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."
The Cellular Secrets of “Young Blood” Are Starting to Be Unlocked
Fabrisia Ambrosio (center) surrounded by her lab staff.
The quest for an elixir to restore youthful health and vigor is common to most cultures and has prompted much scientific research. About a decade ago, Stanford scientists stitched together the blood circulatory systems of old and young mice in a practice called parabiosis. It seemed to rejuvenate the aged animals and spawned vampirish urban legends of Hollywood luminaries and tech billionaires paying big bucks for healthy young blood to put into their own aging arteries in the hope of reversing or at least forestalling the aging process.
It was “kind of creepy” and also inspiring to Fabrisia Ambrosio, then thousands of miles away and near the start of her own research career into the processes of aging. Her lab is at the University of Pittsburgh but on this cold January morning I am speaking with her via Zoom as she visits with family near her native Sao Paulo, Brazil. A gleaming white high rise condo and a lush tropical jungle split the view behind her, and the summer beach is just a few blocks away.
Ambrosio possesses the joy of a kid on Christmas morning who can't wait to see what’s inside the wrapping. “I’ve always had a love for research, my father was a physicist," she says, but interest in the human body pulled her toward biology as her education progressed in the U.S. and Canada.
Back in Pittsburgh, her lab first extended the work of others in aging by using the simpler process of injecting young blood into the tail vein of old mice and found that the skeletal muscles of the animals “displayed an enhanced capacity to regenerate.” But what was causing this improvement?
When Ambrosio injected old mice with young blood depleted of EVs, the regenerative effect practically disappeared.
The next step was to remove the extracellular vesicles (EVs) from blood. EVs are small particles of cells composed of a membrane and often a cargo inside that lipid envelope. Initially many scientists thought that EVs were simply taking out the garbage that cells no longer needed, but they would learn that one cell's trash could be another cell's treasure.
Metabolites, mRNA, and myriad other signaling molecules inside the EV can function as a complex network by which cells communicate with others both near and far. These cargoes can up and down-regulate gene expression, affecting cell activity and potentially the entire body. EVs are present in humans, the bacteria that live in and on us, even in plants; they likely communicate across all forms of life.
Being inside the EV membrane protects cargo from enzymes and other factors in the blood that can degrade it, says Kenneth Witwer, a researcher at Johns Hopkins University and program chair of the International Society for Extracellular Vesicles. The receptors on the surface of the EV provide clues to the type of cell from which it originated and the cell receptors to which it might later bind and affect.
When Ambrosio injected old mice with young blood depleted of EVs, the regenerative effect practically disappeared; purified EVs alone were enough to do the job. The team also looked at muscle cell gene expression after injections of saline, young blood, and EV-depleted young blood and found significant differences. She believes this means that the major effect of enhanced regenerative capacity was coming from the EVs, though free floating proteins within the blood may also contribute something to the effect.
One such protein, called klotho, is of great interest to researchers studying aging. The name was borrowed from the Fates of Greek mythology, which consists of three sisters; Klotho spins the thread of life that her sisters measure and cut. Ambrosio had earlier shown that supplementing klotho could enhance regenerative capacity in old animals. But as with most proteins, klotho is fragile, rapidly degrading in body fluids, or when frozen and thawed. She suspected that klotho could survive better as cargo enclosed within the membrane of an EV and shielded from degradation.
So she went looking for klotho inside the EVs they had isolated. Advanced imaging technology revealed that young EVs contained abundant levels of klotho mRNAs, but the number of those proteins was much lower in EVs from old mice. Ambrosio wrote in her most recent paper, published in December in Nature Aging. She also found that the stressors associated with aging reduced the communications capacity of EVs in muscle tissue and that could be only partially restored with young blood.
Researchers still don't understand how klotho functions at the cellular level, but they may not need to know that. Perhaps learning how to increase its production, or using synthetic biology to generate more copies of klotho mRNA, or adding cell receptors to better direct EVs to specific aging tissue will be sufficient to reap the anti-aging benefits.
“Very, very preliminary data from our lab has demonstrated that exercise may be altering klotho transcripts within aged extracellular vesicles" for the better Ambrosio teases. But we already know that exercise is good for us; understanding the cellular mechanism behind that isn't likely to provide additional motivation to get up off the couch. Many of us want a prescription, a pill that is easy to take, to slow our aging.
Ambrosio hopes that others will build upon the basic research from her lab, and that pharmaceutical companies will be able to translate and develop it into products that can pass through FDA review and help ameliorate the diseases of aging.
Podcast: Should Scientific Controversies Be Silenced?
The recent Joe Rogan/Spotify controversy prompts the consideration of tough questions about expertise, trust, gatekeepers, and dissent.
The "Making Sense of Science" podcast features interviews with leading medical and scientific experts about the latest developments and the big ethical and societal questions they raise. This monthly podcast is hosted by journalist Kira Peikoff, founding editor of the award-winning science outlet Leaps.org.
The recent Joe Rogan/Spotify backlash over the misinformation presented in his recent episode on the Covid-19 vaccines raises some difficult and important bioethical questions for society: How can people know which experts to trust? What should big tech gatekeepers do about false claims promoted on their platforms? How should the scientific establishment respond to heterodox viewpoints from experts who disagree with the consensus? When is silencing of dissent merited, and when is it problematic? Journalist Kira Peikoff asks infectious disease physician and pandemic scholar Dr. Amesh Adalja to weigh in.
Dr. Amesh Adalja, Senior Scholar, Johns Hopkins Center for Health Security and an infectious disease physician
Listen to the Episode
Kira Peikoff was the editor-in-chief of Leaps.org from 2017 to 2021. As a journalist, her work has appeared in The New York Times, Newsweek, Nautilus, Popular Mechanics, The New York Academy of Sciences, and other outlets. She is also the author of four suspense novels that explore controversial issues arising from scientific innovation: Living Proof, No Time to Die, Die Again Tomorrow, and Mother Knows Best. Peikoff holds a B.A. in Journalism from New York University and an M.S. in Bioethics from Columbia University. She lives in New Jersey with her husband and two young sons. Follow her on Twitter @KiraPeikoff.