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."
Scientists search for a universal coronavirus vaccine
Stephen Zeichner, an infectious disease specialist at the University of Virginia Medical Center, has made progress with an early stage 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.”
This month, Matt Fuchs becomes the new Editor-in-Chief of Leaps.org.
This month, Kira Peikoff passes the torch to me as editor-in-chief of Leaps.org. I’m excited to assume leadership of this important platform.
Leaps.org caught my eye back in 2018. I was in my late 30s and just starting to wake up to the reality that the people I care most about were getting older and more vulnerable to health problems. At the same time, three critical shifts were becoming impossible to ignore. First, the average age in the U.S. is getting older, a trend known as the “gray tsunami.” Second, healthcare expenses are escalating and becoming unsustainable. And third, our sedentary, stress-filled lifestyles are leading to devastating consequences.
These trends pointed to a future filled with disease, suffering and economic collapse. But whenever I visited Leaps.org, my outlook turned from gloomy to solution-oriented. I became just as fascinated in a fourth trend, one that stands to revolutionize our world: rapid, mind-bending innovations in health and medicine.
Brain atlases, genome sequencing and editing, AI, protein mapping, synthetic biology, 3-D printing—these technologies are yielding new opportunities for health, longevity and human thriving. COVID-19 has caused many setbacks, but it has accelerated scientific breakthroughs. History suggests we will see even more innovation—in digital health and virtual first care, for example—after the pandemic.
In 2020, I began covering these developments with articles for Leaps.org about clocks that measure biological aging, gene therapies for cystic fibrosis, and other seemingly futuristic concepts that are transforming the present. I wrote about them partly because I think most people aren’t aware of them—and meaningful progress can’t happen without public engagement. A broader set of stakeholders and society at large, not just the experts, must inform these changes to ensure that they reflect our values and ethics. Everyone should get the chance to participate in the conversation—and they must have the opportunity to benefit equally from the innovations we decide to move forward with. By highlighting cutting-edge advances, Leaps.org is helping to realize this important goal.
Meanwhile, as I wrote freelance pieces on health and wellness for outlets such as the Washington Post and Time Magazine, I kept seeing an intersect between the breakthroughs in research labs and our expanding knowledge about the science of well-being. Take, for example, emerging technologies designed to stop illnesses in their tracks and new research on the benefits of taking in natural daylight. These two areas, lab innovations and healthy lifestyles, both shift the focus from disease treatment to disease prevention and optimal health. It’s the only sensible, financially feasible way forward.
When Kira suggested that I consider a leadership role with Leaps.org, it struck me how much the platform’s ideals have informed my own perspectives. The frontpage gore of mainstream media outlets can feel like a daily dose of pessimism, with cynicism sometimes dressed up as wisdom. Leaps.org’s world view is rooted in something very different: rational optimism about the present moment and the possibility of human flourishing.
That’s why I’m proud to lead this platform, including our podcast, Making Sense of Science, and hope you’ll keep coming to Leaps.org to learn and join the conversation about scientific gamechangers through our sponsored events, our popular Instagram account and other social channels. Think critically about the breakthroughs and their ethical challenges. Help usher in the health and prosperity that could be ours if we stay open-minded to it.
Yours truly,
Matt Fuchs
Editor-in-Chief