How Will the New Strains of COVID-19 Affect Our Vaccination Plans?
The mutated strains that first arose in the U.K. and South Africa and have now spread to many countries are prompting urgent studies on the effectiveness of current vaccines to neutralize the new strains.
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."
Gene Transfer Leads to Longer Life and Healthspan
In August, a study provided the first proof-of-principle that genetic material transferred from one species to another can increase both longevity and healthspan in the recipient animal.
The naked mole rat won’t win any beauty contests, but it could possibly win in the talent category. Its superpower: fighting the aging process to live several times longer than other animals its size, in a state of youthful vigor.
It’s believed that naked mole rats experience all the normal processes of wear and tear over their lifespan, but that they’re exceptionally good at repairing the damage from oxygen free radicals and the DNA errors that accumulate over time. Even though they possess genes that make them vulnerable to cancer, they rarely develop the disease, or any other age-related disease, for that matter. Naked mole rats are known to live for over 40 years without any signs of aging, whereas mice live on average about two years and are highly prone to cancer.
Now, these remarkable animals may be able to share their superpower with other species. In August, a study provided what may be the first proof-of-principle that genetic material transferred from one species can increase both longevity and healthspan in a recipient animal.
There are several theories to explain the naked mole rat’s longevity, but the one explored in the study, published in Nature, is based on the abundance of large-molecule high-molecular mass hyaluronic acid (HMM-HA).
A small molecule version of hyaluronic acid is commonly added to skin moisturizers and cosmetics that are marketed as ways to keep skin youthful, but this version, just applied to the skin, won’t have a dramatic anti-aging effect. The naked mole rat has an abundance of the much-larger molecule, HMM-HA, in the chemical-rich solution between cells throughout its body. But does the HMM-HA actually govern the extraordinary longevity and healthspan of the naked mole rat?
To answer this question, Dr. Vera Gorbunova, a professor of biology and oncology at the University of Rochester, and her team created a mouse model containing the naked mole rat gene hyaluronic acid synthase 2, or nmrHas2. It turned out that the mice receiving this gene during their early developmental stage also expressed HMM-HA.
The researchers found that the effects of the HMM-HA molecule in the mice were marked and diverse, exceeding the expectations of the study’s co-authors. High-molecular mass hyaluronic acid was more abundant in kidneys, muscles and other organs of the Has2 mice compared to control mice.
In addition, the altered mice had a much lower incidence of cancer. Seventy percent of the control mice eventually developed cancer, compared to only 57 percent of the altered mice, even after several techniques were used to induce the disease. The biggest difference occurred in the oldest mice, where the cancer incidence for the Has2 mice and the controls was 47 percent and 83 percent, respectively.
With regard to longevity, Has2 males increased their lifespan by more than 16 percent and the females added 9 percent. “Somehow the effect is much more pronounced in male mice, and we don’t have a perfect answer as to why,” says Dr. Gorbunova. Another improvement was in the healthspan of the altered mice: the number of years they spent in a state of relative youth. There’s a frailty index for mice, which includes body weight, mobility, grip strength, vision and hearing, in addition to overall conditions such as the health of the coat and body temperature. The Has2 mice scored lower in frailty than the controls by all measures. They also performed better in tests of locomotion and coordination, and in bone density.
Gorbunova’s results show that a gene artificially transferred from one species can have a beneficial effect on another species for longevity, something that had never been demonstrated before. This finding is “quite spectacular,” said Steven Austad, a biologist at the University of Alabama at Birmingham, who was not involved in the study.
Just as in lifespan, the effects in various organs and systems varied between the sexes, a common occurrence in longevity research, according to Austad, who authored the book Methuselah’s Zoo and specializes in the biological differences between species. “We have ten drugs that we can give to mice to make them live longer,” he says, “and all of them work better in one sex than in the other.” This suggests that more attention needs to be paid to the different effects of anti-aging strategies between the sexes, as well as gender differences in healthspan.
According to the study authors, the HMM-HA molecule delivered these benefits by reducing inflammation and senescence (cell dysfunction and death). The molecule also caused a variety of other benefits, including an upregulation of genes involved in the function of mitochondria, the powerhouses of the cells. These mechanisms are implicated in the aging process, and in human disease. In humans, virtually all noncommunicable diseases entail an acceleration of the aging process.
So, would the gene that creates HMM-HA have similar benefits for longevity in humans? “We think about these questions a lot,” Gorbunova says. “It’s been done by injections in certain patients, but it has a local effect in the treatment of organs affected by disease,” which could offer some benefits, she added.
“Mice are very short-lived and cancer-prone, and the effects are small,” says Steven Austad, a biologist at the University of Alabama at Birmingham. “But they did live longer and stay healthy longer, which is remarkable.”
As for a gene therapy to introduce the nmrHas2 gene into humans to obtain a global result, she’s skeptical because of the complexity involved. Gorbunova notes that there are potential dangers in introducing an animal gene into humans, such as immune responses or allergic reactions.
Austad is equally cautious about a gene therapy. “What this study says is that you can take something a species does well and transfer at least some of that into a new species. It opens up the way, but you may need to transfer six or eight or ten genes into a human” to get the large effect desired. Humans are much more complex and contain many more genes than mice, and all systems in a biological organism are intricately connected. One naked mole rat gene may not make a big difference when it interacts with human genes, metabolism and physiology.
Still, Austad thinks the possibilities are tantalizing. “Mice are very short-lived and cancer-prone, and the effects are small,” he says. “But they did live longer and stay healthy longer, which is remarkable.”
As for further research, says Austad, “The first place to look is the skin” to see if the nmrHas2 gene and the HMM-HA it produces can reduce the chance of cancer. Austad added that it would be straightforward to use the gene to try to prevent cancer in skin cells in a dish to see if it prevents cancer. It would not be hard to do. “We don’t know of any downsides to hyaluronic acid in skin, because it’s already used in skin products, and you could look at this fairly quickly.”
“Aging mechanisms evolved over a long time,” says Gorbunova, “so in aging there are multiple mechanisms working together that affect each other.” All of these processes could play a part and almost certainly differ from one species to the next.
“HMM-HA molecules are large, but we’re now looking for a small-molecule drug that would slow it’s breakdown,” she says. “And we’re looking for inhibitors, now being tested in mice, that would hinder the breakdown of hyaluronic acid.” Gorbunova has found a natural, plant-based product that acts as an inhibitor and could potentially be taken as a supplement. Ultimately, though, she thinks that drug development will be the safest and most effective approach to delivering HMM-HA for anti-aging.
A new study provides key insights in what causes Alzheimer's: a breakdown in the brain’s system for clearing waste.
In recent years, researchers of Alzheimer’s have made progress in figuring out the complex factors that lead to the disease. Yet, the root cause, or causes, of Alzheimer’s are still pretty much a mystery.
In fact, many people get Alzheimer’s even though they lack the gene variant we know can play a role in the disease. This is a critical knowledge gap for research to address because the vast majority of Alzheimer’s patients don’t have this variant.
A new study provides key insights into what’s causing the disease. The research, published in Nature Communications, points to a breakdown over time in the brain’s system for clearing waste, an issue that seems to happen in some people as they get older.
Michael Glickman, a biologist at Technion – Israel Institute of Technology, helped lead this research. I asked him to tell me about his approach to studying how this breakdown occurs in the brain, and how he tested a treatment that has potential to fix the problem at its earliest stages.
Dr. Michael Glickman is internationally renowned for his research on the ubiquitin-proteasome system (UPS), the brain's system for clearing the waste that is involved in diseases such as Huntington's, Alzheimer's, and Parkinson's. He is the head of the Lab for Protein Characterization in the Faculty of Biology at the Technion – Israel Institute of Technology. In the lab, Michael and his team focus on protein recycling and the ubiquitin-proteasome system, which protects against serious diseases like Alzheimer’s, Parkinson’s, cystic fibrosis, and diabetes. After earning his PhD at the University of California at Berkeley in 1994, Michael joined the Technion as a Senior Lecturer in 1998 and has served as a full professor since 2009.
Dr. Michael Glickman