How Will the New Strains of COVID-19 Affect Our Vaccination Plans?
When the world's first Covid-19 vaccine received regulatory approval in November, it appeared that the end of the pandemic might be near. As one by one, the Pfizer/BioNTech, Moderna, AstraZeneca, and Sputnik V vaccines reported successful Phase III results, the prospect of life without lockdowns and restrictions seemed a tantalizing possibility.
But for scientists with many years' worth of experience in studying how viruses adapt over time, it remained clear that the fight against the SARS-CoV-2 virus was far from over. "The more virus circulates, the more it is likely that mutations occur," said Professor Beate Kampmann, director of the Vaccine Centre at the London School of Hygiene & Tropical Medicine. "It is inevitable that new variants will emerge."
Since the start of the pandemic, dozens of new variants of SARS-CoV-2 – containing different mutations in the viral genome sequence - have appeared as it copies itself while spreading through the human population. The majority of these mutations are inconsequential, but in recent months, some mutations have emerged in the receptor binding domain of the virus's spike protein, increasing how tightly it binds to human cells. These mutations appear to make some new strains up to 70 percent more transmissible, though estimates vary and more lab experiments are needed. Such new strains include the B.1.1.7 variant - currently the dominant strain in the UK – and the 501Y.V2 variant, which was first found in South Africa.
"I'm quite optimistic that even with these mutations, immunity is not going to suddenly fail on us."
Because so many more people are becoming infected with the SARS-CoV-2 virus as a result, vaccinologists point out that these new strains will prolong the pandemic.
"It may take longer to reach vaccine-induced herd immunity," says Deborah Fuller, professor of microbiology at the University of Washington School of Medicine. "With a more transmissible variant taking over, an even larger percentage of the population will need to get vaccinated before we can shut this pandemic down."
That is, of course, as long as the vaccinations are still highly protective. The South African variant, in particular, contains a mutation called E484K that is raising alarms among scientists. Emerging evidence indicates that this mutation allows the virus to escape from some people's immune responses, and thus could potentially weaken the effectiveness of current vaccines.
What We Know So Far
Over the past few weeks, manufacturers of the approved Covid-19 vaccines have been racing to conduct experiments, assessing whether their jabs still work well against the new variants. This process involves taking blood samples from people who have already been vaccinated and assessing whether the antibodies generated by those people can neutralize the new strains in a test tube.
Pfizer has just released results from the first of these studies, declaring that their vaccine was found to still be effective at neutralizing strains of the virus containing the N501Y mutation of the spike protein, one of the mutations present within both the UK and South African variants.
However, the study did not look at the full set of mutations contained within either of these variants. Earlier this week, academics at the Fred Hutchinson Cancer Research Center in Seattle suggested that the E484K spike protein mutation could be most problematic, publishing a study which showed that the efficacy of neutralizing antibodies against this region dropped by more than ten-fold because of the mutation.
Thankfully, this development is not expected to make vaccines useless. One of the Fred Hutch researchers, Jesse Bloom, told STAT News that he did not expect this mutation to seriously reduce vaccine efficacy, and that more harmful mutations would need to accrue over time to pose a very significant threat to vaccinations.
"I'm quite optimistic that even with these mutations, immunity is not going to suddenly fail on us," Bloom told STAT. "It might be gradually eroded, but it's not going to fail on us, at least in the short term."
While further vaccine efficacy data will emerge in the coming weeks, other vaccinologists are keen to stress this same point: At most, there will be a marginal drop in efficacy against the new variants.
"Each vaccine induces what we call polyclonal antibodies targeting multiple parts of the spike protein," said Fuller. "So if one antibody target mutates, there are other antibody targets on the spike protein that could still neutralize the virus. The vaccine platforms also induce T-cell responses that could provide a second line of defense. If some virus gets past antibodies, T-cell responses can find and eliminate infected cells before the virus does too much damage."
She estimates that if vaccine efficacy decreases, for example from 95% to 85%, against one of the new variants, the main implications will be that some individuals who might otherwise have become severely ill, may still experience mild or moderate symptoms from an infection -- but crucially, they will not end up in intensive care.
"Plug and Play" Vaccine Platforms
One of the advantages of the technologies which have been pioneered to create the Covid-19 vaccines is that they are relatively straightforward to update with a new viral sequence. The mRNA technology used in the Pfizer/BioNTech and Moderna vaccines, and the adenovirus vectors used in the Astra Zeneca and Sputnik V vaccines, are known as 'plug and play' platforms, meaning that a new form of the vaccine can be rapidly generated against any emerging variant.
"With a rapid pipeline for manufacture established, these new vaccine technologies could enable production and distribution within 1-3 months of a new variant emerging."
While the technology for the seasonal influenza vaccines is relatively inefficient, requiring scientists to grow and cultivate the new strain in the lab before vaccines can be produced - a process that takes nine months - mRNA and adenovirus-based vaccines can be updated within a matter of weeks. According to BioNTech CEO Uğur Şahin, a new version of their vaccine could be produced in six weeks.
"With a rapid pipeline for manufacture established, these new vaccine technologies could enable production and distribution within 1-3 months of a new variant emerging," says Fuller.
Fuller predicts that more new variants of the virus are almost certain to emerge within the coming months and years, potentially requiring the public to receive booster shots. This means there is one key advantage the mRNA-based vaccines have over the adenovirus technologies. mRNA vaccines only express the spike protein, while the AstraZeneca and Sputnik V vaccines use adenoviruses - common viruses most of us are exposed to - as a delivery mechanism for genes from the SARS-CoV-2 virus.
"For the adenovirus vaccines, our bodies make immune responses against both SARS-CoV-2 and the adenovirus backbone of the vaccine," says Fuller. "That means if you update the adenovirus-based vaccine with the new variant and then try to boost people, they may respond less well to the new vaccine, because they already have antibodies against the adenovirus that could block the vaccine from working. This makes mRNA vaccines more amenable to repeated use."
Regulatory Unknowns
One of the key questions remains whether regulators would require new versions of the vaccine to go through clinical trials, a hurdle which would slow down the response to emerging strains, or whether the seasonal influenza paradigm will be followed, whereby a new form of the vaccine can be released without further clinical testing.
Regulators are currently remaining tight-lipped on which process they will choose to follow, until there is more information on how vaccines respond against the new variants. "Only when such information becomes available can we start the scientific evaluation of what data would be needed to support such a change and assess what regulatory procedure would be required for that," said Rebecca Harding, communications officer for the European Medicines Agency.
The Food and Drug Administration (FDA) did not respond to requests for comment before press time.
While vaccinologists feel it is unlikely that a new complete Phase III trial would be required, some believe that because these are new technologies, regulators may well demand further safety data before approving an updated version of the vaccine.
"I would hope if we ever have to update the current vaccines, regulatory authorities will treat it like influenza," said Drew Weissman, professor of medicine at the University of Pennsylvania, who was involved in developing the mRNA technology behind the Pfizer/BioNTech and Moderna vaccines. "I would guess, at worst, they may want a new Phase 1 or 1 and 2 clinical trials."
Others suggest that rather than new trials, some bridging experiments may suffice to demonstrate that the levels of neutralizing antibodies induced by the new form of the vaccine are comparable to the previous one. "Vaccines have previously been licensed by this kind of immunogenicity data only, for example meningitis vaccines," said Kampmann.
While further mutations and strains of SARS-CoV-2 are inevitable, some scientists are concerned that the vaccine rollout strategy being employed in some countries -- of distributing a first shot to as many people as possible, and potentially delaying second shots as a result -- could encourage more new variants to emerge. Just today, the Biden administration announced its intention to release nearly all vaccine doses on hand right away, without keeping a reserve for second shots. This plan risks relying on vaccine manufacturing to ramp up quickly to keep pace if people are to receive their second shots at the right intervals.
"I am not very happy about this change as it could lead to a large number of people out there with partial immunity and this could select new mutations, and escalate the potential problem of vaccine escape."
The Biden administration's shift appears to conflict with the FDA's recent position that second doses should be given on a strict schedule, without any departure from the three- and four-week intervals established in clinical trials. Two top FDA officials said in a statement that changing the dosing schedule "is premature and not rooted solidly in the available evidence. Without appropriate data supporting such changes in vaccine administration, we run a significant risk of placing public health at risk, undermining the historic vaccination efforts to protect the population from COVID-19."
"I understand the argument of trying to get at least partial protection to as many people as possible, but I am concerned about the increased interval between the doses that is now being proposed," said Kampmann. "I am not very happy about this change as it could lead to a large number of people out there with partial immunity and this could select new mutations, and escalate the potential problem of vaccine escape."
But it's worth emphasizing that the virus is unlikely for now to accumulate enough harmful mutations to render the current vaccines completely ineffective.
"It will be very hard for the virus to evolve to completely evade the antibody responses the vaccines induce," said Fuller. "The parts of the virus that are targeted by vaccine-induced antibodies are essential for the virus to infect our cells. If the virus tries to mutate these parts to evade antibodies, then it could compromise its own fitness or even abort its ability to infect. To be sure, the virus is developing these mutations, but we just don't see these variants emerge because they die out."
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.