Researchers have identified a potential new treatment that suppresses the replication of SARS-CoV-2, the coronavirus that causes COVID-19. In order to multiply, all viruses, including coronaviruses, infect cells and reprogram them to produce novel viruses. The research revealed that cells infected with SARS-CoV-2 can only produce novel coronaviruses when their metabolic pentose phosphate pathway is activated.
With the application of the drug benfooxythiamine, an inhibitor of this pathway, SARS-CoV-2 replication was suppressed and infected cells did not produce coronaviruses.
The research from the University of Kent's School of Biosciences and the Institute of Medical Virology at Goethe-University, Frankfurt am Main, found the drug also increased the antiviral activity of '2-deoxy-D-glucose'; a drug which modifies the host cell's metabolism to reduce virus multiplication.
This shows that pentose phosphate pathway inhibitors like benfooxythiamine are a potential new treatment option for COVID-19, both on their own and in combination with other treatments.
Additionally, benfooxythiamin's antiviral mechanism differs from that of other COVID-19 drugs such as remdesivir and molnupiravir. Therefore, viruses resistant to these may be sensitive to benfooxythiamin.
Professor Martin Michaelis, University of Kent, said, "This is a breakthrough in the research of COVID-19 treatment. Since resistance development is a big problem in the treatment of viral diseases, having therapies that use different targets is very important and provides further hope for developing the most effective treatments for COVID-19."
Professor Jindrich Cinatl, Goethe-University Frankfurt, said, "Targeting virus-induced changes in the host cell metabolism is an attractive way to interfere specifically with the virus replication process."
More information: Denisa Bojkova et al, Targeting the Pentose Phosphate Pathway for SARS-CoV-2 Therapy, Metabolites (2021). DOI: 10.3390/metabo11100699
An increasing number of studies suggest a link between a neighborhood's built environment and the likelihood that its residents will develop chronic diseases such as heart disease, type 2 diabetes (T2D) and certain types of cancers. A new nationwide study led by researchers from NYU Grossman School of Medicine published online today inJAMA Network Opensuggests that living in neighborhoods with higher availability of fast-food outlets across all regions of the United States is associated with higher subsequent risk of developing type 2 diabetes.
Findings also indicated that the availability of more supermarkets could be protective against developing T2D, particularly in suburban and rural neighborhoods.
The study -- notable for its large geographic breadth -- uses data from a cohort of more than 4 million veterans living in 98 percent of U.S. census tracts across the country. It counted fast-food restaurants and supermarkets relative to other food outlets, and is the first, according to the researchers, to examine this relationship in four distinct types of neighborhoods (high-density urban, low-density urban, suburban, and rural) at the hyperlocal level nationwide.
"Most studies that examine the built food environment and its relationship to chronic diseases have been much smaller or conducted in localized areas," said Rania Kanchi, MPH, a researcher in the Department of Population Health at NYU Langone and lead author of the study. "Our study design is national in scope and allowed us to identify the types of communities that people are living in, characterize their food environment, and observe what happens to them over time. The size of our cohort allows for geographic generalizability in a way that other studies do not."
How the Study was Conducted
The research team used data from the U.S. Veterans Health Administration (the largest single-payer healthcare system in the country) that captures more than 9 million veterans seen at more than 1,200 health facilities around the country. Using this data, the researchers then constructed a national cohort of more than 4 million veterans without diabetes from the VA electronic health records (EHR) between 2008 and 2016. Each veteran's health status was followed through 2018 or until the individual either developed diabetes, died, or had no appointments for more than two years.
Within each of four distinct neighborhood types, the proportion of restaurants that were fast food, and the proportion of food outlets that were supermarkets were tabulated within a one-mile walk in high- density urban neighborhoods, a two-mile drive in low-density urban neighborhoods, a six-mile drive in suburban communities, and a 10-mile drive in rural communities.
Veterans were followed for a median of five and a half years. During that time, 13.2 percent of the cohort were newly diagnosed with T2D. Males developed T2D more frequently than females (13.6 versus 8.2 percent). Non-Hispanic Black adults had the highest incidence (16.9 percent), compared to non-Hispanic Whites (12.9 percent), non-White Asian and Hispanics (12.8 percent), Native Hawaiian and Pacific Islanders (15 percent), and Native American and Alaskan Indians (14.2 percent).
When stratifying by community types, 14.3 percent of veterans living in high density urban communities developed T2D, while the lowest incidence was among those living in suburban and small town communities (12.6 percent).
Overall, the team concluded that the effect of the food environment on T2D incidence varied by how urban the community was, but did not vary further by region of the country.
"The more we learn about the relationship between the food environment and chronic diseases like type 2 diabetes, the more policymakers can act by improving the mix of healthy food options sold in restaurants and food outlets, or by creating better zoning laws that promote optimal food options for residents," said Lorna Thorpe, PhD, MPH, professor in the Department of Population Health at NYU Langone and senior author of the study.
One limitation of the study, according to the authors, is that the study may not be fully generalizable to non-veteran populations, as U.S. veterans tend to be predominantly male and have substantially greater health burdens and financial instability than the civilian population. They are also at greater risk of disability, obesity, and other chronic conditions.
The next phase of the research, say Thorpe and Kanchi, will be to better understand the impacts of the built environment on diabetes risk by subgroups. They plan to examine whether or not the relationships between fast-food restaurants, supermarkets and community types vary by gender, race/ethnicity, and socioeconomic status.
Funding for the study was provided by the Centers for Disease Control and Prevention.
In addition to Thorpe and Kanchi, other NYU Langone researchers include Priscilla Lopez, MPH; Pasquale E. Rummo, PhD; David C. Lee, MD; Samrachana Adhikari, PhD; Mark D. Schwartz, MD, and Brian Elbel, PhD. Other research support was provided by Sanja Avramovich, PhD, Department of Health Administration and Policy, George Mason University; Karen R. Siegel, PhD; Deborah B. Rolka, MS and Giuseppina Imperatore from the Division of Diabetes Translation at the Centers for Disease Control and Prevention.
Rania Kanchi, Priscilla Lopez, Pasquale E. Rummo, David C. Lee, Samrachana Adhikari, Mark D. Schwartz, Sanja Avramovic, Karen R. Siegel, Deborah B. Rolka, Giuseppina Imperatore, Brian Elbel, Lorna E. Thorpe. Longitudinal Analysis of Neighborhood Food Environment and Diabetes Risk in the Veterans Administration Diabetes Risk Cohort. JAMA Network Open, 2021; 4 (10): e2130789 DOI: 10.1001/jamanetworkopen.2021.30789
For the first time, researchers have used human data to quantify the speed of different processes that lead to Alzheimer’s disease and found that it develops in a very different way than previously thought. Their results could have important implications for the development of potential treatments.
The international team, led by the University of Cambridge, found that instead of starting from a single point in the brain and initiating a chain reaction which leads to the death of brain cells, Alzheimer’s disease reaches different regions of the brain early. How quickly the disease kills cells in these regions, through the production of toxic protein clusters, limits how quickly the disease progresses overall.
The researchers used post-mortem brain samples from Alzheimer’s patients, as well as PET scans from living patients, who ranged from those with mild cognitive impairment to those with full-blown Alzheimer’s disease, to track the aggregation of tau, one of two key proteins implicated in the condition.
In Alzheimer’s disease, tau and another protein called amyloid-beta build up into tangles and plaques – known collectively as aggregates – causing brain cells to die and the brain to shrink. This results in memory loss, personality changes and difficulty carrying out daily functions.
By combining five different datasets and applying them to the same mathematical model, the researchers observed that the mechanism controlling the rate of progression in Alzheimer’s disease is the replication of aggregates in individual regions of the brain, and not the spread of aggregates from one region to another.
The results, reported in the journal Science Advances, open up new ways of understanding the progress of Alzheimer’s and other neurodegenerative diseases, and new ways that future treatments might be developed.
For many years, the processes within the brain which result in Alzheimer’s disease have been described using terms like ‘cascade’ and ‘chain reaction’. It is a difficult disease to study, since it develops over decades, and a definitive diagnosis can only be given after examining samples of brain tissue after death.
For years, researchers have relied largely on animal models to study the disease. Results from mice suggested that Alzheimer’s disease spreads quickly, as the toxic protein clusters colonise different parts of the brain.
“The thinking had been that Alzheimer’s develops in a way that’s similar to many cancers: the aggregates form in one region and then spread through the brain,” said Dr Georg Meisl from Cambridge’s Yusuf Hamied Department of Chemistry, the paper’s first author. “But instead, we found that when Alzheimer’s starts there are already aggregates in multiple regions of the brain, and so trying to stop the spread between regions will do little to slow the disease.”
This is the first time that human data has been used to track which processes control the development of Alzheimer’s disease over time. It was made possible in part by the chemical kinetics approach developed at Cambridge over the last decade which allows the processes of aggregation and spread in the brain to be modelled, as well as advances in PET scanning and improvements in the sensitivity of other brain measurements.
“This research shows the value of working with human data instead of imperfect animal models,” said co-senior author Professor Tuomas Knowles, also from the Department of Chemistry. “It’s exciting to see the progress in this field – fifteen years ago, the basic molecular mechanisms were determined for simple systems in a test tube by us and others; but now we’re able to study this process at the molecular level in real patients, which is an important step to one day developing treatments.”
The researchers found that the replication of tau aggregates is surprisingly slow – taking up to five years. “Neurons are surprisingly good at stopping aggregates from forming, but we need to find ways to make them even better if we’re going to develop an effective treatment,” said co-senior author Professor Sir David Klenerman, from the UK Dementia Research Institute at the University of Cambridge. “It’s fascinating how biology has evolved to stop the aggregation of proteins.”
The researchers say their methodology could be used to help the development of treatments for Alzheimer’s disease, which affects an estimated 44 million people worldwide, by targeting the most important processes that occur when humans develop the disease. In addition, the methodology could be applied to other neurodegenerative diseases, such as Parkinson’s disease.
“The key discovery is that stopping the replication of aggregates rather than their propagation is going to be more effective at the stages of the disease that we studied,” said Knowles.
The researchers are now planning to look at the earlier processes in the development of the disease, and extend the studies to other diseases such as Frontal temporal dementia, traumatic brain injury and progressive supranuclear palsy where tau aggregates are also formed during disease.
The study is a collaboration between researchers at the UK Dementia Research Institute at the University of Cambridge, University of Cambridge and Harvard Medical School. Funding is acknowledged from the Sidney Sussex College Cambridge, the European Research Council Grant Number, the Royal Society, JPB foundation, the Rainwater foundation, the NIH and the NIHR Cambridge Biomedical Research Centre which supports the Cambridge Brain Bank.
Georg Meisl, Eric Hidari, Kieren Allinson, Timothy Rittman, Sarah L. DeVos, Justin S. Sanchez, Catherine K. Xu, Karen E. Duff, Keith A. Johnson, James B. Rowe, Bradley T. Hyman, Tuomas P. J. Knowles, David Klenerman. In vivo rate-determining steps of tau seed accumulation in Alzheimer’s disease. Science Advances, 2021; 7 (44) DOI: 10.1126/sciadv.abh1448
This is a true story about heroes and villains in the age of coronavirus and how no one can agree on who is which.
The doctor, one of the protagonists of this story, is a pediatric intensive care specialist in Colorado Springs working with some of the sickest children in the state. She’s unvaccinated against COVID-19, despite both state and employer mandates requiring vaccination.
In one telling of this tale, the doctor is the hero, a devoutly religious person who has made a moral choice consistent with those beliefs and is being unconstitutionally punished for them. In another telling, the doctor is the villain, using her religion as cover for a personal belief that is recklessly endangering her patients and colleagues.
Both versions of the story are contained within the pleadings of an ongoing lawsuit in federal court in Denver that challenges the University of Colorado Anschutz Medical Campus’s vaccination requirement for physicians and medical students. Which version is the right one will be the subject of a complicated — and closely watched — legal analysis where the outcome is unclear and the arguments have veered into philosophical debates over the very nature of the country.
“In a religiously pluralistic society, we have to respect people’s religious objections,” said Peter Breen, an attorney representing the doctor and her co-plaintiff, a medical student at the University of Colorado School of Medicine.
CU responded in court by quoting from an 1878 U.S. Supreme Court decision: “To permit this would be to make the professed doctrines of religious belief superior to the law of the land, and in effect to permit every citizen to become a law unto himself.”
Ultimately, the Supreme Court could decide again. But beyond the courtroom battle, the case shows the difficulty Colorado hospitals and other health care organizations have faced in sorting out what is a valid religious exemption to the COVID vaccine mandate, what is not and whether they should be making that decision at all.
“The standard for a sincerely held religious belief is so general, it’s open to different kinds of arguments,” said Christopher Jackson, a Denver-based attorney who specializes in constitutional and appellate law.
Doe v. CU
The two plaintiffs in the federal lawsuit against CU are anonymous — they go by Dr. Jane Doe and John Doe in the court documents.
Both say that requiring them to take a coronavirus vaccine conflicts with their religious beliefs. The doctor, who is Catholic, and the medical student, who is Buddhist, say they are opposed to the use of cell lines that were derived from cells taken decades ago from aborted fetuses. The plaintiffs say the cell lines, which are frequently used in medical research, were used in either the production or testing of the three coronavirus vaccines currently approved in the United States.
The student also says he has a religious objection to vaccination in general.
Officials on the University of Colorado’s Anschutz Medical Campus denied their requests for a religious exemption. In court filings, the university questions whether the plaintiffs’ religious objections are sincere, noting that the student has received at least once vaccine previously and that the doctor regularly prescribes medicines that were tested using the same cell lines.
“Plaintiffs’ failure to raise prior objections to vaccinations and medications demonstrates that their professed religious objection to these vaccines is not a ‘sincerely held belief,’ but rather a personal, or perhaps a political, choice,” the university wrote in one case filing.
CU also notes that major leaders of the plaintiffs’ religions — including, in the case of Catholicism, the pope — have spoken in favor of vaccination against COVID.
“Dr. Doe … did not articulate an individualized Catholic belief different from the views of the Vatican doctrinal office or the U.S. Conference of Catholic Bishops, which have come out strongly in favor of vaccination against COVID-19,” CU wrote in the filing.
But, to Breen, this is offensive. He said the university’s initial policy on vaccine religious exemptions was “flagrantly religiously bigoted” and that the CU Anscutz campus may be the worst in the country for accomodating religious objection to vaccination.
“I’ve never seen a case where a government has been so vicious in attacking what are clearly sincere religious beliefs,” said Breen, who is the senior counsel for the Thomas More Society, an organization that often takes on religious liberty cases.
But, even more than its legal tactics, Breen said CU has violated an important provision of the constitutional separation of church and state.
The doctor, Breen said, has a master’s degree in Catholic bioethics. And Catholic viewpoints on the COVID vaccines arevaried. Breen noted that some Catholic leaders — including those in Colorado — have come out against mandates for the coronavirus vaccine, saying that Catholic teaching stresses the importance of honoring individual conscience.
“The people of Colorado should be outraged that their government is getting into the nuances of Catholic theology and trying to tell individual Catholics what they do and don’t believe,” Breen said.
To CU, though, these debates are missing an equally important point: the stakes involved. More than 8,000 people have now died due to COVID-19 in Colorado. The purpose of the vaccine mandate isn’t to trample religious belief but to protect patients, it says.
The university said in a court filing that the plaintiffs’ arguments contain “barely a mention of the magnitude of the COVID crisis and the risk their refusal to be vaccinated presents to the most vulnerable.”
In a statement, the university said: “Each year, School of Medicine faculty members provide care for more than 2 million patients and our mandatory vaccination requirement offers the best way to protect the patients in their care. We have adopted this policy in recognition of our responsibility to provide public health leadership in our state and beyond.”
The first major decision in the lawsuit came down Monday, when U.S. District Court Judge Raymond P. Moore denied the plaintiffs’ request for a preliminary injunction against CU. But he did so for a technical reason — the policy on religious exemptions that the plaintiffs were trying to stop CU from enforcing has since been rescinded and replaced with a new policy.
Breen said his side may soon be adding more plaintiffs and amending the lawsuit to include more challenges to the new policy.
Jackson, the constitutional law attorney, said courts have generally tried to stay out of fights over religious exemptions. As long as an employer’s policy is one of “general applicability” — that is, as long as it applies to everyone equally and doesn’t single out one religion — then it usually passes muster.
“Under the current law as it stands, these kinds of cases are relatively easy,” Jackson said.
But the makeup of the current U.S. Supreme Court — conservative-leaning with multiple justices who often rule in favor of religious liberty claims — throws that into question.
Guidance for handling religious vaccine exemptions continues to confound, as well.
On Monday, the U.S. Equal Employment Opportunity Commission released new “technical assistance” for employers instituting COVID vaccine mandates.
The guidance says employers “should assume that a request for religious accommodation is based on sincerely held religious beliefs” but also says that employers may “be justified in making a limited factual inquiry and seeking additional supporting information” about the sincerity of an employee’s beliefs. Employers should accommodate non-traditional religious beliefs but not beliefs that are personal or political.
Employers can deny exemption to employees who have previously acted inconsistently with their beliefs but employees “need not be scrupulous in their observance” in order to receive religious protection.
“No one factor or consideration is determinative,” the EEOC wrote, “and employers should evaluate religious objections on an individual basis.”
Ultimately, how officials decide which religious exemptions are valid and which are not could have a huge impact on Colorado’s health care system.
In addition to a number of mandates by employers, such as the CU School of Medicine’s, Colorado’s Board of Health has also issued a COVID vaccine mandate for health care workers. Hospitals, nursing homes and other facilities are required to have 100% compliance.
But, faced with imminent staff shortages if unvaccinated workers had to leave their jobs, health care facilities across the state have allowed employees to claim religious exemptions to the COVID vaccine mandate.
There’s a catch, though. The state’s current mandate considers employees who are claiming such an exemption to not be in compliance with the order, meaning their facilities can’t reach the required 100% vaccination rate.
This means those facilities must ask the Colorado Department of Public Health and Environment with a waiver from the mandate. State regulators have received more than 900 waiver applications, each of which they are currently reviewing.
Jill Hunsaker Ryan, executive director of the Colorado Department of Public Health and Environment, makes a point during a news conference Wednesday, July 7, 2021, to introduce the fifth and final $1-million winner in the state’s vaccine lottery at the governor’s mansion in Denver. (AP Photo/David Zalubowski)
In a letter sent earlier this month, CDPHE Executive Director Jill Hunsaker Ryan wrote that her agency would consider a facility’s number of employees claiming an exemption when deciding whether to approve a waiver. Rural hospitals, especially, have raised concerns about what would happen if CDPHE takes a hard line on religious exemptions. CDPHE, meanwhile, has not announced publicly how deeply it will dig to determine if a religious exemption is valid.
CDPHE has said it plans to amend its mandate in the coming months to better align with a federal mandate for health care workers, the rules of which have not yet been finalized.
That leaves much unknown about the future of Colorado’s vaccine mandates for health care workers — and about how, in a polarized time when religious belief and personal belief and political belief overlap and merge, the state will determine who is the hero and who is the villain.
“It’s difficult to do,” said Jackson. “It’s very difficult to look into someone’s mind.”
The White House’s coronavirus response coordinator indicated that the Biden administration could be flexible as it enforces the president’s executive order requiring federal workers and employees of government contractors to be vaccinated.
“To be clear, we’re creating flexibility within the system. We’re offering people multiple opportunities to get vaccinated. There is not a cliff here,” Jeff Zients said.
Barring an unforeseen breakthrough, intelligence agencies will not be able to conclude whether COVID-19 spread by animal-to-human transmission or leaked from a lab, US officials say in releasing a fuller version of their review into the origins of the pandemic.
The paper issued by the Director of National Intelligence elaborates on findings released in August of a 90-day review ordered by US President Joe Biden.
That review said that US intelligence agencies were divided on the origins of the virus but that analysts do not believe the virus was developed as a bioweapon and that most agencies believe the virus was not genetically engineered.
China has resisted global pressure to co-operate fully with investigations into the pandemic or provide access to genetic sequences of coronaviruses kept at the Wuhan Institute of Virology, which remains a subject of speculation for its research and reported safety problems.
Biden launched the review amid growing momentum for the theory - initially broadly dismissed by experts - that the virus leaked from the Wuhan lab.
Former president Donald Trump and his allies long argued that a lab leak was possible.
China remains an exceedingly difficult place for intelligence operations and has fought back against allegations that it mishandled the emergence of the pandemic, which has killed almost five million people worldwide.
Senior officials involved in the full report's drafting said they hoped it would better inform the public about the challenges of determining COVID-19's origins.
"We don't think we're one or two reports away from being able to understand it," said one official, who spoke on condition of anonymity to discuss intelligence matters.
The full report notes that the Wuhan Institute of Virology "previously created chimeras, or combinations, of SARS-like coronaviruses, but this information does not provide insight into whether SARS Cov-2 was genetically engineered by the WIV".
Information that lab researchers sought medical treatment for a respiratory illness in November 2019 "is not diagnostic of the pandemic's origins," the report said.
And allegations that China launched the virus as a bioweapon were dismissed because their proponents "do not have direct access to the Wuhan Institute of Virology," are making scientifically invalid claims or are accused of spreading disinformation, the report said.
Four agencies within the intelligence community said with low confidence that the virus was initially transmitted from an animal to a human.
A fifth intelligence agency believed with moderate confidence that the first human infection was linked to a lab.
Prior to writing the report, analysts conducted what the report describes as a "Team A/Team B" debate to try to strengthen or weaken each hypothesis.
Confirming with 100 per cent certainty the origin of a virus is often not fast, easy or always even possible.
In the case of Severe Acute Respiratory Syndrome, or SARS - a disease caused by a beta coronavirus, like the current coronavirus - researchers first identified the virus in February 2003.
Later that year, scientists discovered the likely intermediary hosts: Himalayan palm civets found at live-animal markets in Guangdong, China.
But it was not until 2017 that researchers traced the likely original source of the virus to bat caves in China's Yunnan province.
Pfizer’s chief executive, Albert Bourla, made a bold promise in June. Standing next to US President Joe Biden at a press conference in St Ives, UK, just before the G7 summit meeting, Bourla said that should the need arise for a new COVID-19 vaccine, his company could get one ready within 100 days.
The need he was referring to is the possible emergence of an ‘escape variant’ — a dominant strain of SARS-CoV-2 that evades the fledgling immunity established through vaccines and previous infections. No such strain has yet been identified, but Pfizer and other leading COVID-19 vaccine makers are gearing up for that scenario.
What does it take to be nimble enough to design and test an updated vaccine against an unknown viral strain, in record time? Nature spoke to three COVID-19 vaccine makers — Pfizer, Moderna and AstraZeneca — to find out exactly how they are preparing.
DRESS REHEARSAL
Over the past few months, all three companies have been running dress rehearsals by practising on known SARS-CoV-2 variants. This involves updating their vaccines to match variants such as Beta and Delta, testing them in clinical studies, tuning their internal workflows and coordinating with regulators. Their goal is to learn from these warm-up trials and smooth out kinks in their processes, so that they can move fast if, or when, a true escape variant emerges.
“At some point, inevitably, we’re going to have to make variant vaccines — if vaccines are the way population immunity will be maintained — but we’re not at the point where we can confidently predict the evolution of the virus,” says Paul Bieniasz, a virologist at the Rockefeller University in New York City. “Practising with existing variants seems like a reasonable approach.”
The first generation of COVID-19 vaccines seems to be holding up against Delta and other known variants, at least in preventing severe disease and hospitalization. Pfizer, Moderna and AstraZeneca say that their vaccines, which are based on the original SARS-CoV-2 strain that was first detected in Wuhan, China, still offer the best protection against all known variants. “There really isn’t a need at this time to make a new vaccine that will be more effective, because it looks like the old ones work very well [against] the Delta variant,” says Kathryn Edwards, scientific director of the Vanderbilt Vaccine Research Program at Vanderbilt University Medical Center in Nashville, Tennessee.
If an escape variant emerges, RNA vaccine makers such as Pfizer and Moderna could probably design and synthesize an initial prototype jab against it in a few days. Viral-vector vaccines, such as AstraZeneca’s, could follow closely behind. Making an RNA vaccine typically involves generating a new genetic sequence and encapsulating it in a fatty substance such as a lipid. Viral-vector vaccines are generated by inserting the key genetic sequence into a harmless carrier virus, culturing large quantities of the virus in a bioreactor, and purifying them.
But before these shots can be deployed, they will have to be tested in humans, and that will take time. So pharma companies are doing dry runs. Pfizer, with its partner BioNTech, based in Mainz, Germany, is testing a Beta-specific RNA vaccine in a randomized, placebo-controlled clinical trial with up to 930 participants. In August, the companies began a trial of a multivalent vaccine that targets both the Delta and Alpha variants.
“We’re not doing that because we actually think we need a new vaccine for those strains,” says Philip Dormitzer, vice-president and chief scientific officer of viral vaccines and mRNA at Pfizer, based in New York City. “We want to practise all aspects of executing a strain change — the preclinical research, the manufacturing, the clinical testing and the regulatory submissions — so that if we do see a variant out there that truly escapes vaccine immunity, we’re ready to go fast.” Dormitzer says Pfizer currently has no plans to deploy its Beta or Delta vaccines among the public.
Moderna, based in Cambridge, Massachusetts, is recruiting cohorts of 300–500 participants to test new RNA vaccines against Beta, Delta and a combination of Beta and the original strain. The company also plans to test a Beta–Delta multivalent vaccine. The purpose is to submit test cases to the US Food and Drug Administration and “establish a process by which this could happen more quickly in the future”, says Jacqueline Miller, a senior vice-president and head of infectious-disease research at Moderna.
Beta is a particular focus because it carries mutations that make it more resistant than any other known variant to neutralization by antibodies created in a person’s body after they’ve been vaccinated. “If there’s another strain that evolves those mutations in the future, we can capitalize on what we’ve already learned from studying the Beta variant,” Miller says.
AstraZeneca, based in Cambridge, UK, has begun a large study of a Beta-specific viral-vector vaccine. Launched in June, the study is enrolling more than 2,800 participants, many of whom have already been vaccinated with either a messenger RNA vaccine or AstraZeneca’s first-generation viral-vector vaccine. “We’re definitely practising with this one, but we are also developing it, and if it’s successful, we will have it ready to use,” says Mene Pangalos, executive vice-president of biopharmaceuticals research and development at AstraZeneca.
REAL-WORLD EFFECTIVENESS
Determining the true efficacy of variant vaccines will be difficult. In regions where COVID-19 vaccine trials are well established, it can be hard to find volunteers who have not yet received a vaccine, yet are willing to enrol in an experimental trial of a new one. There might also be ethical concerns around recruiting placebo groups for randomized controlled trials, given that effective vaccines are available.
“If we’re not going to do randomized controlled trials for efficacy, one alternative would be to do immunogenicity studies, plus really robust, well-designed real-world effectiveness studies,” says Matthew Hepburn, who until August was the director of COVID-19 vaccine development at the US government’s Countermeasures Acceleration Group (formerly Operation Warp Speed) and is now a special adviser at the White House Office of Science and Technology Policy.
Immunogenicity studies would measure the immune responses triggered by variant vaccines — for instance, an increase in antibody or B-cell levels — and compare those with the effects of the first-generation vaccine. That seems to be where some vaccine makers are heading: on the basis of guidance from European regulators, AstraZeneca will use this approach in its Beta-vaccine trial.
Moderna is also focusing on immunogenicity data, and is collaborating with a hospital system in southern California to collect real-world data on vaccine effectiveness. In these observational studies, participants can choose whether they get a vaccine or not, and researchers monitor the two groups to see how they fare. Such studies “aren’t perfect”, concedes Miller, because the two groups might have different behaviours and risk factors.
How public-health authorities will determine that a variant has escaped — and therefore the world needs a new COVID-19 vaccine — isn’t yet clear. Pangalos offers one way to measure that: “If we start to see lots of people going into the hospital that have been vaccinated, then we have a problem,” he says. “But right now, we’re nowhere near that.”
The World Health Organization has a regimented process for determining when and how to change an influenza vaccine to match an emerging strain. These decisions are based in part on a long history of monitoring and immunizing against the virus’s evolution. “That doesn’t exist for COVID,” says Hepburn.
Miller hopes that the process of updating a COVID-19 vaccine will eventually become as streamlined as changing a flu vaccine, which typically doesn’t require much in the way of clinical studies. And because RNA vaccines can be manufactured more quickly than conventional jabs, she adds, “the idea would be to make that switch even more rapidly than we’re able to do with flu”.
