cells.
According to the researchers, this third type of brain cell, which they call a “glutamatergic astrocyte,” could offer a way to treat Alzheimer’s, Parkinson’s, and other disorders of the nervous system.
“Its discovery opens up immense research prospects,” said study co-director Andrea Volterra.
The study: Neurotransmission starts with a neuron releasing a chemical called a neurotransmitter, so the first thing the researchers did in their study was look at whether astrocytes can release the main neurotransmitter used by neurons: glutamate.
By analyzing astrocytes taken from the brains of mice, they discovered that certain astrocytes in the brain’s hippocampus did include the “molecular machinery” needed to excrete glutamate. They found evidence of the same machinery when they looked at datasets of human glial cells.
Finally, to demonstrate that these hybrid cells are actually playing a role in brain signaling, the researchers suppressed their ability to secrete glutamate in the brains of mice. This caused the rodents to experience memory problems.
“Our next studies will explore the potential protective role of this type of cell against memory impairment in Alzheimer’s disease, as well as its role in other regions and pathologies than those explored here,” said Andrea Volterra, University of Lausanne.
But why? The researchers aren’t sure why the brain needs glutamatergic astrocytes when it already has neurons, but Volterra suspects the hybrid brain cells may help with the distribution of signals — a single astrocyte can be in contact with thousands of synapses.
“Often, we have neuronal information that needs to spread to larger ensembles, and neurons are not very good for the coordination of this,” researcher Ludovic Telley told New Scientist.
Looking ahead: More research is needed to see how the new brain cell functions in people, but the discovery that it plays a role in memory in mice suggests it might be a worthwhile target for Alzheimer’s disease treatments.
The researchers also found evidence during their study that the cell might play a role in brain circuits linked to seizures and voluntary movements, meaning it’s also a new lead in the hunt for better epilepsy and Parkinson’s treatments.
“Our next studies will explore the potential protective role of this type of cell against memory impairment in Alzheimer’s disease, as well as its role in other regions and pathologies than those explored here,” said Volterra.